Mammographic density (MD) is a strong risk factor for breast cancer. We examined the association between annual MD change and risk of breast cancer, and how adding annual MD change to baseline measure of MD influenced risk prediction of breast cancer.
We used the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort (N = 43,347 Swedish women), with full access to risk factors for breast cancer and pre-diagnostic mammograms. MD was measured as dense area (cm2) using the STRATUS method. We calculated the relative MD area change between repeated examinations. Relative MD area change was categorized as stable (less than 10% decrease per year) and decrease (more than 10% decrease per year). Cox proportional hazard regression (HR) estimated the association of breast cancer with MD change. Interaction analyses investigated how relative MD change modifies the association between baseline MD and breast cancer risk. All statistical tests were two-sided.
Women who did not experience a MD decrease over time had a 27% significantly increased risk of breast cancer (HR = 1.27; 95% CI = 1.02 to 1.59) compared to those who decreased by at least 10% per year. The increased risk was confined to postmenopausal women. Stratifying women based on baseline MD did not seem to add to risk prediction with the exception of women in the lowest baseline MD group where women did not experience a MD decrease had a 74% higher risk (HR = 1.74; 95% CI = 1.10 to 2.75), again only seen in postmenopausal women.
Our results suggest that annual MD change influences breast cancer risk in postmenopausal women but that adding MD change to baseline MD do not seem to substantially improve breast cancer risk prediction.
Per Hall (Principle investigator).
Märit and Hans Rausing’s Inititive Against Breast Cancer.
All authors have declared no conflicts of interest.
Ductal carcinoma in situ (DCIS) of the breast includes several subtypes with a divergent biological behavior. Data regarding the composition of DCIS-associated immune cells and their potential role in DCIS progression is limited. We studied DCIS-associated immune response by characterizing immune cell subsets according to DCIS subtypes.
DCIS-associated tumor infiltrating lymphocyte (TIL) density and distribution were evaluated based on H&E stained sections of excision specimens from 473 patients with DCIS. These cases were subtyped based on ER, PR and HER2. Patients were categorized as TIL-high or TIL-low. The DCIS-associated immune cells of TIL-high cases were immunostained on consecutive whole slides with CD4 (T-helper cells), CD8 (cytotoxic T-cells), CD20 (B-cells), CD68 (macrophages), FOXP3 (regulatory T-cells), PD-L1 (immune checkpoint ligand, clones SP142 and SP263).
In total, 131/473 patients (27.7%) were considered as TIL-high and the percentage of TIL-high cases was significantly associated with DCIS subtype (11.4% of ER+PR+/-HER2-, 38.8% of ER+PR+/-HER2+, 61.2% of ER-PR-HER2+ and 63.6% of the TN subtype, P < 0.0001). There was no statistical difference in the immune cell composition according to DCIS subtypes. However, individual DCIS subtype comparison showed that the ER+PR+/-HER2+ subtype was associated with a significantly higher proportion of CD8+ T-cells compared to the TN subtype (P = 0.047). The ER-PR-HER2+ subtype was associated with a higher proportion of CD4+ T cells compared to the TN subtype, though significance was not reached (P = 0.061). PD-L1 expression by both clones was low. However, the mean value of PD-L1 SP263 was higher compared to PD-L1 SP142, for both TILs and tumor cells (P < 0.0001).
High numbers of TILs are mainly observed in HER+ and TN DCIS subtypes. The ER+ HER2+ DCIS subtype attracts more CD8+ T-cells compared to the TN subtype. This suggests a more pronounced anti-tumor immunity in HER2+ DCIS, which could play a role in its biological behavior.
Erasmus Medical Center Cancer Insitute, the Department of Pathology.
Roche.
All authors have declared no conflicts of interest.
Preclinical studies suggest that HER2 mutations lead to constitutive HER2 activation, but knowledge about effective treatment options and clinical resistance mechanisms remain uncharacterized.
We performed dynamic monitoring of > 300 serial plasma samples collected from 49 metastatic breast cancer patients used targeted sequencing of 425 clinically relevant genes, to detect HER2 mutations and track resistance to HER2-targeted treatments in HER2-mutant breast cancer.
We identified activating HER2 mutations (S310F, D769Y, V777L, 778insGSP) in ctDNA and paired tissue samples from four patients with ER positive/HER2-amplification negative metastatic breast cancer, who had developed resistance to multi-line (>3) endocrine therapy. Two patients achieved a durable partial response (approximately 1 years) to trastuzumab combined with everolimus. Intriguingly however, analysis of ctDNA revealed that the NF2 mutation was acquired from a patient with HER2S310F/V777L who had developed resistance to HER2-targeted treatments. We showed that HER2S310F/D769Y/V777L/778insGSP mutations were constitutively active, and T47D and MCF7 overexpressing HER2S310F/V777L/778insGSP were sensitive to HER2 targeted therapies combined with everolimus. Consistent with our clinical findings, NF2 knockdown in HER2 S310F/V777L/778insGSP overexpressing T47D and MCF7 contributed to HER2-targeted therapy resistance. Furthermore, MEK inhibitor remarkably sensitized NF2 knockdown and HER2 mutations co-expressing T47D and MCF7 cells to trastuzumab.
Dynamic monitoring of ctDNA could provide the candidate resistance genes for metastatic HER2-mutant breast cancer. Our findings validated NF2 mutations as a potential mechanism of resistance to HER2-targeted therapy, and the combined use of HER2 and ERK inhibitors may overcome resistance to HER2 targeted therapy in HER2-mutant breast cancer.
Dalian Medical University.
Has not received any funding.
All authors have declared no conflicts of interest.
The value of a high-risk surveillance program for mutation carriers compared to non-carriers at high familial breast cancer risk is not well understood. The Breast and Ovarian Cancer Risk Management Clinic (BOCRMC) was established to provide multimodality screening and risk management strategies. The purpose of this study was to compare breast cancer diagnoses for BRCA1, BRCA2 and other germline mutation carriers versus non-carriers attending the BOCRMC.
Clinical data from mutation carriers and non-carriers with a ≥ 25% lifetime risk of developing breast cancer who attended between 2010 and 2018 were extracted from clinic records and compared. The pattern and mode of detection of breast cancers were determined.
A total of 206 mutation carriers and 305 non-carriers attended the BOCRMC and underwent screening on at least one occasion. Median age was 37 years. After a median follow-up of 34 months, 15 (7 invasive) breast cancers were identified in mutation carriers (median age: 45 years) and 7 (6 invasive) in non-carriers (median age: 48 years). Of these, 90.9% were detected by annual screening, while 9.1% were detected as interval cancers among BRCA1 mutation carriers. Median size of the invasive breast cancers was 11 mm. Most (76.9%) were axillary node negative. In women aged 25-49 years, the annualised breast cancer incidence rate was 1.6% in BRCA1, 1.4% in BRCA2 mutation carriers and 0.5% in non-carriers.
Screening was effective at detecting early-stage cancers in both groups. The incidence of breast cancer events in young non-carriers was substantially higher than in the general population. This justifies ongoing management through a specialty clinic although further research to personalise risk assessment in non-carriers is required.
G. Bruce Mann.
Has not received any funding.
All authors have declared no conflicts of interest.
The PI3K signaling pathway is frequently dysregulated in breast cancer (BC), effected through mutations in PIK3CA, which encodes for the catalytically subunit p110-alpha. An influence of PIK3CA mutations in therapy response resistance associated with a worse clinical outcome has previously been shown in HER2+ BC. Mutations in exon 9 or 20 may play a role in cell proliferation and therapy response.
We investigated PIK3CA mutation status in 484 BC patients, randomized in three clinical multicenter trials: GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880). Classical Sanger sequencing in exon 9 and 20 was performed on formalin-fixed paraffin embedded pretherapeutical core biopsies with a tumor content > =20%.
Mutation analysis of exon 9 and 20 were successful in 431 cases: PIK3CA was mutated in 21.6%, exon 9 in 8.8% and exon 20 in 13.9% of cases. Detection of a PIK3CA mutation was not significantly associated with a higher proliferation rate (Ki67 >20%: 76.3% mut. vs. 75.0% WT, p = 0.878). TN tumors were more often Ki67 low (38.5%) when exon 20 was mutated compared to wildtype (6.5%) (p = 0.005). There were no significant differences in proliferation in hormone receptor positive or HER2 positive tumors. Lower stromal lymphocyte infiltration was seen when exon 9 was mutated compared to wildtype in HER2+/HR- (Infiltration >60%: 28.5% mut. vs. 5.6% WT, p = 0.012), but not overall or in other subtypes. Detection of any PIK3CA mutation was significantly associated with lower pathologic complete response (pCR, ypT0ypN0) (24.7% in PIK3CA mutated vs. 38.2% in wildtype; p = 0.020). However, patients with mutation in exon 9 (21.1% mutated vs. 36.6% wildtype; p = 0.074) or 20 (25% mutated vs. 36.9% wildtype; p = 0.081) did not reach statistical significance for pCR.
PIK3CA mutation is not linked with a higher tumor proliferation, but in HER2+/HR- tumors associated with a lower stromal lymphocyte infiltration. However, PIK3CA could be used as a biomarker for a worse outcome in terms of a lower rate of pCR after neoadjuvant anthracycline-taxane–based chemotherapy.
GeparQuattro (NCT00288002), GeparQuinto (NCT00567554), GeparSixto (NCT01426880).
GBG Forschungs GmbH.
Has not received any funding.
All authors have declared no conflicts of interest.
Human epidermal growth factor receptor 2 (HER2) status is a crucial predictive factor for prognostic assessment and targeted therapy selection, which may be influenced by intratumor heterogeneity and molecular divergence between the primary site and different metastases. Therefore, we performed a prospective study to confirm the concordance of HER2 amplification in circulating tumor DNA (ctDNA) with primary tumor tissue and verified its clinical implications.
A total of 105 breast cancer patients were enrolled, and dynamic monitoring of HER2 copy numbers in ctDNA was conducted in 31 participants during the treatment. In total, 186 plasma samples were prospectively obtained and blinded to test HER2 copy numbers in ctDNA based on low-coverage whole genome sequencing (WGS) by next-generation sequencing (NGS).
Comparing HER2 copy numbers in ctDNA collected before the initiation of the next line of anticancer treatment with primary tumor tissue, the concordant rate of HER2 amplification was 86.5% (χ2= 52.901, p < 0.001), with a positive and negative predictive value of 94.9% and 80.7%, respectively. Histopathologically positive, high-level amplification of HER2 copy numbers in the baseline was significantly correlated with the best objective response during the anticancer therapy (p = 0.010). Moreover, HER2 copy numbers fluctuated with HER2-targeted therapeutic response, and the patients with a constantly positive level after 6 weeks of treatment appeared to suffer from significantly reduced progression free survival (p < 0.001).
HER2 amplification in ctDNA, with a concordance rate of over 80% with primary tumors, may be a predictive index for prognostic evaluation and therapeutic response monitoring in a noninvasive, repeatable and practical method for breast cancer patients.
National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.
National Natural Science Foundation of China (81472453, 81874122), and the CAMS Initiative for Innovative Medicine (2017-I2M-3-004).
Y. Niu, S. Lu: Employee: Yikon Genomics Co. Ltd.
Steroid hormone receptors (HRs), estrogen receptor (ER) and progesterone receptor (PR), are crucial biomarkers for clinical management in breast cancer. However, limited data are available regarding single HR-positive, making it difficult for treatment decision and survival prediction in these patients.
Breast cancer patients were retrieved in Surveillance, Epidemiology, and End Results database. Patients without ER, PR, or breast cancer-specific survival (BCSS) data were excluded. We stratified patients into ER+/PR+, ER+/PR-, ER-/PR+, and ER-/PR- groups. BCSS analysis was performed by Kaplan-Meier method. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
This study included 823,339 breast cancer patients (553,165 [67.18%] ER+/PR+, 100,319 [12.18%] ER+/PR-, 13,368 [1.62%] ER-/PR+, and 156,547 [19.01%] ER-/PR-). Significant differences were detected between the four groups involving age, sex, race, tumor size, lymph node status, AJCC stage, grade, histology type, and HER2 status. Survival analyses showed that the ER/PR status were significantly associated with BCSS; the estimated mean BCSS months was 261.3, 241.2, 233.6, and 227.6 for ER+/PR+, ER+/PR-, ER-/PR+, and ER-/PR-, respectively (p < 0.001). Compared with ER+/PR+, ER+/PR- (HR, 1.67; 95% CI, 1.64-1.70) and ER-/PR + (HR, 1.83; 95% CI, 1.74-1.92) patients were associated with poor BCSS. When compared with ER-/PR- (vs. ER+/PR-, HR, 1.39; 95% CI, 1.37-1.42 and vs. ER-/PR+, HR, 1.12; 95% CI, 1.08-1.16), ER+/PR- and ER-/PR+ patients had a better BCSS. ER-/PR + (HR, 1.17; 95% CI, 1.13-1.22) was significantly associated with poorer BCSS than ER+/PR-. In multivariable Cox regression analysis, when compared with ER+/PR+, the risk of breast cancer-specific death increased 37% for ER+/PR- (HR, 1.37; 95% CI, 1.34-1.39), 59% for ER-/PR + (HR, 1.59; 95% CI, 1.53-1.65), and 76% for ER-/PR- (HR, 1.76; 95% CI, 1.73-1.78) (p for trend<0.001).
There are significant distinctions between ER+/PR+, ER+/PR-, ER-/PR+, and ER-/PR- phenotype. Importantly, the clinical and prognostic features of single HR-positive breast cancer should be re-recognized and re-oriented.
Guosheng Ren.
National Natural Science Foundation of China.
All authors have declared no conflicts of interest.
HER2-targeting agents are standard of care for the treatment of HER2+ breast cancer (BC), but resistance inevitably occurs and the underlying molecular mechanisms remain poorly characterized. The comparison between mutational profiles of primary (treatment-naïve) and metastatic (who will mostly have received multiple courses of HER2-targeting agents) tumors can inform the search for resistance-inducing genetic alterations to be modeled in vitro and in vivo.
We analyzed the mutational spectrum of metastatic vs primary HER2+ BC by retrieving data from ERBB2-amplified cases in the MSKCC-IMPACT and the TCGA datasets, containing almost exclusively samples from metastatic sites and primary tumors, respectively. Multiple in vitro (HER2+ cell lines with stable RNA interference of candidate genes, 2D- and 3D-culturing) and in vivo models (NOD-SCID xenografts and the MMTV-neu transgenic mice) are used for validation.
Mutations in NF1, TSC2 and HER2 were significantly enriched in metastatic cases. All are plausible mediators of resistance, being associated with signalling pathways downstream of HER2 or the HER2 receptor itself. NF1 in particular is a tumor suppressor gene which encodes a RAS-GTPase that negatively regulates Ras/MEK/ERK and PI3K/AKT/mTOR pathways. NF1 alterations were the most significant (Odds Ratio 11.7, p = 0.00018, FDR=0.23) and the most prevalent in metastatic cases (∼10%). As NF1 mutations lead to protein loss of function, we modeled their effect in vitro by RNA interference and found that it induces an increase in mTOR activation. Stably-interfered HER2+ cell lines will be used to explore synergistic drug combinations in vitro and in vivo.
We provide proof of concept that secondary resistance to anti-HER2 agents can be mapped to specific genetic alterations in a sizeable fraction of patients. Ongoing efforts are aimed at investigating if NF1 loss instructs HER2+ BC with a metastasis-promoting phenotype as well as metabolic and transcriptional changes.
European Institute of Oncology.
Fondazione IEO-CCM University of Milan.
G. Curigliano: Advisor: Roche, Pfizer, Novartis, Lilly. All other authors have declared no conflicts of interest.
The National Cooperative Cancer Network Guidelines (v3.2018, Oct 2018) state that 21-gene assay (Oncotype DX Breast Recurrence Score®, Genomic Health, Inc.) is the preferred multigene assay (MGA) to predict chemotherapy (CT) benefit for early stage breast cancer (ESBC). We assessed the potential effects of substituting another MGA, PAM50-ROR (Prosigna®, NanoString), for the 21-gene assay on clinical outcomes.
We conducted a decision analysis using Markov Chain Monte Carlo simulation (rjags package in R) to estimate posterior distributions in a cohort of 100,000 women with ESBC. The discordance of PAM50-ROR with the 21-gene Recurrence Score® result threshold for beneficial effects of CT (Sparano NEJM 2018) was extracted from the only three published discordance studies. Effects of adjuvant CT on distant recurrence, overall survival, and toxicities were based on Chandler et al. (JCO 2018) outcomes over 25-year time horizon. Primary endpoints are incidence of distant recurrence, incidence of chemotoxicities, and overall survival.
About 1 in 4 women (25%; IQR 16 - 28) tested with PAM50-ROR have results discordant with 21-gene assay, resulting in an average increase of 2,466 of 100,000 women tested receiving CT (IQR -1,647 – 9,702). PAM50-ROR classifies 7% of women as high risk who have RS ≤ 25 (with chemotoxicities and no chemobenefit), 11% as low/intermediate risk who have RS > 25 (with increased distant recurrence and decreased survival among those not treated with CT), and 25% as intermediate who have RS ≤ 25, of whom >7% are likely to receive CT. The consequent effect of treatment choices based on discordant test is an increased incidence of distant recurrences (3,052; IQR 1,212 – 3,319), increased incidence of toxicities (696; IQR -324 – 2,228), and decreased years of overall survival (34,255 y; IQR 16,586 – 38,118).
Use of PAM50 ROR compared with the 21-gene assay may lead to an increase in CT recommendations and potentially less desirable clinical consequences. Implementation of new incentives to create value-based oncology care needs safeguards to focus use towards optimal interventions.
Genomic Health, Inc.
Genomic Health, Inc.
C.J. Markopoulos: Consultant: Genomic Health Inc.; Educational grants: AstraZeneca, Pfizer, Novartis. L. Hochheiser: Consultant: Abbott (providing guidance and direction as part of a Payor Advisory Board); Manuscript consultant: Genomic Health, Inc. J. Hornberger, E. Hytopoulos, M.C. Stoppler: Employee, owns stock: Genomic Health, Inc. M. Gitlin: Consultant: Genomic Health.
Quantitative measurements of HER2 might identify the probability to respond to anti-HER2 ADCs better than semi-quantitative methods such as immunohistochemistry (IHC).
Expression of 55 BC-related genes was determined by nCounter in tumor samples from a retrospective series of 58 T-DM1-treated patients (pts) with advanced BC from two independent institutions. Genes associated with T-DM1 overall response (OR; partial or complete) were identified using two-class unpaired SAM. Cutoff Finder (Plos One 2012) was used to optimize cutoff to predict OR. Uni- and multi-variate analysis for OR were performed using logistic regression. Nine BC cell lines (4 HER2-) were treated with T-DM1 (1.25 µg/ml) for 72 hours; treatment response (reduction in cell viability) was correlated to ERBB2 levels. Finally, % of ERBB2-high tumors across HER2 IHC groups was explored in 392 and 368 primary BCs from an in-house (nCounter) and the TCGA (RNAseq) datasets, respectively.
HER2 IHC status in T-DM1-treated pts was: IHC0 (n = 5), IHC+1 (n = 3), IHC+2 (n = 12), IHC+3 (n = 35). 60% of pts were HR+, 72% received 1 prior line of trastuzumab and 93% had visceral metastases. OR rate was 43%, median PFS was 5.3 months (95% CI 3.9-7.6). GRB7 and ERBB2 were the top 2 genes associated with OR (FDR<1%). Although HER2 IHC (3+ vs ≤ 2+) was associated with OR in univariate analysis (p = 0.027), only ERBB2 expression (ORR 1.93, p = 0.021) and number of prior therapy lines (0-1 vs ≥ 2) were independently associated with OR. An ERBB2 cutoff was optimized to predict OR (100% sensitivity, 36.4% specificity, AUC 0.69). In BC cell lines, the ERBB2 cutoff predicted T-DM1 activity (median cell viability 43% vs. 100%, p = 0.015). Importantly, T-DM1 response across BC cell lines strongly correlated with ERBB2 continuous expression (r = 0.88). Finally, ERBB2-high distribution within HER2 IHC groups in both datasets (in-house and TCGA) was: 0% and 0% (IHC0), 1.10% and 0.59% (IHC+1), 0% and 0% (IHC+2/non-amplified), 9.38% and 25% (IHC+2/amplified) and 76.68% and 79.63 (IHC+3).
ERBB2 expression is associated with T-DM1 efficacy in BC regardless of HER2 IHC status. Lower ERBB2 cutoffs might be needed for highly potent anti-HER2 ADCs such as DS-8201.
Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
Asociación Española Contra El Cancer (AECC, Postdoctoral 2017) University of Padua (DOR 1721185/17 - DOR 1830512/18).
G. Griguolo, T. Giarratano: Travel grants: Pfizer. T. Pascual: Advisory board: Roche. M.V. Dieci: Consultancy role: Eli Lilly, Genomic Health; Advisory boards: Eli Lilly, Celgene. V. Guarneri: Institutional research grant: Roche; Advisory boards: Eli Lilly, Roche, Novartis; Speaker’s bureau: Eli Lilly, Novartis. A. Prat: Advisory role, speaker fees: Daiichi Sankyo, NanoString, Roche, Novartis, Pfizer, Lilly; Funding: NanoString Technologies, Roche, Novartis. All other authors have declared no conflicts of interest.
ctDNA is emerging as a non-invasive disease-monitoring biomarker alternative to a tissue biopsy. In this study, we characterized ctDNA from patients with ER+, HER2- MBC 1) starting first-line non-steroidal aromatase inhibitors (NSAIs) and 2) refractory to treatment with NSAI.
Patients starting treatment with NSAIs (cohort 1, n = 100) and patients refractory to NSAIs, starting treatment with everolimus/exemestane (cohort 2, n = 164) were included in this analysis. Longitudinal plasma samples and whole genome sequencing (WGS) data from paired metastatic tissues, collected at baseline, were available from 23 patients in cohort 1. Cell-free DNA (cfDNA) (10ng) was characterized by targeted next generation sequencing (NGS) for hotspot mutations in 10 genes. Numbers of specific mutations and mutant molecules/mL and numbers were compared for both cohorts and related to PFS for cohort 1.
Patients in cohort 2 more often had detectable ctDNA (76% vs 53%, p < 0.001) and ≥3 specific mutations (18% vs 3%, p = 0.001) when compared to patients in cohort 1. Mutations in ESR1 (40% vs 9%, p < 0.001) and PIK3CA (46% vs 29%, p = 0.009) were enriched in patients in cohort 2, of whom ESR1 mutations were more often polyclonal (11% vs 1%, p = 0.009). The most frequently identified ESR1 variants were p.E380Q in cohort 1 (n = 4) and p.D538G and p.Y537S in cohort 2 (n = 38, n = 27). Mutations in KRAS and ERBB3 were only detected in cohort 2 (p = 0.331, p = 0.232). The median number of mutant molecules/mL in ctDNA-positive patients did not significantly differ between cohort 1 and cohort 2 for all mutations (48 vs 54, p = 0.87). In cohort 1, mutant molecules/mL and numbers of mutations were not significantly associated with PFS (p = 0.393, p = 0.384). Analysis of 23 patients with longitudinal plasma samples and WGS data from metastatic tissue is ongoing and will be presented at the meeting.
Patients refractory to endocrine therapy develop more heterogeneous disease demonstrated by higher number of mutations detected in ctDNA.
Plasma samples from cohort 2 were prospectively collected in the Everolimus Biomarker (EB) Study (Eudract 2013-004120-11).
Erasmus Medical Center.
Novartis Merck KGaA.
All authors have declared no conflicts of interest.
Mutations in the ESR1 gene that evolve under endocrine treatment are associated with resistance to therapy and with worse prognosis of HR positive metastatic breast cancer patients. Here we aimed to study the incidence and clinical implication of these mutations in local recurrence events and newly diagnosed metastases.
A total of 130 archived tumor samples were collected from 103 endocrine-treated breast cancer patients having long-term follow-up. The cohort consisted of 41 patients having at least one loco-regional recurrence sample and 62 patients with metastatic samples, of which 41 samples were from newly diagnosed metastasis and 28 samples from advanced metastatic patients. The 5 ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed.
The prevalence of ESR1 mutations was 5/41 (12%) for newly diagnosed metastasis and 5/28 (18%) for advanced metastases, at allele frequency >1%. In contrast to advanced metastases, most mutations in newly diagnosed metastases (4/5) emerged under Tamoxifen treatment alone. Progression free survival was significantly shorter in metastatic patients with ESR mutations treated with AI. For loco-regional recurrence events, ESR1 mutations were identified in 15/41 (36%) patients with 4/41 (10%) at allele frequency >1%. Again, most mutations (3/4) emerged under Tamoxifen treatment. Disease free survival and distant recurrence free survival were significantly shorter in patients that had ESR1 mutations (>1%) in their loco-regional recurrent tumor.
ESR1 mutations are prevalent in breast cancer local recurrence to a similar extent as newly metastatic hormone receptor positive breast cancer patients. The results may have important implications for choosing the optimal adjuvant treatment for these patients.
Breast Cancer Translational Research Group, Sheba Medical Center.
Israel Cancer Association.
All authors have declared no conflicts of interest.
Antiangiogenic therapy using bevacizumab has proven effective for a number of cancers; however, in breast cancer there is an unmet need to identify patients that benefit from such treatment.
In this phase II clinical trial (NeoAva-NCT00773695), patients (n = 132) with HER2 negative primary tumors of ≥ 25 mm were treated with neoadjuvant chemotherapy and randomized (1:1) to receive bevacizumab or chemotherapy only. Ratio of the tumor size before and after treatment was calculated to obtain a continuous scale reflecting the response to therapy. Tumor biopsies at week 0, 12 and 25 were analyzed by reverse phase protein arrays (RPPA) for expression levels of 210 proteins (of which 54 phospho-specific). Proteins with low variance across samples were filtered out and Lasso regression was then used to derive a predictor of tumor shrinkage from the expression of proteins prior to treatment. Leave-one-out cross-validation (LOOCV) was used to select the optimal Lasso model.
From the Lasso analysis with LOOCV, we discovered a signature consisting of nine proteins which was capable to predict patients responding to treatment with bevacizumab in combination with chemotherapy with high accuracy. The corresponding protein score obtained as a weighted sum of the protein expressions was significantly different in patients with/without pathological complete response (pCR) or low/high residual cancer burden (RCB </ = > 2). The nine-protein signature was applied to corresponding mRNA data and the resultant score also showed significant separation in the above groups. Finally, the nine-protein signature was validated in an independent mRNA data set from a similar phase II clinical trial (PROMIX-NCT00957125) with scores significantly separating patients with/without pCR.
In this study we demonstrate that integration of multiple protein-expressions to create a signature is a promising approach for prediction of response to treatment with bevacizumab combined with chemotherapy in breast cancer patients. A prospective clinical trial is planned to confirm the potential clinical benefit of using the protein signature for treatment selection.
NeoAva: NCT00773695 Promix: NCT00957125.
Oslo University Hospital HF (PI. Olav Engebråten).
Oslo University Hospital HF was sponsor and Roche Norway was co-sponsor of the clinical trial NeoAva.
G. Mills: Consultant, speaker, grant, research support: AZ/MedImmune, Tarveda, Myriad Genetics, AbbVie, Critical Outcomes Technology, Pfizer, Takeda/Millennium Pharm, Tesaro. A-L. Borresen-Dale: Shareholder, board member: Arctic Pharma AS; Consulting: PubGene AS, Saga Diagnostics AS. O. Engebråten: Research funds: Roche Norway was a co-sponsor of the NeoAva study. All other authors have declared no conflicts of interest.
Most studies have used genomic profiles to dissect the heterogeneity of breast cancer (BC) to improve clinical outcome, however, very few studies pay attention to protein profiles. Thus, we aimed to explore the prognostic value of reverse phase protein array (RPPA)-based proteins and integrated them into a nomogram with clinical variables to predict outcomes in non-metastatic BC after surgery.
From the Cancer Genome Atlas (TCGA) database, we identified 767 non-metastatic BC patients with RPPA-based proteins data and clinical features, and randomly classified them into the discovery (n = 460) and validation (n = 307) cohorts. A least absolute shrinkage and selection operator (LASSO) Cox’s proportional hazard model was used to build the RPPA-based proteomic signature. A nomogram was constructed combing the proteomic signature and some predictive clinical variables. And the predictive accuracy of the predictive models was assessed with Brier score and Harrell’s concordance index (c-index).
Using the LASSO Cox model, we built a RPPA-based proteomic signature (RPSBC) for BC based on 15 proteins: ATM, B-Raf, Bim, CD49b, Heregulin, Ku80, Lck, P-Cadherin, PDK1, PRAS40pT246, RbpS807_S811, SETD2, SrcpY527, Tuberin, eEF2K. To develop a more quantitative model to predict recurrence, a nomogram (nomoRCBC) combining RPSBC and clinical features (age, T stage, N stage, menopause status, and histological type) was constructed. Using recurrence scores calculated in the nomoRCBC, patients were classified into high-risk or low-risk groups. Between these groups, recurrence-free survival was significantly different in the discovery and validation (hazard ratio[HR]: 2.95,95%CI 1.51-5.77; p = 0.002) cohorts. In addition, the nomoRCBC had better prognostic validity than the TNM stage and other published predictive models. Moreover, this nomoRCBC could be used to predict which patients might benefit from adjuvant chemotherapy after surgery for breast cancer.
Our nomoRCBC is a reliable prognostic and predictive tool for survival in patients with non-metastatic BC, which may facilitate personalized adjuvant chemotherapy.
The results published here are in whole based upon data generated by The Cancer Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutes who constitute the TCGA research network can be found at http://cancergenome.nih.gov.
The authors.
Grants from the National Natural Science Foundation of China (Nos. 81472386, 81272340, and 81572901), the National High Technology Research and Development Program of China (863 Program) (No. 2012AA02A501), and the Science and Technology Planning Project of Guangdong Province, China (Grant Nos. 2014B020212017 and 2014A020209024).
All authors have declared no conflicts of interest.
Measurement of hormone receptors, HER2 and Ki-67 is prognostic for breast cancer (BC) outcome and prediction of therapy response. The Xpert® Breast Cancer STRAT4 based on RT-qPCR, is used to classify BC tissues regarding their hormone receptor status, HER2 and proliferation via Ki-67. This study compares the mRNA expression analysis of ER, PR, HER2, and Ki-67 in a large clinical trial cohort by an automated in-vitro diagnostic platform and central IHC.
Breast cancer patients from the prospective GBG multicenter trial GeparX (NCT02682693) (still recruiting) were included in this biomarker project. We used formalin-fixed paraffin embedded (FFPE) pretherapeutical core biopsies with a tumor content >10%. A 4µm FFPE tissue section was first processed with the Xpert® FFPE Lysis Kit, the sample lysate was placed in the GeneXpert® cartridge system in which the purification, amplification and real-time detection of the gene expression of ER, PR, HER2 and Ki-67 took place automatically.
Of 503 samples with valid mRNA measurements, 258 samples (51,3%) were ER-positive, 196 (39%) PR-positive, 78 (15,5%) HER- positive and 421 (83.7%) were Ki-67-high (>20%). The simple kappa coefficient was for ER = 0.7938, PR = 0.6540, HER2=0.8172 and Ki-67=0.3655. This implies that the ER, PR and HER2 measurements show a high correlation between both methods, whereas the Ki-67 measurement does not. The accuracy between the STRAT4 and IHC was 89.7% for ER, 83.3% for PR, 94.6% for HER2 and 86.7% for Ki-67.
Our results show a high concordance between standardized central IHC and automated mRNA expression analysis for the most important BC biomarkers ER, PR and HER2. For the continuous proliferation marker Ki-67, the concordance is slightly lower. The STRAT4 assay might offer an additional option to conventional methods for BC biomarker assessment, in particular in situations where ICH is not feasible. To determine the clinical validity, additional outcome analyses are necessary.
GeparX NCT02682693.
GBG Forschungs GmbH.
The clinical trial was supported by Celgene and Amgen and this study by Cepheid.
All authors have declared no conflicts of interest.
The Prosigna breast cancer assay provides independent additional prognosic value compared to classic pathohistological and immunohistochemical (IHC) parameters and assists adjuvant therapy decisions. In the present study, we retrospectively evaluated correlation of Prosigna breast cancer assay intrinsic subtype (IST) with immunohistochemical (IHC) IST estimation in a clinical setting.
We included all tumors (150 tumors from 146 women) that were analysed using the Prosigna assay at the Medical University of Vienna between December 2014 and July 2018, and of which detailed IHC status (ER/PR receptor, HER-2 and Ki67) could be accessed. 3 tumors with HER-2 enriched Prosigna IST were excluded from the analysis. For our analysis Ki67 cutoff values alone were used for discriminating Luminal (Lum) A from Lum B IHC IST estimation (Lum B: ≥20%, ≥30% and ≥40% Ki67). In addition the role of the cut off value of KI67 ≥20% and ≥30% in combination with PR receptor expression and grading were evaluated, regarding clinical and genomic correlation for defining subtypes. Statistical analyses were conducted using Cohen’s kappa coefficient.
In total we analysed 150 tumors from 146 women (median age 55.5 years), of whom 60% were lymph node positive. 79.3% (n = 119) of the tumors were of Prosigna Lum B subtype and 52% (n = 78) IHC Lum B IST, when using a cutoff of ≥ 20% Ki67 for Lum B disease. We found only a fair agreement between Prosigna and IHC IST (kappa 0.326). When using KI67 ≥30% as a cutoff, a slight improvement in agreement (kappa 0.411) was noted. Using a cutoff of ≥ 40 % KI67% to define IHC luminal IST, agreement decreased again (kappa 0.227).
Agreement between Prosigna luminal IST and estimation of luminal IST based on IHC over a range of Ki67 cutoff values between 20% to 40% proves to be fair at best. Our study demonstrates, that molecular-genetic tests, such as the Prosigna assay, provide crucial information for adjuvant chemotherapy decision management in cases where Ki67 IST estimation alone is not sufficient for therapy decision. These associations should be addressed by further studies to ensure an exact and cost-effective utilisation of the assay.
Department of Pathology, Medical University of Vienna.
K.A. Tendl: Travel support: Roche, MSD, Novartis, outside the submitted work. F. Fitzal: Travel support, scientific support: Pfizer, Comesa, Novartis, Roche, AstraZeneca, Pfizer, Myriad, NanoString, Lilly und Bondimed outside the submitted work; Editor for Oncoplastic Surgery part I and II, Springer. L. Müllauer: Research support: NanoString, outside the submitted work. Z.A. Bago-Horvath: Grants: Boehringer Ingelheim; Personal fees: Novartis, Roche; Travel support: Roche, outside the submitted work. All other authors have declared no conflicts of interest.
The receptor activator of NFkB (RANK)-RANK ligand (RANKL) pathway, pivotal regulator of bone remodeling, has emerged as a major mediator of progesterone-driven breast cancer (BC) carcinogenesis. RANK expression is particularly elevated in triple negative BC and has been associated with aggressiveness and poor prognosis. This study addressed the impact of elevated RANK expression in estrogen receptor (ER)-positive BC.
In silico analysis of RANK (TNFRSF11A) expression was performed in the TCGA BC cohort. ER+HER2- cell lines overexpressing RANK were obtained by lentiviral transduction and standard assays were used for gene expression and phenotype evaluation. In vivo tumor growth was measured in orthotopic xenografts or after tail vein inoculation. Comparisons between two groups were performed using unpaired t-test. Survival analyzes used the Kaplan–Meier method and log-rank test.
RANK expression was higher in ER- breast tumors (p < 0.001); and associated with decreased 5-year overall survival (HR = 2.12 (1.16-3.87), p = 0.012). However, 5% of ER+ tumors were found to express RANK within the ER- 75%Q range. ER+ cell lines overexpressing RANK (MCF-7OE and T47DOE) were characterized by hyper activation of downstream pathways; upregulation of mesenchymal and stem cell phenotype. In silico, elevated RANK expression in ER+ tumors was significantly correlated with mesenchymal and stemness-related genes. In vivo, MCF-7OE xenografts were consistently smaller in comparison with parental ones. However, tail vein inoculation showed that MCF-7 and MCF-7OE cells where identically metastatic in the lungs and skeleton, and animals harboring MCF-7OE cells had more circulating tumor cells.
Our data shows for the first time that RANK expression in ER+ BC is not unneglectable, and may impact on the tumor progression, particularly in the metastatic setting.
Instituto de Medicina Molecular.
This project was funded by National Funds (FCT-MEC), under the research project PTDC/MED-ONC/28636/2017. IG is supported by FCT grant SFRH/BD/139178/2018.
S. Casimiro: Research support: Amgen. L. Costa: Research support, advisory board: Amgen. All other authors have declared no conflicts of interest.
Patients (pts) with ER+, HER2– early breast cancer (EBC) do not universally benefit from adding adjuvant chemotherapy (CT) to hormonal treatment (HT). The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay is uniquely designed and validated to guide CT treatment decisions in this population.
The primary objective of the KARMA Dx study was to assess the impact of the RS result on treatment recommendations in high-risk patients for whom CT benefit was uncertain. Secondary objective was the evaluation of physicians’ confidence in their recommendation. This study was performed before the recent publication of the TAILORx trial that definitively determined RS cut-points for CT benefit. Eligible EBC pts were ER+, HER2– candidates for CT based on high-risk clinicopathologic features: · Cohort A: grade 3, N0/N1mic · Cohort B: grade 1-2, N1-3, or · Cohort C: cT > 2 cm N0 by imaging (not T4) and planned for neoadjuvant CT Recommendations were captured before and after availability of individual RS results. Primary outcome was the percent change in CT recommendations post- vs. pre-RS results.
Cohort Changes in recommendation Recurrence Score (RS) groups Total n 0-17 18-30 31-100 CT + HT to HT alone 99 (86%) 39 (53%) 2 (10%) 140 (67%) No change 16 (14%) 35 (47%) 18 (90%) 69 (33%) Total n 115 74 20 209 CT + HT to HT alone 5 (56%) 3 (27%) 1 (10%) 9 (30%) No change 4 (44%) 8 (73%) 9 (90%) 21 (70%) Total n 9 11 10 30 CT + HT to HT alone 78 (91%) 31 (54%) 0 109 (73%) No change 8 (9%) 26 (46%) 7 (100%) 41 (27%) Total n 86 57 7 150 CT + HT to HT alone 16 (80%) 5 (83%) 1 (33%) 22 (76%) No change 4 (20%) 1 (17%) 2 (67%) 7 (24%) Total n 20 6 3 29
219 pts with median age of 55 years were recruited in 7 Spanish centers and 209 pts were included in the final analysis. Recommendations changed from CT + HT to HT alone for 67% (140) of patients. The table shows changes in recommendations by cohort and RS group. Considering that 85% of patients had RS 0-25, using these TAILORx cut-points might further affect CT reduction. Physicians’ confidence in their final recommendation increased in 34% of cases.
RS testing resulted in an overall 67% reduction in CT recommendation in pts considered candidates for CT based on clinicopathologic criteria. These results reached 76% for patients in cohort C. The findings of the present study indicate the significant potential of the 21-gene assay to spare CT in high-risk EBC pts.
Hospital Arnau de Vilanova.
Genomic Health Inc.
A. Llombart: Grants/research support: Genomic Health Inc.; Stock shareholder: MedSIR. All other authors have declared no conflicts of interest.
Defects in DNA damage recognition and repair has been implicated in hereditary breast cancer (BC). Several studies demonstrated, that Fanconi Anemia (FA) associated genes-coding proteins and products of BRCA1/2 genes cooperate in a DNA repair pathway which is required for resistance to DNA interstrand crosslinks. Our aim was to analyze nucleotide variants in FA genes predisposing with an increased risk of hereditary cancers.
Targeted NGS was performed in a cohort of 630 BC patients with strong evidence of hereditary background of cancer. The NimbleGenSeqCap EZ Choice® kit (Roche) was used for target enrichment, and sequencing was performed using Illumina MiSeq® (Illumina) following manufacturers protocol.
Mutations Mean age (range) HER 2+, % HER2-, % Triple negative BC Logistic likelihood ratio, test P FA genes 52 (25-69) 33.7 66,3 25,0 0,011 BRCA1/2 42 (25-67) 20,9 71,9 47,5 0,002 All hereditary breast cancer 61 (22-88) 58,7 41,3 17,9 0,452
36 (5,7%) patients had heterozygous mutations in PALB2, FANCI, FANCL, FANCC, FAM175A, FANCM, FANCG, FANCD2 genes implicated in the causation of FA. Among these variants 30,5% were pathogenic, and 69,5% had uncertain significance. All variants had strong susceptibility with BC, the combined odds ratio of having a mutation was 27,3 (95% CI 1,25–4,64;P = 0,002)Six patients carried complementary pathogenic mutations in BRCA1/2, XRCC2 or MLH3 genes. Heterozygous mutations PALB2 and FANCL were significantly associated with estrogen receptor (ER)-positive disease, while those in FANCI were associated with ER-negative BC. Mutations in FANCI and FANCL genes had an association with progesterone receptor (PR)-negative BC, and PALB2 mutations were associated with PR-positive BC.
Heterozygous germline mutations in FA genes are strongly associated with a higher risk of BC. Triple negative BC is more common among carriers of mutations in FA genes than in common cohort of BC patients. Clinical characteristics of women with different germline mutations inBC.
The reported study was funded by Russian Foundation for Basic Research grant no 18-415-160009 and by the Russian Government Program of Competitive Growth of Kazan Federal University
National BioService, Saint Petersburg, Russian Federation.
Kazan Federal University.
All authors have declared no conflicts of interest.
Somatic mutations in HER2 (ERBB2) are oncogenic and may confer resistance to endocrine therapy in hormone receptor-positive (HR+) metastatic breast cancer (MBC). Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has single-agent clinical activity in HER2mutant MBC and is synergistic with fulvestrant in preclinical studies. In SUMMIT (NCT01953926), a phase 2 basket trial of neratinib in HER2-mutant solid tumors, the HR+ MBC cohort had encouraging outcomes with neratinib plus fulvestrant (N+F) [Oct 2018 datacut; Smyth et al. SABCS 2018; #PD3-06]. Updated results from this cohort will be reported, detailing the impact of prior therapies on clinical efficacy of N+F in HER2-mutant HR+ MBC.
HR+ HER2 non-amplified MBC patients with locally detected HER2 mutations received oral neratinib 240 mg once daily and intramuscular fulvestrant (labeled dose). Loperamide prophylaxis was mandatory during cycle 1. Efficacy endpoints were: objective response rate (ORR); clinical benefit rate (CBR); duration of response (DOR); and progression-free survival (PFS). Response was assessed by RECIST 1.1 and/or PET Response Criteria.
A total of 47 patients were enrolled between Jul 2013 and Jan 2019. Most (79%) patients had visceral disease and were heavily pretreated; the median number of prior metastatic therapies was 3 (range 1–11). ORR was 30%, CBR was 47% and median DOR in the 14 patients with a confirmed response was 9.2 months. Median PFS was 5.4 months. Twenty-five patients (53%) had received prior fulvestrant and 20 (43%) had received prior CDK4/6 inhibitor (CDK4/6i) therapy, with ORRs of 16% and 30%, respectively. Diarrhea was the most common adverse event (grade 3, 11%; median duration, 1.5 days) but did not lead to treatment discontinuation.
N+F is clinically active in heavily pretreated HER2-mutant HR+ MBC patients, including in those who had received prior fulvestrant and CDK4/6i therapy, where some durable responses were noted. No new safety signals were identified; the incidence of diarrhea was similar to that seen with single-agent neratinib and was not dose limiting.
Lee Miller (Miller Medical Communications Ltd).
NCT01953926.
Puma Biotechnology Inc.
Puma Biotechnology Inc.
L.M. Smyth: Consulting or advisory role: Roche Genentech, AstraZeneca; Research funding (Inst): Puma Biotechnology, AstraZeneca, Roche Genentech; Travel, accommodations, expenses: Pfizer; Honoraria: Pfizer, AstraZeneca. C. Saura: Consulting fees: Puma Biotechnology Inc. S.A. Piha-Paul: Contracted research: Puma Biotechnology Inc. I.A. Mayer: All (unrelated) financial disclosures below: Institutional research funding: Novartis, Genentech, Pfizer; Ad. board consultant: Novartis, Genentech, Lilly, AstraZeneca, GSK, Immunomedics, Seattle Genetics, Macrogenics. A.M. Brufksy: Consultant: Puma Biotechnology, Roche, Eisai, Celgene, Pfizer, Lilly, Novartis. I. Spanggaard: Research grant: Puma Biotechnology Inc. M. Arnedos: Honoraria: Novartis, AstraZeneca, Pfizer, Seattle Genetics; Research grants: Eli Lilly, Pfizer; Travel expenses: AstraZeneca, Pfizer. R.E. Cutler: Employment: Puma Biotechnology Inc. D.M. Hyman: Consulting, advisory role: Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Genentech; Research funding: Loxo Oncology, Puma Biotechnology, AstraZeneca. All other authors have declared no conflicts of interest.
The mechanisms contributing to the aggressive biology of inflammatory breast cancer (IBC) are still under investigation. Our lab reported a 79-gene signature that is shaped by specific immune response programs and discriminates between IBC and non-IBC (nIBC). In this study we assessed the spatial associations between immune cells in IBC.
Affymetrix gene expression data of 105 IBC patients were analyzed using the CIBERSORT module to narrow down the number of stainings. Serial slides were stained according to a validated protocol, scanned, virtually aligned and evaluated using VISIOPHARM® software. We used five validated antibodies: PD-L1 (SP142 AB), CD79α (B cell lineage), CD8 (cytotoxic T cells), FOXP3 (Tregs) and CD163 (TAMs, Tumor-associated macrophages). Using staining-specific image analysis algorithms, we located each positive cell using XY coordinates. Spatial co-localization was examined using point pattern (effector index, EI) and quadrant analysis (Morisita-Horn index, MHI), developed for ecological studies. The EI is based on the number of cells within a circle of 30 μm around a CD8+ cell and the MHI measures the dissimilarity in cells between two quadrants.
A total of 51 patients (= 104 tissue samples) were analysed and 23.5% achieved complete pathological response (pCR) after neo-adjuvant chemotherapy. A negative HR-status (P= .01) and a the presence of more CD8+ cells (P= .04) predicted pCR. Interestingly, a higher number of CD79α + (P= .005) or FOXP3+ cells (P= .02) in close distance of CD8+ T cells was associated with pCR (using both EI and MHI), while solely the number of CD79α+ or FOXP3+ cells did not predict prognosis nor pCR. PD-L1 positivity and the number of CD8+ cells were not associated with OS, but patients with more PD-L1+ cells (> 0.7 cells/ 30 μm) in close contact with CD8+ cells had a worse survival outcome (5y OS: 50% vs 68%, P= .03).TAMs surrounding CD8+ cells also seem to inhibit a good cytotoxic immune response as the EI for CD163+ TAMs was also prognostic (P= .02), while the absolute number of TAMs was not.
In a discovery cohort of 51 patients we showed that not only the presence, but also the spatial localization of immune cells predicts prognosis and response to therapy in IBC. By May we will have data of 148 IBC cases.
Translational Cancer Research Unit, GZA Hospitals & CORE, MIPRO, University of Antwerp, Antwerp, Belgium.
PhD grant for CVB, from the Research Foundation - Flanders (FWO) [grant number 1189617N].
K. Marien, Y. Waumans: Employee: HistoGeneX NV, which performs immunohistochemistry and molecular testing for pharmaceutical companies as part of (pre)clinical studies that evaluate new anticancer drugs. M. Kockx: CEO: HistoGeneX NV, which performs immunohistochemistry and molecular testing for pharmaceutical companies as part of (pre)clinical studies that evaluate new anticancer drugs. All other authors have declared no conflicts of interest.
Human epidermal growth factor receptor 2 positive (HER2+) breast cancer is an aggressive cancer form due to regulation and initiation of intracellular signaling pathways that promote cell survival and proliferation. Although HER2-targeted therapy, like trastuzumab and lapatinib, has improved outcome for HER2+ breast cancer patients, not all patients respond to treatment. We hypothesize that HER2+ breast cancer cells with poor response to targeted treatment can be sensitized by combining microRNAs (miRNAs) with traditional targeted therapy.
Two HER2+ cell lines with poor response to trastuzumab and lapatinib, KPL4 and SUM190, were transfected with a panel of 810 miRNA mimics and 816 inhibitors. The cells were treated with the miRNAs alone and in combination with trastuzumab and/or lapatinib. Viability was measured after incubation for 72 hours. In addition, cell lysates were prepared and protein expression of cPARP, KI67, AKT, pAKT, ERK, pERK, HER2, pHER2-Y1222 and pHER2-Y877 were measured using a lysate microarray. Based on the findings, 17 miRNAs were chosen for further validation.
Of the 17 miRNAs validated from the screen, eight miRNAs show a sensitization effect and significantly improve the effect of trastuzumab and lapatinib in vitro. The cell viability is reduced with 14-83 % by the miRNAs alone compared to negative control; 14-76 % compared to trastuzumab; 18-69 % compared to lapatinib; and 13-59 % compared to the two drugs in combination. The protein lysate arrays show that some of the miRNAs affect the protein expression levels, and this will be further explored.
Eight miRNAs in combination with the HER2-targeting drugs trastuzumab and lapatinib reduce breast cancer cell viability in vitro. This implies the potential of miRNAs as a combinatorial therapeutic together with targeted drugs to improve the effect for poor-responding HER2+ breast cancer patients.
Research Unit, Vestre Viken HF.
South-Eastern Norway Regional Health Authority.
All authors have declared no conflicts of interest.
PALB2 loss-of-function (Lof) mutation strongly suggests it as a tumor suppressor in familial breast cancer (BC). In Knudson’s hypothesis, mutation in both alleles is required for a single functional tumor suppressor to sufficiently cause malignant phenotype. But, some reports suggest the inhibition of one copy of PALB2 can lead to malignant phenotype (haploinsufficiency).
143 familial BC patients were enrolled. All the cases were assessed by Familial Cancer specialists and determined to be eligible for clinical genetic testing. Tumors and blood specimens were obtained and subjected to the whole-exome or big-panel gene sequencing. Both germline and somatic mutations were analyzed. Somatic mutation of PALB2 in local and public cancer database were analyzed, too.
In both the public and our local database, the somatic PALB2 mutation rate is 0.8%∼1.6% , much less than the germline mutation rate of 4.03%∼4.8%, in sporadic BC samples. In recruited 143 familial BC patients, ten (6.99%) had mono-allelic PALB2 germline mutations. The hotspots were c.1057A[3>2] and c.3114-1G>A. Other mutations included c.389delA, c.2068C>T, c.2167_2168delAT, c.2629delT and c.2968G>T. All were high risk stop gain, frameshift or splicing mutations, leading to truncated protein. Out of the ten patients, only one had accompanied somatic PALB2 mutation, one had accompanied germline BRCA1 heterozygous mutation, and three patients had other accompanied somatic gene mutations (eg. TP53, PIK3CA, etc). For the rest four patients, the germline PALB2 mutation was the only DNA hit, conforming to the haploinsufficient hypothesis; their germline PALB2 mutations concentrated in EX5 to EX9 regions, which were the key functional regions to binding to MRG15 and RAD51. The mono-allelic mutation caused a low expression level and severely functional damages, explaining their dominant pathological clinical phenotypes.
Many familial breast cancer patients with mono-allelic germline PALB2 mutations had the single DNA hit, suggesting a haploinsufficiency theory. The mutations concentrated in EX5-EX9, the MRG15 and RAD51-binding region, resulting in severe functional defects and breast cancer phenotype.
Hunan Provincial Cancer Hospital and Geneplus Beijing Institute.
Hunan Provincial Key Research Prokect (2018SK2124, Quchang Ouyang).
All authors have declared no conflicts of interest.
Several studies have shown that there may be change in the expression of steroid hormone receptors (ER and PR) as well as Her-2 as possible therapeutic relevant targets during disease progression (primary tumor versus metastatic disease). However, it is rarely considered into primary therapy that there can be already differences between the primary tumor and synchronous lymph node metastases (LMN). The aim of the present study was to compare the HER2/ER/PR expression profiles of primary tumors and synchronous LNM.
159 patients with breast cancer and LNM who underwent surgery (either SLNB or ALND) between 2008 and 2016 at the university hospital of Leipzig were included in this study. Formalin-fixed and paraffin-embedded (FFPE-material) were routinely examined immunohistochemically according to the ASCO/CAP guidelines using Ventana-platform. The results for ER, PR and Her-2 were analysed cay-by-case comparing results from the primary tumor within the breast and axillary lymph nodes. Proliferative activity was determined by MIB-1 immunohistochemistry and according to well established guidelines, the tumors were grouped into the different intrinsic subtypes as luminal A and B, Her2-enriched and triple-negative by the different immunohistochemical staining results.
The discordance rates between primary tumors and axillary LNM were 14% (22/159) for HER2, 10% (16/159) for ER and 23% (36/159) for PR. The subtypes between primary tumor and LNM were different in 35% of all cases (56/159 patients); gain of HER2 in 5/56, activation of HRs in 6/56, loss of HER2 in 19/56 and loss of HRs in 37/59 cases.
Our results imply the high frequency of subtype differences between primary tumor and LNM. Subtype changes should be taken into account for an optimal and individual treatment. Larger studies are necessary to validate these data and gain further information.
B. Aktas.
Has not received any funding.
All authors have declared no conflicts of interest.
This study aimed to assess the effects of three doxorubicin, paclitaxel or carboplatin-containing neoadjuvant chemotherapy regimens on tumor infiltrating lymphocytes and immune checkpoints in a murine model of triple-negative breast cancer (BC).
Syngeneic model of locally-advanced BC was established in immunocompetent mice using 4T1 cell line. Tumor-bearing animals were treated with human-equivalent dosages of doxorubicin, paclitaxel, paclitaxel and carboplatin combination (PCb), and placebo. Infiltration of CD3+, CD8+, and FoxP3+ cells into the tumor were assessed by immunohistochemistry. Expression of immune checkpoints including PD-1, CTLA-4, and TIM-3 were assessed by real-time PCR.
In our study, absolute count of CD3+ and CD8+ cells was significantly (p < 0.0001) higher in tumors treated with doxorubicin when compared to the other groups. The relative expression of PD-1 was significantly (p < 0.05) lower in tumors treated with doxorubicin when compared to tumors of the control group. PCb regimen decreased the expression of PD-1 in tumor tissues significantly (p < 0.05) compared to the placebo. Tumors treated with doxorubicin presented significantly (p < 0.05) lower expressions of TIM-3 when compared to the other groups.
Our results suggest that neoadjuvant chemotherapy of triple-negative BC with doxorubicin enhances anti-tumor immunity via increased infiltration of TILs. It also seems that doxorubicin inhibits immunosuppression in tumor by down-regulation of PD-1 and TIM-3 immune checkpoints. The study data demonstrate that PCb regimen can also decrease expression of PD-1. The data also raise new questions about the efficacy of PD-1 inhibitors after neoadjuvant chemotherapy with doxorubicin or PCb.
Deputy of Research - Tehran University of Medical Sciences.
Tehran University of Medical Sciences.
All authors have declared no conflicts of interest.
The vast majority of male breast cancers (male BC) are luminal-like hormone receptor (HR) positive invasive ductal carcinomas. Agter surgery, endocrine treatment (ET) therefore should be the mainstay in both adjuvant and metastatic setting. According to the RARECAREnet study, 5-year relative survival until 2007 in Bulgarian male BC patients is 59%, compared to 77 % on average for Europe. We therefore analyze available data from the National Cancer Registry to identify reasons for these low survival rates and aim to assess the role of ET in the management of male BC patients in Bulgaria.
This is a retrospective population based study of all 521 male BCs (520 patients, one had bilateral BC), diagnosed between 2002 and 2013 in Bulgaria. Data was collected from the National Cancer Registry. To compare trends in the use of ET, numbers were divided in two time intervals (2002-2007 and 2008 – 2013) and data about ET were recorded and analyzed.
HR status and ETTime period Patients with HR + HR+, cM0 Adj ET, n/% HR+, cM1 ET for metastatic disease, n/% 2002-2007 100 70 10/14.3% 30 10/ 33.3% 2008-2013 126 96 36/37.5% 30 7/23.3%
Median age of all 243 patients, diagnosed in the period 2002-2007 was 65 years; for the 278 patients, diagnosed in 2008-2013 median age was 66.6 years. Data for hormone receptors (HR) were available in 118/243 (84.7%) male BCs for the first time interval and in 156/278 (80.8%) for the second. HR positivity (ER+ or ER/PR+) was considered as indication for endocrine treatment (ET), both adjuvant (ADJ) or in the metastatic setting. Data on HR positivity, M status and ET are shown in Table.
As a rare disease, management of male BC is suboptimal in Bulgaria. Despite the fact that male BC is predominantly endocrine-responsive disease, in Bulgaria ET is still largely underused, both in the adjuvant and in the metastatic setting. Still, there is a clear trend towards an increase in the use of adjuvant ET, but unfortunately this is not seen in the metastatic setting. The underuse of ET might be one of the reasons for the shorter survival of Bulgarian male BC patients. We hope that identification of the problem after analysis of available data from the National Cancer registry, together with improvement of the knowledge about male BC might serve as first steps towards better management of this rare disease.
Minka Yordanova, Expert System Software and Database.
Assia Konsoulova.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer stage at diagnosis has a large impact on the 10-year survival probability. Mammography based screening has enabled early detection of breast cancer. However, mammography has limited sensitivity, and suffers from overdiagnosis and overtreatment. We aim to improve screening by developing a classification algorithm based on mRNA signatures from blood platelets (Tumor Educated Platelets; TEP).
Platelet mRNA was sequenced from 265 women with stage I-IV breast cancer, 216 asymptomatic female controls, 144 women with non-cancerous disease and 321 women with other tumor types. The samples were randomly divided in age-matched training and evaluation series for development of the TEP-based breast cancer classification algorithm. Two optimal classifier thresholds were selected, to attain a test with either a high sensitivity or a high specificity. This enables employment of the algorithm for two clinically relevant purposes. The first application is to rule out breast cancer in women with an abnormal mammography. The second application is to conform, or ‘rule in’, breast cancer in asymptomatic women who are being screened due to increased breast cancer risk. We examined if classifications depended on patient age, tumor stage, subtype, BRCA mutation status, and breast density. In addition, we applied the algorithm to a pan-cancer cohort to test if it was breast cancer specific.
Validation of the algorithm in early-stage breast cancer patients and non-cancer samples, resulted in an AUC of 0.72 (CI95% 0.66 – 0.79, p < 0.001). Setting the threshold according to the rule-out application resulted in a sensitivity of 91% with a specificity of 37%. For the rule-in application the specificity was 92% with a 30% sensitivity. Correct classification by the TEP-based algorithm is independent of tumor stage, clinical subtype, BRCA1/2 status, and breast tissue density. By training a second algorithm, we show that TEP profiles from breast cancer patients can be discriminated from those with other tumor types (Validation n = 245, AUC 0.78, CI95%: 0.73 – 0.84, p < 0.001).
RNA signatures from tumor educated platelets enable detection of early breast cancer, and warrant validation in a confirmatory and screening setting.
VU University Medical Center, Netherlands Cancer Institute.
The European Research Council E8626 and 336540, the Dutch Organisation of Scientific Research 93612003 and 91711366, and 531002002, the Dutch Cancer Society, NCI at NIH CA176359 and CA069246.
T. Würdinger: Funding: Illumina; Shareholder: Grail, Inc. All other authors have declared no conflicts of interest.
MicroRNAs (miRNAs) are small, non-protein-coding RNAs that can bind and suppress specific target messenger RNAs (mRNAs). Their dysregulation has been shown to affect the hallmarks of cancer and an increasing number of studies have identified miRNAs as potential biomarkers for cancer diagnosis. The ability to detect local oncogenic or tumor suppressor miRNAs in nipple aspirate fluid (NAF) could be of great value for early breast cancer diagnosis. To define the landscape of miRNAs physiologically present in the breast ducts, we analyzed their expression patterns in healthy NAF samples.
A total of 41 NAF samples (8 ng total RNA) from healthy women were profiled using the TaqMan™ OpenArray™ Human Advanced MicroRNA Panel (ThermoFisher Scientific) targeting 754 human mature miRNAs. Non-parametric statistical analyses were performed using SPSS statistics®.
Out of the 754 interrogated miRNAs, 39% had measurable expression levels in NAF. In line with previous miRNA studies in breast milk, the majority of highly expressed miRNAs in NAF (36/top 50) have immune-related roles. Few of the top 50 miRNAs in NAF were significantly correlated with BMI (miR-223-3p) or parity (let-7b-5p, miR-92a-3p, miR-29b-3p and miR-30d-5p). No correlation was found between miRNA expression and age or having a first degree relative with breast cancer. Interestingly, NAF sample color significantly affected the expression level of 4/50 miRNAs. MiR-205-5p, miR-200b-3p, miR-26a-5p and miR-210-3p showed significantly lower expression levels in green or brown samples compared to bloody, orange or pink samples (p = 0.029, p = 0.022, p = 0.011, and p = 0.009, respectively).
MiRNAs can reliably be detected in NAF of healthy subjects and most of them are immune-related. Our data reveals the first documented NAF-derived miRNA physiological expression pattern, with very few highly expressed miRNAs associated with established breast cancer risk factors. Of note, caution should be taken when interpreting miRNA expression levels in differently colored samples, as this proves to be a significant confounder. Currently, breast cancer NAF samples are being collected in the context of a Dutch trial and their analysis will soon reveal whether breast cancer specific miRNAs can be identified.
METC 14-497 (Dense-on) and METC 16-337 (Ornament).
Department of Pathology, UMC Utrecht.
Pink Ribbon, KWF.
All authors have declared no conflicts of interest.
Breast cancer (BC) is the second leading cause of cancer-related death among women worldwide. Within Asia, the incidence of BC is highest among Pakistani women and it is estimated that every ninth women is at risk of BC in her life. Early diagnosis via reliable non-invasive biomarkers is crucial in successful management of BC patients. MicroRNAs (miRNAs) regulate biological processes via post-transcriptional regulation of their target genes. Interestingly, miRNAs are also stably expressed in body fluids and are reflective of disease pathology, thus can act as novel disease biomarkers. In the present study, a combination of five oncogenic/tumor-suppressor miRNAs (miR-21-5p -221-3p, -155-5p, -146a-5p, -99b) was evaluated as potential diagnostic biomarkers for BC.
The present case-control study comprised of 140 age-matched participants (pre-operative/treatment-naive BC (n) = 80; non-cancerous healthy controls (n) = 60). The expression levels of selected miRNAs were then measured via qPCR followed by statistical analysis to compute expression differences and clinical correlations among groups. Receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic potential of miRNAs.
The miR-21, miR-155 and miR-221 levels were significantly upregulated in BC patients in comparison to controls (P = 6.3 x 10-3, P = 2.68 x 10-2 and P = 9 x 10-4 respectively) whereas, miR-146a and miR-99b were non-significant. miR-221 levels were significantly elevated in ER+ patients in comparison to ER- and correlated with tumor status (P < 0.01). Furthermore, miR-21, miR-155, and miR-221 were able to differentiate BC patients from controls with an area under curve of 0.871, 0.815 and 0.940 respectively. The highest sensitivity: specificity ratio (%) was noted for miR-221 (92:100) followed by miR-155 (50:100) and miR-21 (100:60). A significantly improved diagnostic accuracy was observed following combined ROC analysis of 3-miRNAs. No significant correlations were noted between expression of miRNAs and clinicopathological features.
In summary, serum miR-21, -155, and -221 panel have the potential to serve as non-invasive diagnostic biomarker option in BC patients thereby assisting in improved clinical care.
Triple negative breast cancer is at the greatest interest for the study. Cells of this type of breast cancer do not have receptors for steroid hormones or tyrosine kinases. For successful treatment of triple negative cases additional points of application are needed. Such targets could be cancer stem cells. For these types of cells, as well as for other stem cells, there are three main cascades are typical - WNT, Hedgehog and NOTCH. However, the conducted studies indicate the existence of other signaling mechanisms of regulation. In our work, we investigated the expression of the NF-kB, PI3K signaling pathways, as well as WNT, Hedgehog, NOTCH in cells of triple negative breast cancer with high and low content of cancer stem cells (ALDH1A1 level).
The material of 54 cases of infiltrative breast cancer was used. To determine the presence of stem cells in tumor population, the presence of ALDH1A1 protein in cancer cells was investigated. Expression of steroid hormone receptors, HER-2 and Ki-67 was studied by immunohistochemical method to identify cases of triple negative breast cancer. The expression of signaling molecules PI3K, NF-kB, WNT, Notch, Hedgehog was also explored by innunohistochemical method.
All cases were investigated for ALDH1A1 expression and were divided into two groups - with low (expression of ALDH1A1 was estimated as 0 and 1+) and high (expression of ALDH1A1 was estimated as 2+ and 3+) content of cancer stem cells. It was found that 20% of cases of triple negative breast cancer are positive for ALDH1A1. Expression of explored signaling molecules in cases with high and low content of cancer stem cells is shown in the table.
NF-kB PI3K PTEN NOTCH WNT HH high ALDH1A1 100% 100% 33% 11% 11% 0% low ALDH1A1 100% 100% 20% 25% 33% 14%
It was found that cases with high content of cancer stem cells are less regulated by signaling pathways NOTCH and WNT. Expression of NF-Kb and PI3K signaling molecules (which are responsible for activation of eponymous signaling pathways) appeared in all studied cases, while expression of PTEN phosphatase, which inhibits PI3K signaling pathway, was more common for cases with high content of cancer stem cells.
Institute of Medical Cell Technologies, Ekaterinburg, Russian Federation.
Ministry of Healthcare of Sverdlovsk Region of Russian Federation.
All authors have declared no conflicts of interest.
Breast cancer (BC) is the most common cancer in women and the leading cause of cancer-related death. HER2 is overexpressed in approximately 15-20% of BCs. HER2 expression is not only a prognostic biomarker but a predictive biomarker of response to HER2 targeted therapies. The ONCOLLEGE-001 project addresses the distribution & disparities of HER2-testing (H2T) methods (IHC or in situ hybridization (ISH), which may use either fluorescent (FISH), chromogenic (CISH) or silver (SISH) detection method) in breast cancer, with the aim of painting the global picture (GP).
A simple, internet-based survey was developed by the international ONCOLLEGE (ONC) working group and the questionnaire was sent to 227 oncology providers by email, was shared on medical social networks (using snowballing as a multiplier effect of promotion and diffusion). Data were analysed per country-income (World Bank groupings) and WHO Regions. Responders authorized for the use of the data.
210 providers responded, across 45 countries (27% from high-income HIC; 35% upper-middle UMIC; 38% lower-middle and low, LMICs; 50% in the Eastern Mediterranean Region), mostly medical and clinical oncologist (58%; 20%) from research hospitals (52%) and public non-teaching (17%) or private institutions (17%). H2T was available only in private setting or abroad in 5%, 42% and 34% of HIC, UMIC and LMICs responders’ institutions. Only IHC (no ISH) may be performed as H2T in 7% & 9.4% of UMIC & LMICs. FISH (54%) and CISH+FISH (14%) were the most common ISH H2T. IHC and ISH were available within 14 days (55%; 29%) and 28 days (38%; 44%) with no dramatic income-restricted patterns of delay. 30% of the responders from LMICs reported affordability issues related to H2T, more for ISH, related to out of pocket expenses and exposure to catastrophic health expenditure, compared to 12% of UMIC and none for HIC (full reimbursement).
The GP of H2T provided by the ONC networking painted a heterogeneous picture, with disparities related to the availability of appropriate cancer testing and affordability with high risk of financial toxicity in the diagnostic phase. An ongoing further analysis addresses also the prioritization and access to HER2 medicines in our ONCOLLEGE-001 project.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Although both kinases and phosphatases have equally important roles in maintaining cellular homeostasis, the protein phosphatases are understudied and their functional relevance in human malignancies is not fully understood yet. This project aims to better understand the role of a major serine threonine phosphatase called protein phosphatase 2A (PP2A) in cancer particularly basal-like breast cancer (BLBC). BLBC is the most challenging breast cancer subtype as it is very aggressive with no targeted therapies, and the main reason can be attributed to poor understanding of the molecular mechanisms that drive this cancer subtype. Hence, there is a critical clinical need to identify new targets and develop novel therapies for this subtype. Our research group discovered CIP2A (cancerous inhibitor of PP2A) (Cell, 2007) and its role as an oncoprotein in breast cancer and several studies have indicated that high CIP2A expression correlates with more aggressive cancer and poor prognosis in the clinic. This project aims to unravel the molecular mechanisms by which CIP2A drives tumour initiation in BLBC and to establish CIP2A biomarker signature which can serve as a predictive and prognostic tool for better clinical management of BLBC.
The key methods used in the project are CIP2A Knockout mouse models, RNA sequencing of basal like breast cancer cell lines, Immunohistochemistry (IHC) of patient material, DNA Damage Ionization radiation induced foci (IRIF) formation, Colony formation experiments with depletion of CIP2A using siRNA, Flow cytometry, Western blotting, Co-Immunoprecipitation (CO-IP), Immunofluorescence and microscopy.
Our results have shown that CIP2A knockout mice were resistant to DMBA induced BLBC tumour formation. Mechanistic studies indicated that it has an important role in DNA Damage Response signaling. Analysis of patient material revealed that CIP2A has a prognostic benefit particularly in basal type TNBC patients. We generated a CIP2A Biomarker signature (269 genes, p = 0.01) by RNA Seq of CIP2A depleted BLBC cell lines and validated it with publicly available TCGA and METABRIC datasets.
CIP2A is a promising novel target for BLBC and it has the potential to be used as a predictive and prognostic biomarker for BLBC.
Jukka Westermarck (Principal investigator).
Finnish Cancer Foundation, Business Finland, University of Turku Graduate School.
All authors have declared no conflicts of interest.
Ki-67 is a widely used marker of tumor proliferation, but the prognostic value of Ki-67 in triple-negative breast cancer (TNBC) is still controversial. The aim of present meta-analysis was conducted to evaluate the association between Ki-67 expression and survival in TNBC patients receiving neo-adjuvant or adjuvant chemotherapy.
Relevant literatures were identified from PubMed, Embase, Web of Science, China National Knowledge Infrastructure, and Cochrane Library, up to March 14, 2018. Hazard ratio (HR) with 95% confidence intervals (CI) were calculated as effect values, and heterogeneity, sensitivity analysis and publication bias analyses were also performed.
35 studies enrolling 7716 patients were eligible for inclusion. Data on overall survival (OS) and disease-free survival (DFS) were available from 25 and 29 studies, respectively. The pooled results showed that high Ki-67 expression was significantly associated with poor DFS (HR: 1.73, 95% CI: 1.45–2.07, p < 0.001) and OS (HR: 1.65, 95% CI: 1.27–2.14, p < 0.001) compared with low Ki-67 expression in TNBC. Similar results were observed on subgroup analysis by Ki-67 or ER/PR cut-off value, treatment strategies, or districts.
High Ki-67 was a poor prognostic factor for TNBC who received neo-adjuvant or adjuvant chemotherapy.
Wen Li.
Has not received any funding.
All authors have declared no conflicts of interest.
The success of molecular subtyping leads to numerous prognostic algorithms for personalized treatment of breast cancer patients. However, until now, immunohistochemistry (IHC)-based subtyping method still plays a dominant role in daily clinical practice. The discordance between mRNA based and protein based method is well recognized in the field. In this study, we aimed to reconcile these two types of subtyping methods by measuring ER, PR, Her2 and Ki67 as absolute and continuous variables in 1048 Formalin Fixed Paraffin Embedded (FFPE) specimens.
Total protein from 2X15 mm FFPE slices provided by local hospitals sequentially and non-selectively were extracted and used for Quantitative Dot Blot (QDB) analysis using the same antibodies for IHC analysis, including SP1 for ER, 1E2 for PR, EP3 and 4b5 for Her2, and MIB1 and UMAB107 for Ki67. Purified recombinant proteins, either prepared in house, or acquired commercially, were used as protein standard to achieve absolute quantification of these biomarkers.
When using absolute and quantitative levels of ER, PR and Her2 as X, Y, and Z axes, we found the samples naturally segregated into three distinct groups. Those samples with high Her2 levels were exclusively wrapped around Z axis (Her2 group), while samples with ER or PR overexpression were spread at the ER and PR floor (HR group). This pattern persisted until a small block with ER < 0.2 nmole/g, PR < 0.8 nmole/g and Her2 <0.3 nmole/g can be observed with samples distributed inside randomly. We named this small block as corner group. Interestingly, when using 0.3 nmole/g as cutoff for Her2, we observed 93.6% concordance between results from QDB and 786 IHC scores provided from local hospitals. The corner group was also found to be most heterogeneous, with those samples with highest Ki67 levels exclusively accumulated within this group.
We believe what we observed of the 3D distribution of samples by ER, PR and Her2 levels is the projection at protein levels of various molecular subtypes. Thus, the absolute and quantitative measurement of biomarkers at protein level may provide a simple, reliable 3D prognostic tool to incorporate what we have learned at both protein and mRNA level to be used in personalized treatment of breast cancer patients.
Yantai Quanticision Diagnostics, Inc.
Quanticision Diagnostics, Inc & Binzhou Medical University of China.
J. Zhang, J. Lv Y. Zhang, F. Tang: Employee: Yantai Quanticision Diagnostics, Inc & Quanticision Diagnostics, Inc. who owned or has filed patent application for QDB plate and QDB method to measure biomarkers in FFPE specimens. All other authors have declared no conflicts of interest.
Because of the high costs associated with genetic analyses, BRCA1/2-testing has traditionally been restricted to breast cancer patients having an ’a priori high risk’ of being a carrier. Particularly, according to The National Institute for Health and Care Excellence (NICE) in the UK, BRCA testing should be offered to breast cancer patients with a probability of having a mutation ≥ 10%. Regardless of family history, International Guidelines include among the BRCA testing Criteria, a personal history of triple negative breast cancer diagnosed ≤ 60 years. According to previous research, 15-30% of unselected TNBC had confirmed BRCA mutations. Whereas, among patients without breast/ovarian cancer family history mutation prevalence decrease to 6-15 %.
In the archives of the Modena Family Cancer Clinic, we identified 126 patients diagnosed with TNBC without family history of breast/ovarian cancer, which underwent BRCA-genetic testing. Mutation prevalence and clinical-pathological characteristics were evaluated.
Among 126 triple-negative breast cancer patients without a family history of breast and/or ovarian cancer, a total of 20 patients (15.8%) were BRCA mutation carriers: 18 BRCA1 (14.2%), 2 BRCA2 (1.5%), 2 BRCA2 VUS (1.5%). The mutation prevalence was 7/20 (35%) in the age group 30-39 years, 9/55 (16.3%) in 40-49, 4/48 (8.3%) in 50-59, 0/1 (0%) in 60-69 and 0/2 (0%) in 70-79. BRCA1 patients were younger at diagnosis (44 yrs) than non-carriers (48 yrs). Histotype, tumor grade, ki-67 and the presence of second primary BC were equally distributed between carriers and non-carriers.
Our results are aligned with the recent results of the German Consortium for Hereditary Breast and Ovarian Cancer, and justify BRCA mutation screening among women with TNBC diagnosed before the age of 60 years and no family history.
Laura Cortesi.
Has not received any funding.
All authors have declared no conflicts of interest.
Senescence is a well characterized effect of the CDK4-6 inhibitors, and senescent cells have been described to produce inflammatory mediators as part of a “senescence associated secretory phenotype (SASP)”. We hypothesized that CDK4/6 inhibitors, following cell cycle arrest and induction of senescence can increase the production of inflammatory mediators by breast cancer cells, such as IL-8, that are known to enhance the activity of anti-PD-L1 agents.
Four cell lines were used in this study, the HER2+ AU565, the luminal A MCF-7and the triple negative (TN) MD-MB-231 and MD-MB-468 cell lines. Cells were treated for 5 days to determine if palbociclib induces senescence. Senescence was characterized through the expression of acidic beta-galactosidase and morphologic changes. Quantification of IL-8 mRNA was performed by RT-Q-PCR using the ABI Prism 7900HT.
Beta-galactosidase staining revealed a significant number of senescent cells after palbociclib treatment in AU565, MCF-7 and MD-MB231 lines, which also underwentmorphological changes characteristic of cell cycle arrest and senescence under microscopic examination. IL8 mRNA analyses revealed that palbociclib significantly induced IL8 expression in all the cell lines tested, including the triple negative MDA-MB-468, where senescence changes had not been observed.
Palbociclib significantly upregulates the inflammatory mediator IL-8 in the four breast cancer cell lines tested, which included luminal, HER2+ and triple negative cells. Our resuls warrant further molecular characterization of the effects of palbociclib on tumor inflammatory microenvironment and analysis of the possible synergy of CDK4-6 inhibitors with anti-PD-L1 drugs in breast cancer.
Pangaea Oncology.
Has not received any funding.
All authors have declared no conflicts of interest.
Germline mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2 are associated with inherited predisposition for breast and ovarian cancer. Pattern of mutations varies considerably among different populations, and there are groups with high prevalence of particular mutations according to geographical area, as the c.156_157insAlu BRCA2 rearrangement, a founder mutation of Portuguese origin and one of the most frequent BRCA2 mutations described to date. In this study we review the clinical and pathological characteristics of the patients with Hereditary Breast and Ovarian Cancer Syndrome (HBOC), the BRCA1 and BRCA2 mutation spectrum and evaluate its relation with clinical outcomes.
Retrospective analysis of families with HBOC of our clinic between January 2007 and December 2017. Myriad or BRCAPRO model was applied and individuals with score ≥ 10% were tested for BRCA1/2 mutations, using PCR sequencing and MLPA technique. Data was analyzed with SPSS statistics software.
Ninety-four families with 378 members were evaluated. BRCA1 mutation was identified in 182 individuals, and BRCA2 in 111 individuals. In BRCA1 population, 42 individuals (40 females, 2 males) with cancer (affected individuals – AI) were identified, mainly with triple-negative breast cancer (BC) (57%). The most frequently detected mutations were exon 16_17del, c.1121_1123delCACinsT and c.2037delGinsCC which together represented 31% of total pathogenic mutations. In BRCA2 population, 62 AI were identified (55 females, 6 males), mainly with luminal BC (71.4%). The c.156_157insAlu BRCA2 rearrangement represented 61% of total pathogenic mutations. Rate of risk reducing surgeries was similar in both groups. Five-year overall survival was 82.5% in BRCA1 AI vs 86.4% in BRCA2 AI.
Our results are consistent with literature in terms of genotype-phenotype relation and frequency of founder mutations. Identify the most frequent mutations in each population is crucial for a personalized approach of patients and to define strategies of surveillance for patients and relatives at risk. Prognostic impact of these mutations in outcomes in BC has not been fully determined to date. Further studies including this population are warranted.
Susana Amaral.
Has not received any funding.
All authors have declared no conflicts of interest.
Metastasis continues to be a crucial problem for the clinical management and treatment of breast cancer (BC). Among breast carcinoma of no special type (BC-NST), grade 1 tumors do have the best prognosis in terms of recurrence and overall survival. However, rarely they metastasize to the axilla, suggesting a more aggressive behaviour. Our study aimed to uncover the mechanism responsible for the dissemination of tumor cells of grade 1 BC-NST into axillary lymph nodes in order to better understand lymph node metastasis phenomenon in BC.
Whole-exome sequencing technique was used to analyze a total of 7 BC with lymph node metastases and 8 without, all Luminal A BCs. Analysis compared the molecular profiles of the selected cases by Enlis Genome Research software, Cravat application and QueryOr software.
Analyzing the data, we can explain the presence of metastasis for 3 different samples because of the presence of mutation in AKT1 and PI3K. However, surprisingly, the group of patients with positive lymph node shared the same polymorphism (rs406113) in GPX6 gene. The rs406113 polymorphism is a missense variation, which in combination with other mutations, had previously been associated with the risk of breast cancer. To further investigate the role of the GP6X polymorphism on the onset of metastases, we collected 32 blood samples from breast cancer female patient. We performed a Kaplan-Meier analysis on metastatic free survival, without highlighting an increased risk due to the presence of the mutation (HR 1.01; 95% CI 0.41-2.45; P = 0.976). By using Cox Regression Analysis, after adjusting the model, to confound for Triple Negative status, MIB-1 levels, neoadjuvant and adjuvant therapy, the presence of GPX6 polymorphism confers an increased risk of metastasis onset (HR 2.1; 95% CI 0.76-5.8; P = 0.15). We have genotyped further 80 triple negative breast cancer blood samples and are in the process of collecting all clinical-pathological information to strengthen the statistical analysis.
Further analysis will be performed to confirm data obtained, to make in vitro study to investigate it possible role in metastatic process of breast cancer.
Fabio Beltram.
Has not received any funding.
All authors have declared no conflicts of interest.
Endocrine therapy for breast cancer patients is currently determined based on positive estrogen receptor alpha (ER) staining measured by immunohistochemistry. However, not all selected patients will respond to this therapy, suggesting that ER staining is not an optimal predictor for therapy response. We previously described a new method to measure functional signal transduction pathways based on a Bayesian inference from measurements of mRNA levels (microarray, qPCR) of the specific ER pathway related target genes. Initial evaluation suggested that ER pathway activity score of the primary biopsy is related to clinical response. In this study, this association is confirmed together with the observation that only the ER pathway activity is targeted by endocrine therapy, making this pathway activity score a possible candidate for response prediction to this therapy.
The Edinburgh Breast Cancer Unit collected pre-treatment biopsies of 29 post-menopausal patients with primary localized ER-positive breast cancer. Patients received neo-adjuvant letrozole treatment and clinical outcome was assessed at 3 months follow-up based on 3D ultrasound measurements (single clinician) and translated into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Archival RNA from fresh frozen (FF) biopsy samples was used to measure gene expression of target genes from several pathways (ER, AR, FOXO, HH, TGFb and Wnt) using RT-qPCR. Pathway activity scores were computed and expressed on a 0-100 scale.
A high ER pathway activity score was correlated with a higher decrease in tumour size (Pearson 0.4; p = 0.02), and low ER pathway score was clearly associated with PD (ER score of 20.2 in PD vs 43.8 in non-PD, two-sided t-test p = 0.03) with an AUC of 0.84 (CI 95% 0.63-1). Similar results were obtained by comparing CR/PR vs SD/PD. Other measured pathway activities did not correlate to clinical response confirming the ER pathway as primary target for endocrine therapy.
This study confirms the potential use of ER pathway activity score from a primary biopsy of ER-positive breast cancer patients as an improved biomarker in the prediction of neoadjuvant endocrine therapy response.
Philips Electronics Nederland B.V., acting through its HealthWorks Molecular Pathway Dx.
Has not received any funding.
D. Keizer, M.A. Inda, D. Clout A. van de Stolpe: Employee: Philips Reasearch. All other authors have declared no conflicts of interest.
In breast cancer, hormone receptor (HR) status is generally a qualitative measure; either positive or negative. Quantitative measurement of HRs has often been proposed as a prognostic and predictive marker in breast cancer, some guidelines even provide different treatment options for patients with strong versus weak expression. We aimed to evaluate quantitative HR load assessed by immunohistochemistry (IHC) as a prognostic and predictive marker for patients with stage 1-3 breast cancer.
We reviewed all available literature on quantitative measurement of HRs by IHC, which is the international gold standard assay.
Combined, all included studies (n = 21) comprised a cohort of 31,146 patients. Overall, only 3 out of 19 studies found a clearly significant correlation between higher ER load and better disease outcome. Only 1 randomised trial examined quantitative ER as a prognostic marker and found no significant correlation between higher ER % and better overall survival. 4 studies addressed the predictive value of quantitative ER for response to endocrine therapy (ET) and they support no correlation between higher ER load and better response to ET. 10 studies examined quantitative PR load and only 2 of those found a significant correlation between higher PR load and better outcome. 2 randomised trials examined quantitative PR as a prognostic marker and both found no correlation between higher PR % and disease outcome. 2 studies addressed quantitative PR load as a predictive marker for response to ET, no clear correlation was found between higher PR load and better response to ET.
There is no clear evidence for using quantitative ER and PR load assessed by IHC as a prognostic measure nor as a predictive marker for response to ET in patients with stage 1-3 breast cancer. Also, as there is no clear definition of weak and strong HR expression, and given the lack of evidence for prognostic and predictive value of quantitative ER and PR load as shown in this review, “stronger” HR expression should not be used to tailor treatment decisions for women with HR positive stage 1-3 breast cancer. We recommend only using a qualitative status for hormone receptor expression in future guidelines and treatment considerations.
J.R. Kroep.
Has not received any funding.
All authors have declared no conflicts of interest.
18F-FDG PET/CT is regarded as one of the essential imaging for establish the efficacy of breast cancer therapy and the measures of tumor burden showed promises to predict OS in patients with mBC. Everolimus leads to decreased protein synthesis, cell metabolism and cell proliferation in solid tumors. Identification of predictive markers for everolimus-based treatment remains a major issue, but to date, no predictive markers have been established. The aim of this study is to evaluate an optimal ΔSUV% [(SUV baseline-SUV 3 months)/SUV baseline] as a predictive factor of OR and DFS in patients with mBC cancer receiving everolimus and exemestane in 1^ line treatment.
The study included 31 patients with a new diagnosed luminal B phenotype mBCs treated with everolimus and exemestane in ASST of Cremona and INT of Milano between May 2013 and March 2018. The 18F-FDG PET/CT and glycemia were performed at baseline and after three months of treatment. Patients who stopped treatment before 10 months were considered as in a progressive disease (PD), otherwise a duration of therapy > 10 months was scored as no PD. ROC analysis was performed to determine the optimal cut-off value of ΔSUV% to differentiate PD from non-PD women using Youden Index. Time to progression survival (TTP) was estimated by Kaplan-Mayer method. Spearman’s rank correlation coefficient (rho) was calculated to describe correlation between ΔSUV% and Δglycemia.
An optimal cut-off ΔSUV% value of 29% was proposed for discriminate patients with PD from those without PD: patients with ΔSUV%<29% had a median TTP of 3.11 months versus 9.29 months for patients with ΔSUV%>29% (p = 0.0036) and more frequently had PD within 10 months: 100% vs 53%, respectively (p = 0.005). There was a negative correlation between ΔSUV% and Δglycemia (rho=-0.32, p = 0.15).
Our results showed that ΔSUV> 30% tested with 18F-FDG PET/CT after 3 months of treatment identified patients who had benefit from the everolimus-exemestane combination in term of response and TTP (>10 months). Moreover we have observed an inverse correlation between ΔSUV and Δglycemia. These results warrant further validation with a potential integration with molecular biomarkers related to tumor metabolism and mTOR signalling.
No editorial assistance
Breast Cancer Unit and Translational Research Unit, Azienda Socio-Sanitaria Territoriale Cremona, Italy.
Has not received any funding.
The author has declared no conflicts of interest.
LR-TNBC is responsive to polychemotherapy regimens including anthracyclines, taxanes and, more recently, carboplatin. However, we are ignorant of the individual contribution of each of these agents to the global activity of the combinations. Identifying single drug activity in the clinical setting is challenging. We used instead PDXs from LR-TNBC to test single chemotherapy drugs and combinations.
PDXs were generated from chemotherapy-naïve LR-TNBC patients, later treated with neoadjuvant docetaxel plus carboplatin. Tumor biopsies were implanted orthotopically into NOD.Cg-Prkdcscid IL2rgtm1Wjl (NSG) female mice (F0) and those that engrafted were later expanded in two successive mice cohorts (passages F1 and F2). PDXs from F2 were allocated into the following five (10-mice) groups: (a) vehicle (ethanol); (b) Docetaxel 8.10 mg/kg i.v once a week; (c) Carboplatin 48.64 mg/kg i.p once a week; (d) combination Docetaxel+Carboplatin 8.10mg/kg +48.64 mg/kg i.v+i.p once a week; (e) Doxorubicin 2.5 mg/kg i.p once a week. Tumor volume was calculated using the following formula: Tumor Volume = [tumor length x tumor width2]/2. Tumor growth inhibition (%TGI) was calculated as (1-(Average relative tumor volume treatment group/Average relative tumor volume vehicle group)*100).
PDXs from 5 LR-TNBC patients, BRCA 1-2 wild type, with different pathological responses to docetaxel+carboplatin, were included. The antitumor activity of drugs in PDXs is shown in the Table.
In this model, carboplatin and docetaxel showed higher single drug activity than doxorubicin. The combination of docetaxel and carboplatin offered the best antitumor activity.
Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM).
Fundación Salud2000-FundaciónSEOM, Roche Pharma and CiberONC.
M. Martín: Remuneration: Pfizer, Lilly; Consultant/advisory honorarium: Roche, Novartis, Pfizer, AstraZeneca, Lilly, Glaxo, PharmaMar, Taiho; Funding: Roche, Novartis. J.Á. Garcia Sáenz: Consultant/advisory honorarium: Novartis, Roche, Lilly, Celgene, Roche; Funding: AstraZeneca. F. Moreno: Consultant/advisory honorarium: Roche, Pfizer, Novartis, AstraZeneca. T. Massarrah: Consulting or advisory boards: AstraZeneca, Novartis, Roche; Travel grants: Novartis, AstraZeneca. S. Lopez-Tarruella Cobo: Consultant/advisory honorarium: AstraZeneca, Novartis, Roche, Pfizer, Gelgene, Pierre-Fabre, Eisai, Lilly. All other authors have declared no conflicts of interest.
Fifty mice per group Only one out of five PDXs showed some sensitivity to doxorubicin, while four out of five showed sensitivity to docetaxel and carboplatin single agents. All five PDXs showed sensitivity to the combination of docetaxel plus carboplatin.Drug(s)* Final tumor volume (mean +/-SD)mm3 Final tumor cellularity (%) TGI (vs vehicle) (%) P value for Final tumor volume (vs vehicle) Vehicle 822.2±281.7 86 NA NA doxorubicin 500.2±305.3 74.50 39 0.135 carboplatin 238.4±207.1 70 71.1 0.0041 docetaxel 285.8±402.2 62 65.3 0.0427 docetaxel plus carboplatin 94±161.4 44 88.6 0.0037
Trastuzumab improves survival in HER2-positive breast cancer patients. But there are no other predictive markers for the treatment and only half of patients benefit from it. Our aim is to evaluate an association between expression of proteins engaged into HER2-signaling pathway and overall survival of patients treated with trastuzumab.
A retrospective analysis of 81 patients with breast cancer treated with trastuzumab in adjuvant (n = 45) or palliative (as a 1st to 5th line; n = 36) regimens in our institution from 2003 to 2010 was done. Immunohistochemistry staining for expression of phosphorylated HER2 (p-HER2), HER3 and PTEN was performed. We analyzed an association between expression of the proteins and overall survival (OS) and overall survival from start of trastuzumab treatment (OStrast) defined, respectively, as a time from date of diagnosis or time from start of trastuzumab to date of death or last observation. The relationship between tested parameters and survival was analyzed by the Cox regression models. We used Kruskall-Wallis analysis of variance and Fisher’s exact test to verify correlation between the proteins expression and clinical features of the patients. Statistical significance was assumed when p < 0.05.
55.6%, 32% and 34.6% of the tumors were positive for HER3, PTEN and p-HER2, respectively. Positivity of HER3 and PTEN correlated with larger size of tumors (p = 0.016 and p = 0.008, respectively) and p-HER2-positivity - with more advanced clinical stage (p = 0.032). Median follow-up was 141 months. We recorded, respectively, 14 and 34 deaths in adjuvant and in palliative group. We have not found any correlation between the expressions of the proteins and survival neither for patients treated with palliative nor adjuvant regimen. For 27 patients treated palliatively with trastuzumab in 1st or 2nd line we have shown a trend toward worse OStrast in p-HER2-positive subgroup (HR 2.39; 95%: 0.99 to 5.79; p = 0.053). For patients treated with adjuvant trastuzumab numerically higher mortality rate was recorded for p-HER2-positive patients (7/15 v. 7/30).
p-HER2 may have predictive value for trastuzumab treatment but this observation needs validation.
Medical University of Lodz Study was approved by Bioethical Committee of Medical University of Lodz (No. RNN/138/09/KE 12-05-.2009).
Study was financed by means of European Social Fund (Integrated Regional Operational Program - Grants for innovative PhD studies) and statutory activities no. 503-1034-2.
M. Krakowska: Sponsorship of a participation in conferences: Merck, Roche. R. Czyzykowski, U. Czernek: Investigator in clinical trial sponsored by Roche. P. Potemski: Lecture fees, travel support: Roche. All other authors have declared no conflicts of interest.
Indoleamine 2,3 dioxygenase (IDO) catalyzes the conversion of tryptophan (Trp) into kynurenine (Kyn), an immunosuppressive metabolite involved in T regulatory cell differentiation. IDO is expressed in many cancer types, including breast cancer (BC), but its association with prognosis is controversial. Here we analyze Kyn/Trp ratio, known as a surrogate indicator of IDO activity, in BC patients and in healthy control (CTRL).
We prospectively enrolled 350 subjects, i.e. CTRL or BC patients (pts). All the subjects underwent a blood sample withdrawal at BC diagnosis or the day of the screening mammography for CTRL. After centrifugation, plasma was collected and stored at -80 °C. Kyn and Trp were determined on a TQ5500 tandem mass spectrometer after chromatographic separation. Statistical analysis was performed with SPSS v24 software.
We enrolled 146 CTRL and 204 stage I-III BC (85.1% ductal, 11.4% lobular, 3.5% other). The median age was 56 years (range 26-86). Overall, 29.7% of the cases were Luminal A, 44.1% Luminal B, 6.9% HER2-enriched and 19.3% triple negative. All the pts received surgery, 126 NAC with 43 pathological complete response (pCR), and 43 adjuvant chemotherapy. We observed significant higher Kyn, Trp and their ratio for CTRL vs BC (Table). We observed a higher Kyn/Trp ratio in estrogen receptor (0.042 ± 0.016 vs 0.038 ± 0.012, p 0.04) and progesterone receptor (0.041 ± 0.016 vs 0.038 ±0.012, p 0.048) negative pts, and a lower ratio for lobular histology (0.033 ± 0.008 vs 0.039 ± 0.014 in ductal vs 0.039 ± 0.008 in other, p 0.005). PCR was associated with higher Kyn (1.81 ± 0.47 µM/L vs 1.65 ± 0.59 µM/L, p 0.039), but not with Kyn/Trp ratio (p 0.367). Moreover, Kyn/Trp ratio was not predictive of disease free survival (p 0.194) and breast cancer specific survival (p 0.509). Table. Kyn and Trp in CTRL and BC pts.
CTRL BC P value Kyn (µM/L) 1.951 ± 0.708 1.770 ± 0.535 <0.0001 Trp (µM/L) 48.8 ± 14.2 44.6 ± 11.1 0.002 Kyn/Trp 0.041 ± 0.019 0.038 ± 0.013 0.019
Kyn/Trp ratio is not predictive of pCR and outcome. Kyn, Trp and their ratio are higher in CTRL than in BC pts. The concomitant reduction of Kyn and Trp suggest a rapid catabolism in presence of BC. Further studies, with the dosage of downstream metabolites are necessary to confirm it.
Laboratory of Human Genetics, GIGA Institute, Liège, Belgium.
FNRS.
All authors have declared no conflicts of interest.
The monoclonal antibody (mAb) therapies trastuzumab (T) and pertuzumab (P) are used to treat the ∼20% of BCs classed as HER2-positive (+). The major modes of action of the mAbs are abrogation of HER2-mediated intracellular signaling, and engagement of immune cells through ADCC. The HER-family targeting TKIs lapatinib (LAP) and neratinib (NER) are approved for the treatment of HER2+ BC. LAP and NER can alter the expression of HER2 and the ADCC response to mAbs in vitro. This in vitro study examines the impact of the TKIs on the levels of HER2, MHC CLASS I, mAb binding and NK cell-mediated ADCC in BC cell line models.
HER2 + (SKBR3 and HCC1954) and HER2-low (MCF-7 and T47D) cell lines were treated with LAP or NER (2µM for 48 hr). HER2 and MHC CLASS I levels were examined by Western blot. Fluorescently-tagged T and P were utilized to examine mAb binding in TKI-treated cell lines using flow-cytometry (% positive cells). A flow cytometry-based assay utilized TKI pre-treated HCC1954 and T47D and healthy volunteer CD56+ NK cells to assess T, P and T+P-mediated ADCC.
LAP-induced increases and NER-induced decreases in HER2 levels were confirmed in all four cell lines by Western blot. In SKBR3 and HCC1954, 98.8% of cells stained T+ and TKI treatment had minimal impact (<3.7% change). In a low-antigen setting, LAP increased (p < 0.05) the T+ cells by 4% (T47D) or 13.5% (MCF-7). NER decreased (p < 0.001) T+ cells by 40.5% (T47D) and 58.4% (MCF-7). 91.7 ± 4.1% SKBR3 and 77.6 ± 4.9% HCC1954 cells stained P+. LAP increased the % P+ cells for both cell lines, significantly so in HCC1954. NER reduced (p < 0.001) P+ cells in both SKBR3 (67.8% decrease) and HCC1954 (50.9% decrease). The TKIs impacted dual T/P binding in the same manner as for each individual mAb. MHC CLASS I expression was reduced (p < 0.05) by LAP in HCC1954 and by NER in T47D. Reduced MHC CLASS I levels were associated with a significant decrease in T-mediated, but not T/P-mediated, ADCC in HCC1954 and T47D.
LAP and NER alter HER2 levels, mAb binding and MHC CLASS I levels. Further investigation is warranted as antigen levels may not be the only factor associated with TKI-altered NK cell-mediated ADCC.
Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland.
The Cancer Clinical Research Trust (Charity No.: CHY12210), Science Foundation Ireland-funded Molecular Therapeutics for Cancer Ireland (08/SRC/B1410), Irish Cancer Society Research Centre Breast Predict, The Irish Research Council, Roche.
D.M. Collins: Research funding: Roche, Puma Biotechnology Inc.; Postdoctoral fellowship held for Roche. N.T. Conlon: Research funding: Puma Biotechnology, Inc. N. O’Donovan: Research funding: Roche, GSK. J.P. Crown: Advisory board meetings: Roche, Novartis, Puma Biotechnology Inc.; Travel support for conference attendance: Roche; Research funding: Roche, Puma Biotechnology Inc., GSK. All other authors have declared no conflicts of interest.
Breast cancer is a heterogeneous disease and triple negative breast cancers (TNBC) have higher histological grade, more aggressive locally along with higher chances of distant visceral metastasis. The present study was undertaken to assess the epigenetic regulation in breast cancer and the role of microRNA 182 and microRNA 18a (MIR 182 and MIR 18a) expression in locally advanced TNBC and comparison with the clinico-pathological variables and survival.
A total of 50 patients of locally advanced TNBC and 19 estrogen/ progesterone receptor positive patients (controls) during the period January 2011 to December 2013 were included in the study. Clinical response evaluation was done post neoadjuvant chemotherapy. The expression level of test genes (MIR 182 and MIR 18a) was determined using Real time polymerase chain reaction from formalin fixed paraffin embedded (FFPE) biopsy blocks. The MIR 182 and MIR 18a expression levels were correlated with the clinico-pathological data including patient outcome and survival.
A total of 36% patients had MIR 182 over-expression (value ≥6.32) whereas 40% patients had MIR 18a over-expression (value ≥8.84). The expression levels of MIR 182 and MIR 18a were significantly higher in the TNBC patients as compared to the non-TNBC group (p < 0.0001). Higher MIR 182 and MIR 18a expression was related to bigger tumour size, higher nodal status and poor clinical and pathological complete response. Also, 56.2% patients with MIR 182 levels <6.32 and 11.1% patients with MIR 182 levels ≥6.32 achieved clinical complete response, p-value 0.002. Around 60% patients with MIR 18a levels <8.84 and 10% patients with MIR 18a levels ≥8.84 achieved clinical complete response, p-value <0.0001. A total of 50% patients with MIR 182 levels <6.32 and 11.1% patients with MIR 182 levels ≥6.32 achieved pathological complete response, p-value 0.007. On univariate cox regression analysis, MIR 182 and MIR 18a overexpression were found to correlate significantly with overall survival.
MIR 182 and MIR 18a overexpression is correlated with worse clinical and pathological tumour characteristics in locally advanced TNBC. This study may be used to develop future biomarkers for prognostication of locally advanced TNBC.
DC Doval.
Rajiv Gandhi Cancer Institute and Research Centre.
All authors have declared no conflicts of interest.
Spindle cell carcinoma is a rare, metaplastic breast cancer (<1% of all breast carcinomas), with reportedly triple-negative (TNBC: ER-/PR-/Her2-) phenotype, associated with a marked resistance to conventional chemotherapy and overall poor outcome.
Twenty pure spindle cell carcinomas of the breast (15 primary and 5 recurrent/metastatic) were comprehensively explored for biomarkers of immuno-oncology (I-O) and targeted therapies using immunohistochemistry and DNA (592 genes panel) and RNA (52 genes panel) sequencing. A cohort of 603 TNBC cases analyzed with NGS was used as a control for the total mutational burden (TMB).
Majority (18/20) of spindle cell carcinomas were triple negative. Estrogen (2 cases) and androgen receptor (one case) expression above the therapeutic thresholds were rarely detected. Pathogenic mutations were detected in 80% including PIK3CA (30%), TP53 (25%), HRAS (20%), NF1 (20%), and PTEN (10%) as the most frequent. One case with matched pre- and post-chemotherapy samples analysis exhibited a consistent mutational profile (PIK3CA and HRAS mutations) in both samples. No gene fusions were identified in matched samples. No NTRK expression was detected in 4 tested cases. In comparison to the large (>600 patients) cohort of TNBC (11 mutations/Mb as 80th percentile cutoff value), the TMB in spindle cell carcinomas was low (below 80th percentile) in all cases (3-9 mutations/Mb). All tumors were microsatellite stable. Tumor cells (TC) PD-L1 expression was present in 6/18 cases.
Spindle cell carcinoma of the breast exhibits mutational profile similar to the published data in other types of metaplastic breast carcinomas. All spindle cell carcinomas have a low TMB and were microsatellite stable. PD-L1 expression was detected in one third of cases and may guide therapy trials with immune checkpoint inhibitors. Rare cases with ER and AR expression were detected and were candidates for respective hormonal therapies.
Zoran Gatalica.
Has not received any funding.
Z. Gatalica, P. Stafford, J. Swensen, J. Xiu, D. Spetzler: Employee: Caris Life Sciences. All other authors have declared no conflicts of interest.
In advanced breast cancer (ABC) some studies suggest a deleterious effect on survival when high levels of myeloid-derived suppressor cells (MDSC)1,2 are detected in peripheral blood. Furthermore, classical therapies like anthracyclines or gemcitabine seem to exert an immunostimulating effect by eliminating and/or altering the function of MDSC3. The objective of this study is to analyze the evolution of blood MDSC in patients with ABC prior to the standard first-line systemic therapy according to Clinical Practice Guidelines.
MDSC levels are measured at three timepoints: basal, and after 2 and 6 months from first line systemic therapy onset. Data are compared the measurements obtained from the MDSC of a control group of healthy women. In addition, MDSC levels are monitorized and correlated with clinical outcomes in terms of overall response rate [clinical benefit (CB, complete response + partial response + stabilization lasting more than 24 weeks) versus (vs.) progression of disease (PD)].
A total of 39 patients with ABC (34 CB, 5 PD) and 20 healthy women have been analyzed. 34 out of 39 patients were considered to obtain CB and 5 patients (12,82%) had PD as best response. Basal MDSC levels were higher in ABC patients prior to initiate any systemic therapy vs healthy population (p < 0,001). The levels of MDSC decreased sharply in those patients with CB (p 0,001), reaching statistical significance. However, no statistically significant differences were found in patients with PD (p 0,317) with respect to basal levels of MDSC (Table).
Basal MDSC levels are higher in patients diagnosed with ABC compared to the healthy population. Systemic therapy seems to decrease the levels of blood MDSC of patients with ABC, which may eventually help to restore a better immunosurveillance profile in ABC patients that could impact on clinical evolution.
The authors.
Andalusian Public Progress and Health Foundation.
All authors have declared no conflicts of interest.
Evolution of the MDSC according to clinical response in ABC and basal MDSC in healthy cohort There is only one patient analyzed in cycle 6 with PD. DP, progression of disease; CB, clinical benefit; ABC, advanced breast carcinoma; MDSC, myeloid-derived suppressor cells; 95% CI, 95% confidence interval.MDSC_Basal (mean) MDSC_Cycle_3 (mean) MDSC_Cycle_6 (mean) P value PD ABC 25,97 (95% CI: 6,47-45,47) 5,38 (95% IC: 4,05-6,71) 1,79* 0,317 CB ABC 13,03 (95% CI: 7,24-18,83) 3,90 (95% IC: 2,56-5,23) 2,98 (95% IC: 1,99-3,98) 0,001 Healthy cohort 0,81 (95% CI: 0,52-1,10) – – <0,001
The objective of this work was to demonstrate that the concerted action of tumor-associated antigens [TAAs] and inflammatory cytokines inflict autoimmune damage to the breast creating a chronic inflammatory milieu that promotes breast cancer [BC] progression.
We immunoscreened a T7 cDNA library constructed from mRNA extracted from BC tumors developing in untreated nude mice and performed PCR, sequence determination and homology searches using BLAST AND BLAT to detect signal transduction molecules involved in creating a chronic inflammatory milieu leading to BC progression in the DCIS.com mouse xenograft model of BC. We treated BC developing in the xenograft model with rituximab and dexamethasone. We performed immunohistochemistry [IHC] to monitor the evolution of the human BC developing in the DCIS.com mouse model.
Breast tumor tissue developing in the xenograft model of BC showed deposition of IgG and complement components C1, C2, C3, C4, C5-C9 on breast epithelial and stromal cells and the expression of IL-4, IL-6, IL-17, TNF-alpha and NFkB detected by IHC staining. Immunoscreening a cDNA library identified autoantibodies recognizing multiple human breast epithelial and stromal antigens and the heavy chain and V regions of immunoglobulins IgG1, IgG3, IgM and both light chains, particularly the lambda LC. Rituximab and dexamethasone treatment markedly modified the morphology of developing tumor in BC developing in the xenograft mouse model.
These results suggest that autoantibody- and inflammatory cytokine-mediated autoimmune damage, triggered by TAAs creates a chronic inflammatory milieu with generation of pro-inflammatory and tumor promoting signals supporting BC progression. Thus, in addition to being a protagonist in immune-surveillance, the B cell response in BC may have a tumor-promoting effect. The dramatic results of the treatment of the xenograft model of BC with rituximab and dexamethasone illustrates the potential of adding modalities proven successful in the treatment of the RADs to existing treatments for BC. The demonstration of a major role of autoimmunity in BC progression may have a transformative impact on prevention, diagnosis and treatment of BC.
Felix Fernandez Madrid.
NIH.
All authors have declared no conflicts of interest.
Inherited predisposition to breast cancer (BC) accounts for about 5–10% of all cases. Women carrying germline BRCA2 mutations have a cumulative risk at 70 years of 55% for BC and 17% for ovarian cancer. The c.156_157insAlu BRCA2 mutation has so far only been reported in hereditary breast/ovarian cancer families of Portuguese origin.
The authors collected information about every family with the c.156_157insAlu BRCA2 mutation followed in our center. The objective of this study is to divulge this mutation among European community, since this mutation is not detectable using the commonly used screening methodologies and must be specifically sought out.
It was identified 27 patients with the mutation, and 51 healthy mutations carriers. All the subjects are natural from the central Portugal. The patients were mainly women (85%), younger than 50 years old at diagnosis (M = 44; SD = 13). Two patients (7.4%) had ovarian cancer, 4 patients (14.8%) had bilateral BC at diagnosis and 9 patients (33.3%) had second cancers some years later (breast, prostate, colorectal and skin). From every BC diagnosed, 55.2% were luminal B like, 24.1% were luminal A like, 6.9% were luminal B Her 2 and 13.8% were triple negative. None of the patients were a stage IV at diagnosis but 30% had metastization during the surveillance time, 24.1% were stage I, 44.8% stage II, and 31.0% stage III. Neoadjuvant chemotherapy was performed in 40% of the patients, with only 2 patients having complete response and 2 patients with no response at all. Adjuvant chemotherapy was prescribed in 53.3%, and palliative treatment in 30%. From the metastasized patients, 66.7% had more than one organ affected, and 66.7% had more than 1 palliative treatment. Presently, 26.9% of the patients are dead. The five-year survival rate is 92.6%. Only 30% of the patients agreed to perform prophylactic surgeries. No relation was found between the age of diagnosis and the clinical stage, the metastization, the chance of a second tumor, and death (p > 0,05).
The authors aimed to sensitize physicians regarding the extension of screening of the c.156_157insAlu mutation to all high-risk breast/ovarian cancer families with Portuguese ancestry since these patients will have a different follow-up due to their chance to have second tumors.
Filipa Macedo.
Has not received any funding.
All authors have declared no conflicts of interest.
Among breast cancer patients, 10-20 % have triple-negative breast tumors (TNBC) and bear the worst prognosis due to the lack of targetable proteins: ER, PR, and Her2. CD73 is a nucleotidase, which converts AMP to adenosine and involved in many processes, such as promotion of cancer cell proliferation, migration and tumor immunoescape. We and others have shown previously that TNBC patients with low tumor TLR9 expression had significantly worse breast cancer-specific survival, as compared with TNBC patients whose tumors had high TLR9 expression upon diagnosis. TLR9 and CD73 expression have demonstrated mutual regulation in immune cells in certain disease conditions, such as diabetes. However, the mutual relationship of these proteins has not been investigated in cancer. The aim of this study was to investigate whether CD73 and TLR9 have mutual effects in TNBC.
The effect of hypoxia (1% O2) on viability and migration of murine 4T1 control and CD73 shRNA murine tumor cells was analyzed with WST-8 and scratch wound experiments. CD73, four adenosine receptors and TLR9 gene expressions was studied with qPCR. Immunofluorescence was used to study TLR9 localization and actin organization. Additionally, expression of TLR9 and cytoskeletal proteins involved in cell migration, such as paxillin, vimentin and cofilin was determined by Western blotting.
In the present study, we show that CD73 suppression induces significant inhibition on cell viability and migration. Lower CD73 gene expression correlated with increased TLR9 mRNA levels in normoxia. On other hand, there was no significant correlation of CD73 and TLR9 on protein level in hypoxic conditions. Cytoskeletal proteins vimentin, cofilin and paxillin had lower protein expression in the CD73 shRNA cells compared to the control shRNA cells in normoxia, but not in hypoxia. Additionally, CD73 shRNA cells showed morphological changes and had less cell protrusions.
The data indicate that hypoxia upregulates TLR9 mRNA expression, but does not affect CD73 or cytoskeletal proteins expression. In addition, CD73 might promote migration and viability of cancer cells. Our findings suggest a CD73-TLR9 dependent pathway.
University of Turku.
Jane and Aatos Erkko Foundation.
All authors have declared no conflicts of interest.
Controlling nutritional status (CONUT), as an index to measure a patient’s nutritional condition, was found to be correlated with outcomes of various cancers. However, its prognostic role in breast cancer patients with curative resection remains unclear. Hence the present study was designed to determine the correlation between CONUT and prognosis in resected breast cancer patients.
A total of 861 breast cancer patients with surgical resection in West China Hospital of Sichuan University between 2007 and 2010 were included in the present study. CONUT was retrospectively evaluated for each patient, and its relationship with various clinicopathological factors and breast cancer prognosis were further evaluated.
When the receiver operating characteristic (ROC) curve analysis was performed, CONUT had a higher area under the ROC curve (AUC) for the prediction of 5-year disease free survival (DFS) and overall survival (OS) compared with the neutrophil lymphocyte ratio (NLR) and prognostic nutritional index (PNI). Besids, the optimal cutoff value for CONUT to predict the 5-year survival was 3. Moreover, high CONUT was significantly correlated with older age, lymph node involvement, advanced T-stage and surgery type. In the multivariate analysis, CONUT-high patients had significantly poorer DFS and OS, when compared with CONUT-low patients. In the subgroup analysis, high CONUT was still an independent prognostic factor for poor DFS and OS for all stages of breast cancer. In addition, these results continued to maintain its significance in the multivariable analysis for patients with luminal B tumors.
The preoperative CONUT is a simple and uesful marker for predicting long term outcomes in breast cancer patients after curative resection.
Qinghua Zhou.
Has not received any funding.
All authors have declared no conflicts of interest.
Male breast cancer (MBC) is a rare entity accounting for less than 1% of all malignancies in men. To date, little emphasis has been placed on the elucidation of serum protein alterations in male breast carcinogenesis, even though serum represents an attractive, non-invasive source for biomarker discovery.
In the present work, we employed two-dimensional gel electrophoresis (2-DE) separation and matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry analysis to detect differences in serum protein expression between MBC patients and healthy controls. The differential expression of selected proteins was confirmed by Western Blot analysis or Enzyme Linked Immunosorbent Assay (ELISA). Functional relationships analysis of the differentially expressed proteins was performed using the STRING v.10 database. The PANTHER database was used to reveal the molecular function and signaling pathway associated with each identified protein.
A panel of differentially expressed serum proteins has been identified in MBC patients compared to controls, including proteins involved in the regulation of the cell cycle (ANCHR, CDC7, PDIP2), in mitochondrial function (ALDH2, TFB1M, NDUAB), in lipid metabolism and transport (APOA1, APOA4, APOE, APOH), in apoptosis and immune response (CD5L, CLUS, CCL14, LFTY2), in transcription (SSX3, STAT3, ZN223, ZN266, ZN273, ZN624, ZKSC7, RNZ2), in invasion and metastasis (FETUA, K1C10, K1C9, VTNC, AX2R, RAB37), in estrogen synthesis (CYP19A1) and with other diverse biological roles (BCAT1, CRYAB, CERU, ERMP1, MLH3, PRP18, RET4, SAMP, SYT1). Concurrently, several proteins were detected only in the MBC group (ARPC4, MP2K4, ENC1, MMP27).
These findings provide new insight into the distinct clinicopathological features of MBC and indicate that select serum proteomic biomarkers might help improve MBC management.
Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
Has not received any funding.
F. Zagouri: Research and advisory grants: Novartis, Lilly, Pfizer. All other authors have declared no conflicts of interest.
The detection of circulating biomarkers by liquid biopsy is of great importance for early diagnosis and prognosis and, thus, can contribute to decreasing the mortality rate of women with breast cancer (BC). The high mortality of BC is related to the occurrence of metastasis, a process that is associated with angiogenesis. The angiogenic process, in turn, is related to the stimulation of pro-angiogenic factors (among them: Insulin-like Growth Factor 1 Receptor - IGF-1R; Hypoxia-Inducible Factors 1α - HIF-1α and Vascular Endothelial Growth Factor - VEGF) and inhibition of anti-angiogenic factors (such as Von Hippel-Lindau protein - VHL). In addition, the regulation of this neovascularization by epigenetic mechanisms involving microRNAs (miRs) is being investigated and, in BC, oncomiR-210 and the tumor suppressor microRNA-152 stand out in this process.
Plasma samples and tumor fragments were collected from women with BC, with benign breast conditions (BBC) and from healthy women (control). For analysis of microRNA expression, the complementary DNA synthesis was performed followed by real-time Polymerase Chain Reaction (qPCR). For the analysis of the expression of the target proteins, immunohistochemistry was then carried out. Values of p < 0.05 were considered significant.
In the plasma samples of women with BC, an increase in the expression of miR-210 and miR-152 was observed. As expected, our results also showed increased oncomiR-210 expression and decreased miR-152 in the fragments of BC. As potential prognostic markers, miR-210 was able to differentiate fragments of BC from good prognosis to poor prognosis. In addition, miR-152 was able to differentiate prognosis in plasma. Finally, it was found that the HIF-1α, IGF-1R and VEGF proteins showed increased expression in BC, whereas the VHL protein presented a decrease.
The increased expression of these microRNAs in liquid biopsy of women with BC is promising in the diagnosis and prognosis of this neoplasm, and makes them potential biomarkers for patients with BC. We also confirmed the oncogenic action of miR-210 and tumor suppression of miR-152 on breast cancer fragments validated by the expression of their target proteins.
LIMC - Laboratório de Investigação Molecular do Câncer da Faculdade de Medicina de São José do Rio Preto (FAMERP).
Fundação de Amparo a Pesquisa do Estado de São Paulo - FAPESP (Proc. nº 17/11807-3).
All authors have declared no conflicts of interest.
HER-2 is overexpressed in 20–30% of BC, indicating poor prognosis. RANKL/RANK pathway is implicated in HER-2(+) BC. The molecular mechanism and the potential dual targeting have been evaluated and showed promising results.
We used SKBR3, BT474, MCF7, MDA-MB-453 human BC cell lines. We examined the expression of RANK and RANKL using RT-PCR, Western-Blot and immunofluorescence. The interaction between RANK and HER-2 was detected using Proximity Ligation Assay (PLA) which enables the visualization of interacting proteins. NF-κB pathway activation was studied using Western-Blot. We used inhibitors of both pathways [trastuzumab (T), pertuzumab (P), denosumab (D)]. Cell viability and cell migration was evaluated using XTT and scratch assay, respectively.
Cell lines differentially express RANK and RANKL. RANK receptor dimerizes with HER-2. RANK/HER-2 dimer number depends on HER-2 expression (SKBR3: 5.4, BT474: 8.2, MCF7: 0.7, MDA-MB-453: 0.3). RANK/HER-2 dimers are decreased in the presence of the inhibitors D, T and P, while they are increased after RANKL (R) treatment in SKBR3 (m:5.4, D:1.2, T:1.9, DT:0.6, TP:1, DTP:0.4, R:11.8,) and BT474 (m:8.2, D:3.1, T:4.3, DT:0.7, TP:3.4, DTP:3.2, R:11.6). MCF7 and MDA-MB-453 do not correspond to inhibitors. The combination treatment of SKBR3 with the inhibitors further decreased NF-κB pathway activation compared to single targeting. SKBR3, after inhibitors treatment, also exhibit reduced cell proliferation (m:100%, D:84.7%, T:51.57%, DT:48.61%, R:111%) and lower metastatic potential (m:26.02%, D:33.56%, T:16.54%, DT:13.75%, R:32.36%) compared to mock cells (m) and increased values in RANKL presence. The combination treatment of SKBR3 with D and T has an advantage in functional proliferation assays compared to single targeting.
The results indicate a novel association between HER-2 and RANKL/RANK pathway that affects HER-2(+) BC growth. We also present data suggesting that the combination of HER-2 targeting and RANKL inhibition has therapeutic benefit and should be further tested for certain BC patients.
Michalis V. Karamouzis.
Has not received any funding.
All authors have declared no conflicts of interest.
Glucocorticoids (GC) are frequently used in the adjuvant treatment of breast cancer (BC). However, they develop numerous side effects including survival of resistant tumor subclones and promotion of metastasis. Biological response to GCs is mediated by glucocorticoid receptor (GR) regulating gene expression via transactivation (TA) associated with side effects of GC, and transrepression (TR), negative interaction between GR and transcription factors. The aims of this study were to investigate: 1) mechanisms of different GC treatment response in different BC cells subtypes; 2) effects of novel selective GR agonist Compound A (CpdA) on BC cells.
MCF-7, MDA-MB-231, MDA-MB-453 cell lines and their subclones with GR knockdown were used as model cells. Cells were treated with Dexamethasone (Dex) and CpdA. Effects on cell growth were evaluated by trypan blue exclusion analysis and by flow cytometry with PI staining. Migration and invasion were determined by the transwell assay. Gap junction entirety was measured by scrape-load dye transfer assay. Expression of TA/TR specific genes as well as 15 genes associated with epithelial–mesenchymal transition and metastasis of BC (ANXA1, CJUN, COL1A1, COX2, CSF1, FIBL1, ICAM1, IL-6, IL-8, iNOS, KLF4, MKP1, MMP9, RHOB, SK1) were evaluated by q-PCR.
Dex and CpdA induced GR-mediated G1-phase arrest and suppressed cell proliferation by 50-70% in BC cells. CpdA shifted GR function towards therapeutically important TR. CpdA as opposed to Dex did not lead to loss of gap junctions. CpdA had a favorable therapeutic effect on 9/15 genes in luminal and 7/15 genes in HER2+ BC cells, down-regulating several mesenchymal markers associated with poor prognosis, in particular, on ANXA1, CJUN, ICAM1, IL-6, IL-8, iNOS, KLF4, RHOB, SK1 in luminal BC cells and on COL1A1, CJUN, COX2, IL-8, MMP9, RHOB, SK1 in HER2+ BC cells.
Dex has stimulated cell motility and migration potential of all BC cells types, the most therapeutically unfavorable effect on metastasis promotion was observed for triple negative BC cells. CpdA keeps all benefits of GC with no effects on TA and migration potential of BC cells.
N.N. Blokhin Medical Research Center of Oncology.
Russian Science Foundation No.17-75-20124.
All authors have declared no conflicts of interest.
Therapies targeting HER2 amplification are a success of modern oncology, yet resistance to these agents remains a major challenge. For example, the mertansine- (DM1-) armed antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla) extends the survival of HER2-positive metastatic breast cancer patients after failure of prior trastuzumab-based therapy. However, T-DM1 provides objective responses in less than half of patients and its effectiveness is limited by both acquired and intrinsic resistance.
We employed whole-genome CRISPR knockout screens using the GeCKOv2 sgRNA library in two trastuzumab-refractory breast cancer cell lines (MDA-MB-361 and MDA-MB-453) to identify and characterise genomic modifiers of sensitivity to T-DM1 and free DM1 in vitro. Genome-scale knockout libraries developed resistance to T-DM1 and DM1 after eight and thirteen weeks of escalating drug treatment, respectively. Positive and negative selection screen hits were identified by sequencing and bioinformatics analysis using MaGECK and PinAPL-Py. In parallel, we undertook RNA sequencing analysis of the DM1 and T-DM1 resistant cells to identify transcriptional adaptations to therapy.
Fourteen genes, highly enriched for positive or negative selection after T-DM1 or DM1 treatment, were selected to assess the impact of individual knockout on T-DM1 sensitivity. This confirmed the role of the putative lysosomal DM1 transporter SLC46A3, in T-DM1 resistance, and identified a set of genes potentially involved in T-DM1 activity. This study revealed consistent changes for both drugs with the genes involved in mitosis and cell cycle regulation highly overrepresented among differentially expressed transcripts. Adaptation to T-DM1 alone involved upregulation of genes related to proteolysis, acidification of vacuoles, intracellular trafficking of vesicles and maturation of lysosomes.
A panel of 550 candidate genes from both the genome-wide knockout screen and transcriptomic profiling informed the generation of a custom sgRNA library for secondary in vitro and in vivo validation screens. Finally, the predictive utility of these genes is being explored in clinical datasets.
The University of Auckland.
Roche.
All authors have declared no conflicts of interest.
We aimed to evaluate the role of breastfeeding as a risk factor of IBC compared to non-IBC and according to hormonal (HR) and human epidermal growth factors receptors (HER2) receptor status.
Cases of IBC (n = 160) and controls of non-IBC (n = 580) were collected from the cohort of breast cancer patients treated in two oncology centers 1:1 matched on the basis of age at cohort entry (+-2 years). Data about breastfeeding were collected, association and odds ratios were calculated. Breastfeeding was also evaluated in 3 further sub-groups: (HR+, HER2-), (HER2+, HR-) and triple negative (TN) patients.
Breastfeeding rate was similar between IBC and non-IBC patients (62% vs 65.3%, p = 0.57). However, breast feeding duration>12months was significantly more common in IBC vs non-IBC (30% vs 8.4%, p = 0.01). This observation was also confirmed in HR positive (32.5% vs 9.2%, p < 0.01) and HER2 positive (35.8% vs 6.35%, p < 0.01) but not in TN groups (24.3 vs 10.7, p = 0,06). We did not observe an association between breast feeding and occurrence of IBC, with an odds ratio of 1.1 [95% confidence interval (CI) 0.7-1.8], neither among HR+, HER2+ and TN groups. Odds ratio for developing IBC in breast feeding duration>12 months relative to shorter duration was 4.6 [2.9-7.2]. In HR+ tumors, it was 3.5 [1.5-8.1], and in HER2+ it was 5.7 [3-10.7]. However in TN tumors, odds ratio was not significant (2.6 [0.9-7.4]).
Patients with breastfeeding duration>12 months, were 4.6 times more likely to develop IBC compared to non IBC. This risk became 3.5 times in HR+ and 5.7 times in HER2.This observation was not confirmed in TN tumors.
Abderrahmen Mami Hospital.
Has not received any funding.
All authors have declared no conflicts of interest.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking targeted therapy options. Novel therapies which also target chemotherapy-resistant cancer stem cells (CSCs) within tumors would lead to improved outcomes for TNBC patients. Breast CSCs can be defined by increased aldehyde dehydrogenase (ALDH) enzymatic activity. Recent evidence suggests that long non-coding RNAs (lncRNAs) contribute to CSC maintenance and are potential novel therapeutic targets.
To discover novel therapeutic targets for TNBC and CSCs we screened lncRNAs that are most enriched in TNBCs and breast CSCs for oncogenic activity. We used quantitative polymerase chain reaction (QPCR), cellular fractionization, flow cytometry, antisense oligonucleotides and mammosphere formation assays to assess lncRNA function and targetability in TNBC cell lines and a patient-derived xenograft.
We identified prostate androgen regulated transcript 1(PART1) as enriched in both TNBCs and CSCs. PART1 is also associated with worse patient outcomes among basal-like breast cancer patients. Knockdown of PART1 decreased cell proliferation of TNBC cell lines HCC1806 and HCC1395, and reduced tumor growth of HCC1806 cells. Cellular fractionization revealed that PART1 is predominately located in the cytoplasm, consistent with potential function as a miRNA sponge. Targeting PART1 with antisense oligonucleotides in a PDX and in the HCC1806 cell line resulted in a decrease in mammosphere forming potential. This suggests that PART1 may contribute to CSC maintenance and could be targeted to reduce CSC numbers in tumors.
PART1 is of interest as a novel therapeutic target for TNBCs and CSCs. Further analysis will focus on investigating its potential function as a miRNA sponge in breast cancer.
The authors.
Canadian Institutes of Health Research Dalhousie University (Killam Award) Cancer Research Trainee Program.
All authors have declared no conflicts of interest.
Triple negative breast cancer (TNBC) is an aggressive subtype of with ill-defined therapeutic targets. Androgen receptor (AR) expression ranged from 32-53% in different reports presenting emerging biomarker in TNBC. Tumor-infiltrating lymphocytes (TIL) play an important prognostic and predictive value in TNBC. The relationship between AR, TIL and clinical behavior is still not fully understood.
Thirty-six TNBC patients were retrospectively selected from a cohort of 800 patients diagnosed in 2012. Clinico-demographic data were collected. Formalin-fixed, paraffin embedded tissue specimens were evaluated for AR (+ ve if ≥ 1% expression), CD3, CD20, CD4, CD8 with IHC. Stromal TIL were quantified following the TIL Working Group recommendations. Lymphocyte-predominant breast cancer (LPBC) are defined as stromal TILs of ≥ 50%.
The mean age was 52.5 years and 27.8% were ≥60 years. The majority of patients (58.3%) were invasive duct carcinoma (IDC), while IDC with medullary features and invasive lobular carcinoma were 22% and 14% respectively. Grade III tumors were 52.8%. Stage III, IV were 54.3%, 8.6% respectively and N+ve were 77%. Seven patients of the total (19.4%) were AR+ve. TIL were assessed in 31 patients where LPBC was 32.3%. Median TIL was 15% and 33% (p = 0.07) and CD20 was 7% and 18% (p = 0.01) in AR+ve and AR-ve respectively. Mean CD3 was 93.3% and 80.6% (p = 0.007) and CD8 was 80.8% and 75% (p = 0.41) in AR+ve and AR-ve respectively. Majority of patients ≥60 years (66.7%) were lymphocyte deficient (TIL˂50%). CD8 was significantly lower in stage III/IV vs I/II (p = 0.04). LPBC type was significantly lower in N+ve vs N-ve patients (p = 0.03). Significant positive correlation presented between CD8 and CD3 (p˂0.001) while significant negative correlation presented between CD20 and CD3 (p = 0.03) and CD4 and CD8 (p = 0.04). Non statistically significant increased median OS in AR+ve vs AR-ve (44 vs 40 months, p = 0.84).
The present study show that T cell marker (CD3) was more predominant in AR+ve TNBC. Older patients and N+ve were lymphocyte deficient (TIL˂50%). More studies are needed to focus on the clinical impact of the relation between AR and TIL in TNBC.
Hagar Elghazawy.
Has not received any funding.
All authors have declared no conflicts of interest.
Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer with elevated metastatic potential, characterized by the frequent presence of tumor emboli in dermal and parenchymal lymph vessels. This study examines the role of TGFβ signaling in the molecular biology of IBC.
TGFβ1 induced cell motility (i.e. xCELLigence, wound healing assays) and gene expression (RNA sequencing) were investigated in a panel of three IBC and three subtype-matched nIBC cell lines. In addition, a series of tissue samples from 75 and 135patients with and without IBC was investigated for nuclear expression of total SMAD2, SMAD3 and SMAD4 using immunohistochemistry. SMAD protein expression data were related to gene expression data from patients with available Affymetrix HGU133plus2 profiles.
TGFβ1-induced cell motility was strongly abrogated in all IBC cells (P = 0.003), independent of their molecular subtype. Genes differentially expressed between IBC and nIBC cells post 4 hours of TGFβ1 revealed attenuated expression of SMAD3 transcriptional regulators with concomitant overexpression of MYC target genes in IBC. IBC patient samplesdemonstrated a near absence of nuclear SMAD3 expression in the primary tumors from (P < 0.001) and a further reduction of SMAD3 staining intensity was observed in tumor emboli (P = 0.019). Integration of gene and protein expressiondata revealed that a substantial fraction of the IBC signature genes correlated with SMAD3 and these genes (i.e. 21/24; P < 0.001) are indicative of attenuated SMAD3 signaling in IBC.
We demonstrate that IBC cells are characterized by attenuated SMAD3 protein expression and transcriptional activity, leading to obliteration of the cell motility inducing capacity of TGFβ1. Recent studies revealed that SMAD3 is essential for TGFβ1 induced cell motility through induction of epithelial to mesenchymal transition (EMT). This study suggests that in the absence of SMAD3 expression, a partial EMT is induced leading to collectively invading cancer cells that are gifted with a high metastatic potential, thereby providing an intriguing explanatory model of the biology of tumor emboli in IBC.
University of Antwerp.
Kom Op Tegen kanker - Emmanuel Van der Schueren.
All authors have declared no conflicts of interest.
The beta-2 adrenergic receptor (ADRB2) drives tumor proliferation and induces treatment resistance in preclinical models of HER2+ breast cancer. This study aimed to evaluate the predictive and prognostic role of ADRB2 expression as a biomarker in HER2+ breast cancer patients.
ADRB2 expression was retrieved from 2 datasets comprising gene expression data of HER2+ early breast cancer patients: 1 dataset included patients who did not receive systemic treatment to assess disease-free survival (DFS; N = 175) and 1 dataset included patients who received neoadjuvant treatment to assess pathologic complete response (pCR; N = 207). Survival was estimated with the Kaplan Meier method and the Cox regression model was used for uni-multivariate analyses. The correlation of ADRB2 expression with gene signatures related to proliferation, invasiveness, immune activation and angiogenesis was performed.
High ADRB2 expression was associated with improved DFS (HR 0.52, 95% confidence interval [CI] 0.32–0.84, p = 0.0068), with a more pronounced impact in HER2+/ER+ patients (HR 0.45, 95%CI 0.24-0.84, p = 0.0097). No association between ADRB2 expression and pCR was observed (OR 1.14, 95%CI 0.63–2.10, p = 0.67). ADRB2 expression was associated with a low expression of angiogenesis-related genes (VEGF -0.21, p = 0.006) and a high expression of genes related to immune activation (Perez +0.41, p < 0.001; STAT1 +0.30, p = 0.014; IRM +0.28, p = 0.017).
Opposing our hypothesis, ADRB2 high expression was a positive prognostic factor in HER2+ early breast cancer. The low expression of angiogenesis-related and the high expression of immune-related genes associated with ADRB2 expression may justify our findings.
Institut Jules Bordet.
Has not received any funding.
R.C. Bitton: Speaker-honoraria: Boehringer Ingelheim, Janssen; Travel grants: AstraZeneca. C. Sotiriou: Patents on gene expression and methylation signatures; Advisory boards, speaker, travel support for medical meetings: Amgen, Astellas, AstraZeneca, Bayer, Celgene, NanoString Technologies, Novartis, Pfizer, Roche. E. de Azambuja: Honoraria, research grant (to the institution): Roche-Genentech; Travel grants outside the submitted work: Roche-Genentech, GlaxoSmithKline. All other authors have declared no conflicts of interest.
Glycogen-rich clear cell carcinoma of the breast (GRCCC) is an uncommon variant of invasive breast cancer with abundant tumor-cell glycogen and thought to have poor outcome. There are conflicting reports on the prognosis of GRCCC and its pathologic/diagnostic criteria. Some features overlap with carcinomas having hepatoid features. We hypothesize that immunomarkers of hepatic differentiation may help distinguish GRCCC from more common breast cancers.
As approved by the institutional research ethics board, cases diagnosed as “glycogen-rich clear cell carcinoma” or “invasive carcinoma with clear cell features” were identified from lab archives. A control cohort of non-GRCCC cases was also identified. All diagnoses were confirmed by pathologist review. Tumor grade, size, and ER/PgR/HER2 status were recorded. Freshly cut 4-μm sections from FFPE tumor blocks were mounted on charged slides and immunostained with Hep Par 1, alpha-fetoprotein (AFP) and GATA3 using standard clinical protocols. Stains were reviewed by 2 pathologists (MCC, JMW).
Eight cases had "clear cell features", and 5/8 met all WHO morphologic criteria for GRCCC (high-grade nuclei, polygonal cells, PAS-positive granules/globules). All GRCCCs had weak to moderate ER staining in 33- 66% of cells, were negative for PgR and HER2, and were positive for Hep Par 1 with a diffuse, strong granular cytoplasmic pattern. GRCCCs were also positive for GATA3 and negative for AFP. The remaining 3 cases “with clear cell features” had grade 2 nuclei, were GATA3-positive, had >90% strong positivity for ER and PgR, and were negative for HER2, Hep Par1 and AFP. The control cohort included 16 “luminal-like” (ER+/HER2 -), 21 HER2+, and 24 triple-negative tumors (total N = 61). GATA3 was positive in 51/61 (84%) of tumors. All tumors in the control cohort were negative for Hep Par 1 and AFP.
True GRCCC of the breast is likely a distinct high-grade tumor with strong granular-cytoplasmic Hep Par 1 staining. GRCCCs tend to be PgR and HER2-negative, and demonstrate weak-to-moderate ER positivity. Criteria for GRCCC should be applied strictly to exclude other tumors with “clear cell features”. Further work is warranted to establish the prognostic significance of this diagnosis.
Martin C. Chang.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer treatment often involves the use of paclitaxel to target tumor cells; however, some patients do not respond to treatment and would be better treated with an alternative drug. Thus, being able to identify the genes which when expressed in a tumor predict paclitaxel response prior to administration would improve treatment efficacy and patient survival.
A genome-wide RNAi screen was performed with MDA-MB-231 tumor xenografts in female NOD/SCID mice. This allowed the identification of enriched and depleted shRNA sequences that theoretically target paclitaxel sensitivity and resistance genes, respectively. The screen identified 40 potential novel paclitaxel response genes in breast cancer.
We generated individual knockdowns of the top screen-identified sensitivity and resistance genes in MDA-MB-231 cells and orthotopically implanted the knockdowns or control clones in the mammary fat pads of NOD/SCID female mice. The resulting tumor bearing mice were treated systemically with either paclitaxel or phosphate-buffered saline. Paclitaxel inhibited the growth of the MDA-MB-231 control clone tumors but did not significantly affect the growth of the paclitaxel sensitivity knockdown clone tumors. This validates the role of the screen-identified gene as a novel paclitaxel sensitivity mediator. In contrast, knockdown of the screen-identified resistance gene caused more regression in paclitaxel treated mice validating its role as a novel paclitaxel resistance mediator. In vitro mechanism studies revealed that both genes affect paclitaxel treatment outcome through effects on cell cycle progression. Additionally, a gene signature derived from the screen hits achieved 82-85% accuracy in predicting breast cancer patient outcomes to paclitaxel-containing treatment regimens across multiple patient tumor gene expression data sets.
A genome-wide RNAi screen has identified novel mediators of paclitaxel response in breast cancer, which also predict patient response to paclitaxel treatment. Additional experiments will enhance the accuracy of the genetic profile and identify breast cancer patients who would most benefit from paclitaxel treatment.
Paola Marcato.
CIHR, NSHRF and BHCRI.
All authors have declared no conflicts of interest.
The adipokine resistin is linked to insulin resistance and has been shown to be upregulated in breast cancer patients. Previously we demonstrated that high levels of newly identified resistin receptor Adenylate Cyclase-Associated Protein-1 (CAP1) in breast tumors was associated with impaired prognosis. We here aim to delineate the molecular linkage between resistin, CAP1 and breast cancer prognosis.
In estrogen receptor (ER)-positive T47D and ER-negative MDA-MB-231 breast cancer cells, CAP1 expression was silenced by 80-90% using small interfering RNA. Functional effects of reduced CAP1 expression and resistin exposure on cell proliferation, colony formation, and signaling pathways were subsequently investigated.
Initial experiments showed that CAP1 knock down resulted in reduced proliferation of both ER-positive T47D and ER-negative MDA-MB-231 cells by approximately 35 and 40%, respectively, P < 0.0001. CAP1 knock down further decreased the colony formation of T47D and MDA-MB-231 cells by 15 and 20%, respectively, compared with control. Resistin-stimulated T47D cells displayed increased CAP1 and STAT3 protein expression. Resistin exposure induced STAT3 activation in MDA-MB-231 cells, which was reduced following CAP1 knock down.
These results indicate that CAP1 is mechanistically important for both ER-positive and ER-negative breast cancer cell proliferation, supporting our earlier clinical results. This could be mediated by the putative resistin-CAP1-STAT3 signaling pathway. Further clinical and experimental studies are ongoing to elucidate the role of resistin-CAP1 in breast cancer prognosis. These studies could provide a biological insight into how factors contributing to obesity and insulin resistance could impact breast cancer.
Lund University.
Swedish Cancer Society, the Swedish Research Council, the Governmental Funding of Clinical Research within the National Health Service (ALF), the Lund University Hospital Fund, the Swedish Breast Cancer Group (BRO), the Albert Pahlsson Foundation, the Mrs. Berta Kamprad Foundation, the Gyllenstienska Krapperup Foundation and the Royal Physiographic Society in Lund.
All authors have declared no conflicts of interest.
Neoadjuvant chemotherapy (NAC) is intensively used for the treatment of locally advanced breast cancer (BC). The aim of this study is to provide a better insight into BC response to neoadjuvant anthracycline based chemotherapy.
Genome-wide methylation analysis of 27 BC biopsy specimens of the luminal B subtype taken before the treatment was performed using the XmaI-RRBS method. Methylation status of the selected markers was next determined by methylation sensitive restriction enzyme PCR in a validating sample of 40 BC biopsy specimens.
By XmaI-RRBS we have identified 10 genes the states of methylation of which most effectively mark BC luminal B sensitivity to anthracycline based NAC. For locus specific assessment of these markers we have developed a multi-locus methylation sensitive PCR system. Based on the methylotyping results obtained for the 40 samples of the validating cohort, the diagnostic properties of the system were estimated: the area under the ROC curve was 84%, with the sensitivity of 82% and the specificity of 80%.
The system including a limited number of methylation markers makes it possible to effectively predict the response of luminal B subtype BC to anthracycline based NAC by an analysis of biopsy material obtained before the treatment. Reasonable diagnostic sensitivity and specificity values are achieved only when the markers are evaluated in complex; in separate the differences in gene methylation frequencies between responding and non-responding tumors may be negligible (Table).
Methylation frequencies of selected genes in tumors responding and not responding to anthracycline based NACGene Responders, % Non-responders, % SLC9A3 28 (7/25) 27 (4/15) C1QL2 20 (5/25) 13 (2/15) DPYS 60 (15/25) 47 (7/15) IRF4 72 (18/25) 33 (5/15) ADCY8 64 (16/25) 40 (6/15) KCNQ2 48 (12/25) 40 (6/15) TERT 80 (20/25) 60 (9/15) SYNDIG1 20 (5/25) 20 (3/15) SKOR2 56 (14/25) 67 (10/15) GRIK1 84 (21/25) 87 (13/15)
Research Centre for Medical Genetics.
Russian Science Foundation (project No.18-15-00430).
All authors have declared no conflicts of interest.
The function of DNA primase is to synthesize the small RNA primers for Okazaki fragments generated during discontinuous DNA replication. This primase is required because DNA polymerases cannot initiate RNA polymer synthesis and they can elongate polymers only using RNA polymers that have already been synthesized. Eukaryotic cells contain PRIM1 and PRIM2 subunits of nuclear DNA primase. PRIM1 is the smallest subunit of the heterotetrameric eukaryotic Pol alpha/primase complex. It alone carries the catalytic function of the enzyme and can elongate primers, whereas PRIM2 does not exert such enzymatic activity.
The methods in this study include: real-time quantitative PCR, cell proliferation and viability assays, DNA synthesis analysis, western blotting, wound-healing cell migration and invasion assay, animal experiments, immunohistochemistry, and chromatin immunoprecipitation assay.
Our results show that PRIM1 mRNA is highly expressed in human breast tumor tissues, particular in poorly differentiated tumor tissues. In the cell model, higher PRIM1 protein expression was detected in ER+ breast cancer cell lines (BT483, BT474, and MCF-7) than in normal breast cell lines (MCF-10A). Stable expression of PRIM1-siRNA in the ER+ BT-474 cells-xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti-tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT-474-xenografted tumor growth volume compared with control (n = 5 per group, *p < 0.05).
This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose.
Li-Ching Chen.
Has not received any funding.
All authors have declared no conflicts of interest.
Great advances have been made in the molecular characterisation of advanced breast cancer (ABC). Still, clinical practice has not changed in terms of assessment of response to therapy. Radiologic imaging and clinical examination help determine disease burden and treatment efficacy. However, imaging heavily relies on the expertise of the radiologist and oncologist and has high intra- and inter-reader variability. Circulating tumor cells (CTCs) enumeration with CellSearchâ has confirmed independent prognostic value compared to conventional radiology and serum markers such as CA15-3. Similarly, quantification of circulating tumor DNA (ctDNA) has also prognostic value in ABC. ctDNA analysis further provides critical information on the mutational status of specific genes which can predict sensitivity to specific targeted therapeutics.
The SCAN-B-rec (NCT03758976) is a prospective multi-center observational study that aims to explore the value provided by ctDNA analysis to determine treatment efficacy when compared to CTCs and conventional radiological imaging in a “real-world” setting. A total of 350 patients with pathologically-confirmed ABC will be recruited. Plasma ctDNA will be extracted and analysed before treatment start (T0) and after three months of therapy (T1). The relative change in mutant allele frequency (MAF) between these two time-points will be calculated. Response to treatment will be defined using pre-specified cut-offs. A comparison with response to treatment according to conventional radiological imaging (RECIST criteria) and CTC enumeration at the same time points will be performed. The primary objective is to establish the prognostic value of ctDNA to predict overall survival. The study will also explore the added value provided by ctDNA mutational analysis to determine biomarkers of sensitivity and resistance to targeted therapeutics approved to treat ABC or other solid tumors that could be used “off-label”. We expect that ctDNA quantification will give a more accurate read-out of treatment response, providing better prognostic information in ABC as well as information on drug sensitivity/resistance in a large proportion of ABC patients.
SCAN-B-rec (NCT03758976).
Lund University Hospital (Region Skane).
BioCARE, Cancer Fonden, ALF (Region Skåne) and Svenska Läkaresällskapet.
A. Bosch: Advisory board meetings: Pfizer, Novartis in Sweden. These have been non-remunarated. L. Saal: CEO: AGA Diagnostics. All other authors have declared no conflicts of interest.
Hormone-receptor (HR) positive, HER2-negative breast cancers make up about 60 % of the primary tumors. For these patients with 0 or up to 3 positive lymph nodes, the indication for chemotherapy is based on an accurate risk stratification. In this situation, conventional clinicopathological parameters are often not suitable for selecting those patients who would not benefit from adjuvant chemotherapy. The EndoPredict test combines a molecular signature with clinical risk factors such as tumor size and nodal status and stratifies patients into “low” or “high” risk groups and thereby improves decision-making. The EndoPredict test can predict the 10-year risk of distant metastases in patients with HR+/HER2- primary breast cancer with endocrine treatment (Evidence level I-B).
Patients with HR+/HER2- primary invasive breast cancer stage I/II and T1 to T3 with 0 to 3 positive lymph nodes and an EndoPredict test within six months prior to inclusion are eligible. Primary objective is to show that patients tested as “low risk” by EndoPredict and treated with adjuvant endocrine therapy alone for at least 5 years have a 10-year distant metastasis-free survival of > 90 %. Secondary endpoints include distant metastasis-free survival, disease-free survival and overall survival in patients with EPclin “low” vs “high” risk. Also, the proportion of patients whose treatment was concordant and non-concordant with EndoPredict test results, will be analyzed for survival. The prognostic performance of classical prognostic factors with respect to survival will also be assessed. Patients will be evaluated annually for 10 years regarding treatment compliance, recurrence, metastases, and survival. Start of accrual was in July 2018. At least 35 sites in Germany and one site in Switzerland will be active. Current data on enrollment will be reported. Survival data of patients who have been tested with EndoPredict are systematically assessed to prospectively prove that patients with a low risk classification by EndoPredict can safely forgo chemotherapy and be treated with endocrine therapy alone.
NOGGO-B3 [18.12.2017].
North-Eastern German Society for Gynaecological Oncology e.V. (NOGGO e.V.).
Myriad Service GmbH.
C. Denkert: Patent holder: EP18209672 Patent application; Consulting fees: Fa, Teva, Novarits, Pfizer, Roche, Amgen, MSD, Daiichi, Celgene, AstraZeneca; Ownership interests: Sividon Diagnostics. M. Untch: Consulting fees: Linde. M. Kiechle: Speakers honorarium: Myriad, January 2018. All other authors have declared no conflicts of interest.
Somatic mutations in HER2 (ERBB2), in the absence of HER2 amplification, are oncogenic and occur in ∼3% to 5% of solid tumors. HER-Seq (PUMA-NER-9501; ClinicalTrials.gov NCT03786107) is an international genomic screening study for the identification of patients with HER2-mutant breast or cervical cancer, who may be eligible for neratinib clinical trials. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has reported clinical activity in HER2-mutant cancers, with the greatest efficacy observed in breast and cervical cancer. The ongoing Phase II SUMMIT trial for HER2-mutant cancers examines the safety and efficacy of neratinib as monotherapy or in combination (ClinicalTrials.gov NCT01953926; EudraCT 2013-002872-42). Identification of somatic HER2 mutations using a rapid and minimally-invasive test offers a novel therapeutic opportunity for this rare molecular cancer subtype.
Patients with histologically-confirmed metastatic breast cancer (MBC) or metastatic cervical cancer (MCC) on active treatment or in follow-up, may be enrolled. Blood samples are collected for circulating tumor DNA (ctDNA) analysis at 3–6-month intervals (coincident with scheduled patient visits). Samples are sequenced centrally for the detection of somatic HER2 mutations, using a custom targeted next-generation sequencing (NGS) assay. Patients found to have a mutation in HER2 are then eligible to screen for therapeutic studies with neratinib. Eligible patients are ≥18 years of age with histologically-confirmed MBC or MCC, an ECOG status of 0–2, and are able to provide blood samples. Excluded are patients with known HER2-positive/HER2-amplified MBC, or those who have previously received neratinib.
Lee Miller (Miller Medical Communications Ltd).
NCT03786107.
Puma Biotechnology Inc.
Puma Biotechnology Inc.
L.M. Smyth: Consulting or advisory role: Roche Genentech, AstraZenaca; Research funding (Inst): Puma Biotechnology, AstraZeneca, Roche Genentech; Travel, accommodations, expenses: Pfizer; Honoraria: Pfizer, AstraZeneca. C. Saura: Consulting fees: Puma Biotechnology Inc. V. Boni: Consulting/advisory board: Loxo therapeutics, Ideya. L. Eli, S.J. Garza: Employee: Puma Biotechnology Inc. A.S. Lalani: Employee, shareholder: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.
Brain metastases form a challenge in breast cancer patients, especially in HER2+ patients whose peripheral metastases can often be controlled using standard-of-care HER2 regimens, but with relapse or progression in the brain. This determines survival for such patients. Penetration in brain lesions as well as the therapeutic outcome can be hampered due to the particular tumour microenvironment. The here used anti-HER2 agent is a single-domain antibody or nanobody that targets HER2 with nanomolar affinity but with a size that is ten-fold smaller than conventional antibodies. This could be an important factor in diagnostic and even therapeutic efficacy for nanobody radiopharmaceuticals. The 68Ga-anti-HER2 VHH1 has been successfully tested in phase I trial in 20 breast cancer patients, confirming safety and tolerability, low irradiation burden for PET/CT procedures and high uptake in HER2-positive lesions. The aim of the current study is to test its application potential for PET/CT imaging of breast cancer brain metastases. If favourable, this would support the development therapeutic analogues for targeted radionuclide therapy.
This is an open label non-randomized monocenter phase II trial in breast cancer patients with brain metastasis, investigating the uptake of the radiopharmaceutical 68Ga-anti-HER2 VHH1 in brain metastasis using PET/CT imaging. To evaluate the specificity of uptake, both HER2-positive and HER2-negative patients are eligible. The tumor targeting potential in brain metastases and other known lesions will be visually scored and quantified by an experienced nuclear medicine physician, unaware of the HER2-status. HER2 amplification will be reassessed on blood-derived cell-free DNA. A total of 30 patients (10 HER2-neg, 20 HER2-pos) will be included. The most important inclusion criteria are (i) presence of at least 1 brain metastasis of at least 8 mm, measured either on CT or MRI; (ii) minimal age 18 years old; (iii) informed consent given. Trial is in progress, with 3 HER2-postive and 1 HER2-negative patients enrolled so far.
EudraCT 2015-002328-24, NCT03331601.
UZ Brussel.
Scientific fund W. Gepts UZ Brussel, IWT-TBM, Kom Op tegen Kanker (stand up against cancer).
M. Keyaerts: Travel and accomodation: Bayer; Research funding: Camel-IDS. C. Xavier: Patents on nanobody imaging and therapy. M. Vanhoeij: Research funding: Etherna. V. Caveliers: Research funding: Camel-IDS, IBA. T. Lahoutte: Co-founder, employee: Camel-IDS; Honoraria: Camel-IDS, IBA, Institut des Radioéléments (IRE). All other authors have declared no conflicts of interest.
Observational studies suggest that cholesterol-lowering medication (CLM) use is associated with longer recurrence-free survival in breast cancer patients. Since 2007, aromatase inhibitors (AIs) have been guideline treatment for estrogen receptor positive (ER+) postmenopausal breast cancer. AI therapy is associated with increased cholesterol levels. We investigated the association of CLM use and breast cancer recurrence rate in patients treated with AIs.
This cohort included all women diagnosed with stage I-III ER+ breast cancer from 2007-2016, treated with AI in the adjuvant setting, and registered in the Danish Breast Cancer Group database. We ascertained incident CLM exposure (≥1 prescription post-diagnosis) from the Danish National Prescription Registry and modelled CLM as a time-varying exposure lagged by 6 months. Follow-up began 6 months after diagnosis and continued to the first event of recurrence, death, emigration, 10 years or 25th September 2018. We estimated recurrence rates, and crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing CLM exposure with non-exposure.
We enrolled 12,947 eligible patients. Median follow-up was 4.6 years. During follow-up, the total person-years of the unexposed group was 56,171 (incidence rate per 1,000 person-years: 11.50 [95% CI: 10.63–12.42]) and 5,246 in the CLM exposed group (incidence rate per 1,000 person-years: 12.20 [95% CI: 9.40–15.58]). There was little evidence of a protective effect of CLM on breast cancer recurrence during total follow-up but some evidence during the first 5 years (Table).
CLM use was not associated with a substantially reduced risk of breast cancer recurrence among AI users.
Aarhus University Hospital.
Jeppe Juhl Stiftelsen.
All authors have declared no conflicts of interest.
No. of recurrences (person-years) Incidence rate per 1,000 person-years (95% CI) Crude HR (95% CI) Adjusted HR (95% CI) Recurrence during total follow-up Not CLM exposed 646 (56,171) 11.50 (10.63 - 12.42) (ref) (ref) CLM exposed 64 (5,246) 12.20 (9.40 - 15.58) 0.84 (0.46 - 1.55) 0.90 (0.68 - 1.20) Recurrence during the first 5 years of follow-up Not CLM exposed 525 (46,590) 11.27 (10.33 - 12.28) (ref) (ref) CLM exposed 35 (3,290) 10.64 (7.41 - 14.80) 0.85 (0.60 - 1.20) 0.76 (0.52 - 1.12)
There is a growing body of evidence supporting the omission of adjuvant chemotherapy in a subset of estrogen receptor (ER) positive (+) / Her2 receptor negative (-) breast cancer patients. We assessed recent trends in the administration of adjuvant chemotherapy thereby evaluating the role of the 70-gene signature (70-GS) testing in decision-making in the systemic treatment of lymph node negative (N0) and lymph node positive (N+) breast cancer patients.
Patients with a national guideline directed indication for 70-GS use treated between 2013-2016 were selected from the Netherlands Cancer Registry (NCR). Time trends in the administration of adjuvant chemotherapy were evaluated within guideline- and age delineated subgroups. The influence of the 70-GS on chemotherapy use was assessed with logistic regression.
During the study period, the overall administration of adjuvant chemotherapy decreased from 49% to 23%. For N0 patients, the decline in chemotherapy was independent of 70-GS use, whereas in N1a disease, the 70-GS was associated with a consistent lower proportion of patients receiving chemotherapy throughout the study period (OR 0.21 95% CI: 0.15-0.29). In patients <50 years and 50-59 years of age, the 70-GS use was associated with less chemotherapy administration and remained independently associated with less chemotherapy use after adjustment by multivariable logistic regression (OR 0.17, 95% CI: 0.13-0.23 and OR 0.53 95% CI: 0.43-0.65).
During a period that chemotherapy administration declined in ER+ breast cancer, the 70-GS contributed to the observed decrease in node positive disease and in younger patients. In N0 patients, the decline in chemotherapy use was independent of the 70-GS. A more selective use of gene-expression analyses is propagated.
Netherlands Comprehensive Cancer Organisation.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer (BrCa) patients with Li-Fraumeni Syndrome (LFS) require customized clinical care, mainly due to elevated lifetime cancer risks that these patients face, as well as the diagnosis of secondary, radio-induced neoplasms. Preclinical data have shown that TP53 deficient cells are at increased risk of malignant transformation in the setting of ionizing radiation. TP53 pathogenic variants are strongly associated with very early onset, frequently HER2-amplified BrCa diagnosis.
In total, thirteen patients fulling clinical criteria for LFS and previously referred to the Molecular Diagnostics Laboratory of NSCR ‘Demokritos’ from 2005 to 2016, carried a pathogenic TP53 variant. Of these, twelve and one had been diagnosed with BrCa as the first and second tumor event, respectively. Eight of these were treated with total mastectomy without postoperative radiotherapy, while five were treated with lumpectomy plus postoperative radiotherapy. A loco-regional relapse was defined as an ipsilateral relapse in either the breast or lymph node bearing areas (axillary, internal mammary, supra-clavicular) or both occurring since the date of the diagnosis. Distant disease was defined as BrCa recurrences that were not in the contralateral breast nor in loco-regional areas. Radio-induced malignancies were defined as malignancies occurring in the radiation area.
Of the five patients who received postoperative radiation, four had a secondary, non-metastatic cancer diagnosis, summarizing a total of six events and more specifically, three were contralateral BrCa, one was a local relapse and two malignancies in other sites, of which one was a radio-induced lung cancer, developed at the site of the radiation area. On the contrary, a single event occurred among patients initially treated with total mastectomy without receiving postoperative radiation.
These data highlight the necessity of TP53 genetic testing, especially in young women diagnosed with BrCa, prior to treatment decision and are in accordance with published clinical observations and favor the avoidance of postoperative radiotherapy in breast cancer patients with LFS.
Hellenic Academy for Oncology.
Has not received any funding.
All authors have declared no conflicts of interest.
Small node-negative breast cancers measuring less than 1 cm are generally associated with a favorable prognosis. Around 10% of these malignances exhibit human epidermal growth factor receptor 2 (HER2) overexpression and/or amplification. Patients with HER2+ tumors have a higher risk of recurrence. Several large retrospective reviews have reported a lower overall survival among HER2+ cases in the pT1a/b N0 patient group where adjuvant treatment was not given. In this retrospective study we looked at our institutional experience of using trastuzumab (Herceptin®) in early breast cancer, and how the outcomes compared to the same stage of HER2+ group not treated with Herceptin®, or HER2- group.
A retrospective review of 963 early breast cancer cases staged pT1a and pT1b N0 who underwent surgical treatment in 2009-2015.The data was collected using clinical electronic resources including Clinical Portal, TrakCare, ChemoCare and PACS. Statistical analysis comparing HER2+ and HER2- groups using an individualised pairwise matching was performed.
In total, 1045 cases of breast cancer treated in the Beatson Cancer Centre between 2009 and 2015 were analyzed. 82 patients were excluded from the analysis due to an upstaging. We had 4.4% of pT1/pT2 N0 breast cancers which were HER2 + (42 cases). We have matched HER2+ group with 42 cases from the HER2- group using age, tumor size, grade, hormonal status, adjuvant treatment and type of surgery, to allow a direct comparison. The recurrence rate was 2.3% in HER2- group compared to 6.8% in HER2+ group when Herceptin® was not given. From our small sample size of 42 HER2+ cases, 31% have received adjuvant Herceptin® and none of those patients had a recurrent disease with an average follow up of 5 years.
The risk of recurrent breast cancer after completion of standard radical treatment appears to be higher in HER2+ve cases even in early stage disease with tumor size less than 1 cm. In HER2+ve breast cancer staged pT1a/pT1b N0, adjuvant treatment with Herceptin® may reduce the risk of recurrence. The sample size is too small to draw any statistically significant conclusions but our data come in tune with the findings from the other trials.
Abdulla Alhasso.
Has not received any funding.
All authors have declared no conflicts of interest.
As a rare disease, knowledge about management of male breast cancer (male BC) is scarce but increasing in the last years. Still, according to RARECAREnet study, 5-year relative survival in Bulgarian male BC patients is 18% less than European mean. We look for potential reasons for this low survival rate; we also identify trends or gaps in the adjuvant (ADJ) management. Analysis of available data would lead to perception of the lack of knowledge about management of MBC and would identify areas for future improvement.
This is a retrospective population based study of all patients with male BC, diagnosed between 2002 and 2013 in Bulgaria. Clinicopathological features and treatment was obtained from the National Cancer Registry. We compare ADJ management in 2 time intervals: 2002-2007 and 2008-2013.
Data about the clinicopathological features of the patients with male BC are shown in Table. Indications for ADJ endocrine treatment (ET), chemotherapy (CHT) or radiotherapy (RT) were considered as per extrapolation for females with BC (Table). Clinicopathological features of patients with male BC, divided in two time intervals. For 2002-2007: Of all 70 nonmetastatic HR+ patients, 10 (14.3%) had ADJ ET; For 2008-2013: Of all 96 nonmetastatic HR+ patients, 36 had ADJ ET (37.5%). For 2002-2007: ADJ RT was delivered to 12 patients of all 70 N+ nonmetastatic male BC (17.1%) For 2008-2013: ADJ RT was delivered to 63 patients of all 94 N+ nonmetastatic male BC (67%) We consider that at least patients with HER+ male BC as well as stages T2-4N+M0 would be indicated for ADJ CHT (73 and 123 for both periods) whereas ADJ CHT was administered to only 9 and 48 patients respectively (12.3 and 39% respectively).
Despite the recommendations to treat male BC as BC in females, use of ADJ modalities, incl. ET, CHT or RT are still largely underused in male BC. There is though a clear trend towards improvement with the years. Data quality of reported cases is improving over time, as well as the staging, diagnosis and ADJ treatment. Despite this, In Bulgaria they remain largely suboptimal and improvement is urgently needed.
Assia Konsoulova.
Has not received any funding.
All authors have declared no conflicts of interest.
Time All pts Pts with known HR HR+ AnyTN,M0 known HER2 HER2+ T2-4 N+M0 known N AnyT, N+ M0 2002-2007 243 118 70 50 15 58 193 70 2008-2013 278 156 96 133 39 84 239 94
Decision-making about adjuvant chemotherapy in node neg, ER+, HER2- EBC requires balancing likely absolute benefits with treatment-related side effects. Health literacy and numeracy in general populations are often poor and many clinicians find explaining risk and uncertainty challenging especially when set against a backdrop of fear and anxiety. We developed and evaluated an educational program to aid discussions about gene expression profiling test (GEP) results from OncotypeDx and EndoPredict.
The 8 hr workshop contained: - a section on the science behind GEP tests, an interactive lecture on the psychology of risk and facilitated group discussions about different strategies demonstrated in 7 filmed scenarios showing doctors talking to patients with high and low risk scores (RSs). Pre and post workshop participants were recorded discussing RSs with trained patient simulators. Recordings were coded using a study specific scoring system by experienced researchers blinded to time-point. A priori hypotheses were that post workshop (a) participants’ communication skills discussing risk of recurrence would improve i.e. competence would be measurably better, (b) participants would feel more confident handling such consultations i.e. self-confidence/self–efficacy would be enhanced.
65 UK cancer healthcare professionals (HCPs) attended workshops. The rate re-rate reliability and inter-rater reliability for researchers coding the digital pre and post course recordings showed kappa statistics of 0.8101, SE.=0.1517 and 0.9123, SE = 0.0712 respectively. Conditional logistic regression models comparing the 2 scores observed at each time-point showed significant and positive changes in odds ratios for every key information area. HCPs’ self-rated confidence levels increased significantly post intervention for each key topic (P < 0.001). Average workshop satisfaction ratings were 9.6/10 All attendees stated they would ‘definitely’ recommend workshops to colleagues.
TARGET workshops significantly improved the communication skills and confidence of HCPs discussing risk and GEP test results in ways likely to assist patient decision-making about adjuvant chemotherapy in EBC.
University of Sussex.
Breast Cancer Research Foundation (BCRF).
All authors have declared no conflicts of interest.
Breast cancer in young women is generally considered to carry a worse prognosis. 50% of our patients (pts) are below the age of 50. We looked at our young patients age <40 years (y) with breast cancer at the American University of Beirut, assessed stages, characteristics and outcome.
Data on breast cancer in young pts seen at our institution between the years 2005 to 2018 was reviewed. Survival was calculated from date of diagnosis till recurrence, death, or last follow up. IRB approval was obtained.
Total number of pts ≤ 40 was 345. Over 300 pts had complete survival data. The median age at diagnosis was 36 years, IDC was present in 94.5% of cases, ILC in 1.2% of cases, and DCIS in 4.3%. Grade 1 disease was present in 8.9% of pts, grade 2 in 36.0%, grade 3 in 55.1%. HER2 positive pts in 28.9%, hormone receptor positive (ER &/or PR) in 75.9%, and 14.8% had triple negative breast cancer (TNBC). 58.2% of pts with Early Breast Cancer (EBC) had a partial mastectomy while 41.8% had a total mastectomy. 45.8% of all pts received adjuvant chemotherapy and 26.5% received neoadjuvant therapy (chemotherapy with or without anti-HER2 therapy). All hormone receptor positive pts received adjuvant hormonal therapy. 53.7% had EBC (stage I, IIA, IIB subset T2N1M0) while 26.7% had Locally Advanced (LABC): IIB subset T3N0M0, IIIA & IIIB. 14.0% had metastatic cancer at diagnosis and 11.2% of pts developed recurrent metastatic disease while 23.2% had metastatic de novo or recurrent disease. Overall Survival (OS) of pts with early stage was 97.8% at 5 years (y) and 77.5% at 10y; OS of pts with LABC was 91.3% at 5y and 73.7% at 10y. OS of pts with de novo MBC was 58.3% at 5y and 43.7% at 10y. OS of pts with recurrent metastatic disease was 70.3% at 5y and 35.6% at 10y while 5y survival of metastatic de novo or recurrent metastatic disease combined is 63.5% and 34.5% at 10 yr.
Prognosis of breast cancer in young women is improved with modern management that includes neoadjuvant therapy, surgery (that included 60% with partial mastectomy), radiation, targeted and adjuvant therapy according to their tumor characteristics, and stage. Young women with breast cancer can be reassured that their age does not mean they have a bad outcome. Biology and tumor characteristics and modern management determine outcome.
American University of Beirut Medical Center.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer is the most frequent cancer diagnosed in adult young women in Europe. Although rare (<5% before 35 years), it is one of the leading causes of death in this age group. The aim of this study is to characterize a cohort of young women regarding incidence, tumor stage, biology, treatment and survival.
We present a retrospective multi-center study of women less than 35 years old, diagnosed with breast cancer between 2008 and 2017. A total of 207 patients from 5 centers were included. Thirty five were excluded: 27 due to lack of data, 1 due to two different synchronous tumors and 7 had ductal in situ carcinoma. Data was analyzed using IBM SPPS statistics.
Median age was 31 years and ductal invasive carcinoma was the most frequent histologic subtype (91%). In the analysis of tumor subtype: 4% of tumors were luminal A, 20% luminal B HER2 positive, 47% luminal B HER2 negative, 8% HER2 positive (hormone receptor negative) and 20% triple negative. Forty eight percent of patients were diagnosed with early breast cancer, 45% were locally advanced and 6% had de novo metastatic cancer. Thirty nine percent of patients were treated with neoadjuvant chemotherapy (CT) and pathological complete response was obtained in 12%. Eighty three percent of patients were treated with adjuvant systemic therapy (CT or endocrine therapy), 18% exclusively with endocrine therapy. The median follow-up time was 53,5 months. Metastatic disease developed in 37 patients: 7 patients with bone metastasis only, 17 with both bone and visceral metastasis and 14 patients with central nervous system in addition to bone and visceral disease. The median survival of metastatic patients was 16,5 months. Local recurrence occurred in 3 patients with a median time of 27 months. Eighty five percent of these women are alive.
As expected, frequency of HER2 positive and triple negative tumors is increased in this age group, and the frequency of locally advanced and de novo metastatic disease is more prevalent. The median survival of metastatic patients is low in this age group as is the median survival. Due to more aggressive biology, initial staging and survival, the group of very young women with breast cancer deserves special treatment approaches.
Inês Fernandes Eiriz.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer is the most common cause of cancer in women worldwide, with more aggressive clinical behavior and poor outcomes in younger patients. This is to their increased risk of presenting with biologically aggressive types of cancer and at more advanced stage. Many studies have attempted to identify risk factors for local recurrence and distant metastases. The aim of this retrospective study was to analyze rates of recurrence in young patients with breast cancer treated at Ticino Breast Unit.
We analyzed medical records of 381 women ≤50 years old, with stage I-III invasive breast cancer, treated with curative intent, from 2010 to 2017. Demographics, tumor biology, type of surgery, neoadjuvant and adjuvant therapy, site of recurrence, time of recurrence and survival were assessed. Overall survival (OS) was defined as the time period from diagnosis to death from any cause. Disease-free survival (DFS) was defined as the time period from surgery to the first loco regional recurrence and/or metastases. Survival curves were calculated using Kaplan-Meier method.
The median age at the time of diagnosis was 45 years (range 23 to 50 years). The median follow-up was 45.6 months (range 1 to 105 months). Twenty-two patients (5.8%) were lost to follow-up. Tumor relapse occurred in 29 cases (7.6%), among which 9 patients died. Fourteen patients (3.7%) developed a loco-regional recurrence, 6 patients (1.6%) developed distant metastases and 9 patients (2.4%) loco-regional plus distant metastases. The most common site of loco-regional failure was the omolateral breast (11 patients). Two patients developed a second tumor in the contralateral breast. The median interval to recurrence was 31 months (range 3 to 87 months). The 3-year and 5-year risk for loco-regional recurrence was 4.7% and 9.5% respectively. The 3-years and 5-year DFS was 94.3% and 91.2% respectively. The 5-years OS was 93.3%.
Loco-regional recurrence and distant metastases rates of our population do not differ from those published in literature. Further analysis is needed to recognize biological and clinical risk factors for recurrence, with the aim of identifying prognostic models and addressing therapies.
Radiation Oncology Clinic.
Has not received any funding.
All authors have declared no conflicts of interest.
The Anti Her 2 drugs (AH2D): Trastuzumab (T) and Pertuzumab (P), are very important tool in the treatment of HER2 + Breast Cancer. (BC), who presented left ventricular dysfunction (LVD) in the follow-up. We analysed prospectively a group of p. who presented a LVD after the therapy with an AH2D. We proposed that the early treatment with Beta-Blockers (BB) (Carvedilol), angiotensin-converting enzyme inhibitor (IECA) (Enalapril) or Angiotensin Receptor Blockers (ARBs) (Valsartan), Aldosterone Antagonist (AA) (eplerenone); could to help for an early recovery of left ventricular ejection fraction (LVEF) and to allow the reintroduction of the AH2D without a new risk of LVD.
We analysed 593 consecutive p. with HER2 + BC who received T. alone or with P. from January 2017 to August 2018 with Anthracyclines (A) before or not . Basal LVEF evaluation was made by ultrasonography (US) before to start the oncological treatment. 40 p. developed LV dysfunction with the AH2D. All of the 40 p. started treatment with BB, IECA or ARBs, abd AA at the moment of the diagnosis of HF and kept going it after the recovery of LVEF. The reintroduction of the AH2D was when the patients recovered their LVEF. They were followed-up with LVEF by US at 30 days, 60 days and 3 months. We used the SPSS for the statistical analysis.
40 p. aged 53 +/- 7, 100% female. Risk Factors: Arterial Hypertension 8 p., Diabetes 4 p, Dyslipemia 5 p., Cigarettes 7 p. Previous oncological therapies: A. - Ciclophosphamide 20 p., Paclitaxel 20 p. Median of the basal LVEF was 60 % and at the moment of de diagnosis of HF was 41% New York Heart Association (NYHA) class I 15 %, II 60% and III 25%.All of the p. left the AH2D. HF treatment: Carvedilol 39 p., Enalapril 30 patients, Valsartan 9 p. and Eplerenone 40 p. In the follow-up 80% of p. presented the recovery of LVEF at 30 days and 95% at 60 days. When the p. recovered the LVEF we restarted the AH2D. In the follow-up at 3 months none p. had a new LVD and NYHA class I 30%, II 25% and asymptomatic 45%.
While the LVD related with AH2D is a real problem that threat the treatment of patients with Breast Cancer, a timely diagnosis and a treatment with therapies for HF to allow the LVEF recovery and to keep going with the specific oncological therapy.
Andrés J. Daniele.
Has not received any funding.
All authors have declared no conflicts of interest.
The cancer treatments bring with it body image challenges, causing low self-esteem and contributing to worsen the quality of life. Chemotherapy (CT)-induced hair loss (HL) is one of the most emotionally distressing side effects of several breast cancer (BC) treatments. The DigniCap system (DCS), using the scalp cooling system, has been shown to reduce CT-induced alopecia (A) in a multicenter prospective trial. The purpose of this prospective observational study was to describe our experience.
Two DCS device are available at the Brindisi Oncology Dpt. From February 2016 and January 2019, 143 consecutive early stage BC pts who received anthracycline and/or taxane-based treatment were enrolled, post local Ethics Committees approval. A nurse and a psychologist were dedicated for these pts. Success of scalp cooling was defined according to the Dean’s scale: G0=no HL; G1 < 25% HL; G2=25–50% HL; G3=50–75% HL; G4 >75% HL.
A total of 143 women were included in the following treatment cohorts: n = 59 (41.2%) received 4 courses of EC (epirubicin at 90 mg/m2 and cyclophosphamide (c) at 600 mg/m2 intravenously (IV) on day 1, with 21 days between cycles) followed by 12 courses of paclitaxel (P) 80 mg/m2 IV once a week (w); n = 54 (37.8%) received only 4 courses of EC, n = 26 pts (18.2%) P (80 mg/m2 IV once a w) and concurrent trastuzumab (2 mg/Kg IV; loading dose 4 mg/kg) for 12 consecutive doses and n = 4 (2.8%) pts received 4 courses of TC (docetaxel at 75 at 90 mg/m2 and c at 600 mg/m2 IV on day 1, every three w. Median age was 49 years (range 31-74). Overall success was observed in 103 pts (72%). Full preservation of the hair (G0) was observed in 34 pts (23.8%), G1 in 42 pts (29.4%) and G2 in 27 pts (18.9%). Most frequent scalp cooling-related symptoms were coldness (n = 116, 81%), neck pain (n = 83, 58%) and headache (n = 105, 73%). Overall, 16% (n = 23) of pts discontinued DCS because of unsatisfactory hair preservation (n = 11, 7.7%) and cold discomfort (n = 12; 8.4%). Furthermore we observed a hair growth when DCS was continued for pts with A G3 – G4.
Our results confirmed and reinforced previous evidences, showing that DCS is a good chance to prevent A during CT with anthracycline and/or taxane-based regimen and supported the wider use to all women with early stage BC.
Saverio Cinieri.
Has not received any funding.
All authors have declared no conflicts of interest.
The aim of this study is to evaluate the hematologic and non-hematologic toxicity of adjuvant treatment with anthracyclines in G6PD deficient patients affected by breast cancer.
From July 2009 to May 2017, we enrolled 40 Caucasian female patients carrier of G6PD deficiency with non-metastatic breast cancer. They were treated with adjuvant chemotherapy including anthracyclines.
As for treatment, 30% of patients were treated with FEC regimen (Fluoruracil 500mg/m2 iv, Epirubicin 75-100 mg/m2i.v., Cyclophosphamide 500-600mg/m2 every three weeks) for 6 cycles. 70% of the women received chemotherapy including anthracyclines and taxanes: 55% with EC regimen (Epirubicin 90 mg/m2i.v. and Cyclophosphamide 600 mg/m2i.v. every two weeks) for 4 cycles and Paclitaxel 80mg/m2i.v. weekly for 12 cycles; 15% were treated with FEC regimen for 3 cycles and Docetaxel 100 mg/m2i.v. every three weeks for 3 cycles. Anemia of grade 1 (83,6%) or 2 (17,4%) occurred in 57,5% of patients. In 42,5% of patients no anemia occurred. Nobody had acute hemolytic anemia and nobody presented neutropenia or thrombocytopenia. Bilirubin levels were normal in all patients (0.2-1,2 mg/dl) such as reticulocytes count (0,5-1,5%).Haptoglobin levels (50-150 mg/dl) were normal too. In 65% of cases LDH levels were lightly increased (200-500 U/L), but this result was due to a G-CSF injection. A common trait that occurred in 100% of the patients was alopecia.Only 17,5% of patients reported fatigue of grade 1.37,5% reported nausea of grade 1 and 2. 5% of patients presented vomit. 7,5% of patients reported constipation of grade 1 or 2 and 2,5% presented diarrhea of grade 2.7,5% of patients reported oral mucositis of grade 1 or 2. Non-hematologic and hematologic adverse events occurred frequently in patients without G6PD mutations.
Despite this is retrospective data and the number of patients analysed in this study is limited, these results prove that the usage of anthracyclines regimen is safe in patients with G6PD deficiency. In the future most clinical trials are welcomed to improve clinical practice.
Clelia Donisi.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer (BC) is a heterogeneous malignancy and it’s possible to identify by inmmunohistochemistry, four subtypes with different clinical and biological behavior. Our aim was to evaluate the prevalence, disease free survival (DFS) and overall survival (OS) influence of these subtypes on the Guatemalam population.
Data of 954 patients Instituto Guatemalteco de Seguridad Social treated from 2008-2014. BC subtypes were categorized in Luminal A (RE+ and/or RP+, HER2-), Luminal B (RE+ and/or RP+, HER2+ o Ki-67> 14%); HER2 (RE-, RP-, HER2+) and triple negative tumors (TNT) (RE-, RP-, HER2-).
Median age was 52 years (23-95), 55% were premenopausal. We found that 522 (56%) of the cases were luminal A, 190 (20%) were triple negative tumors (TNT), luminal B were 73 (8%) and HER2-positive in 152 (20%) of cases. Nine patients (3%) had other breast cancer contralateral. In 438 (70%) of all the cases were found in locally advanced stages (IIB–IIIC); 773 (81%) patients underwent radical mastectomy and 181 (19%) undergoing conservative surgery. We have found in the univariate analysis the following statistically significant variables for DFS: clinical stage (I – IIa vs IIb – IIIC; 88% vs 70%; p = 0.001), nuclear grade (grade 1, 2 vs 3; 83% vs 62%; p = 0.001) and pathologic response to neoadjuvant chemotherapy (total vs other response; 76% vs 54%; p = 0.001), and status Her-2 subtype was borderline (positive vs negative; p = 0.079). Clinical stage (p = 0.05), histologic grade (P = 0.45), response to neoadjuvant (p = 0.01) as significant factors of prognosis for the OS. The OS by molecular subtype were Luminal A (94%), Luminal B (75%), HER2 (79%) and TNT (68%), (p = 0.001).
The prevalence of molecular subtypes of BC is similar to reported internationally. In Guatemala the majority of patients with BC are diagnosed in advanced stage.
Hugo Castro.
Has not received any funding.
All authors have declared no conflicts of interest.
Left-sided breast cancer radiation therapy has been associated with an increased risk of major coronary events. There is evidence demonstrating that the increase is proportional to mean heart dose. Deep Inspiration Breath Hold (DIBH) is a radiation therapy technique that has shown significant dose reduction to the heart and lung in hypofractionated radiotherapy of adjuvant left-sided breast cancers. This study explores the potential benefit of utilizing a DIBH technique to reduce heart and ipsilateral lung doses.
This study was done on 65 patients with adjuvant left breast cancer. Patients are coached and asked to voluntarily hold their breath. For each patient, using Computed Tomography simulator machine, two CT scans corresponding to free breathing (FB) and vDIBH were acquired during simulation. Using Monaco treatment planning system FB and vDIBH plans were generated for each patient. All patients were treated on linear accelerator utilizing a vDIBH technique. 40.05 Gy in 15 fractions was prescribed. The evaluating parameters are target coverage; the volume of ipsilateral lung received 20 Gy (V20); mean heart dose (MHD) and volume of heart received 25 Gy (V25). All patients followed an offline portal imaging protocol, where the patients were imaged on day 1-3 and then weekly.
The comparing result shows there is a significant reduction in ipsilateral lung and heart dose statistics for vDIBH compared to FB plans without compromising the target coverage. For ipsilateral lung, the V20 was reduced by 15% with vDIBH comparing with FB. The volume of the heart receiving >25 Gy was reduced 20% and MHD was reduced by 18%. These reductions are considered to be statistically significant. The vDIBH mean reproducibility was 2mm (range 1- 4 mm) in antro-posterior direction.
Voluntary DIBH technique is successfully implemented and is an important tool for cardiac sparing and has been reproducibly associated with a reduction of mean heart dose. This is a benefit for those patients with left-sided breast irradiation and also has been shown to decrease dose to the lungs.
Academic Group.
Has not received any funding.
All authors have declared no conflicts of interest.
Pathological complete remission (pCR) distinguishes the prognosis of breast cancer patients undergoing neoadjuvant chemotherapy (NAC). On the contrary, non-pCR patients have poorer prognosis and may benefit from escalation or alteration of systemic therapy. Early and accurate identification of non-pCR remains a focused issue.
From December 2013 to January 2017, 805 patients undergoing NAC and serial breast core needle biopsy (CNB) were recruited at our center. Serial CNB was performed under ultrasound guidance after 2-4 cycles of NAC. The results of contrast enhanced-magnetic resonance imaging (CE-MRI) performed by the time of serial CNB and were evaluated per the RECIST1.1 criteria. An objective response was defined as complete or partial remission. Diagnostic values of serial CNB pathology and simultaneous CE-MRI were compared for predicting non-pCR.
A total of 653 patients were eligible for analysis and underwent a median of 6 (IQR: 4-7) cycles of chemotherapy. Serial CNB was performed after 2 (IQR: 2-3) cycles. Serial CNB pathology predicted non-pCR more accurately than simultaneous CE-MRI (0.793 vs 0.516, p < 0.001) with higher sensitivity (0.851 vs 0.365, p < 0.001). Multivariate analysis revealed the estrogen receptor, human epidermal receptor (HER2) status and serial CNB pathology as independent factors of non-pCR. Superior non-pCR prediction was evident in the HER2+ subgroup population.
Serial CNB pathology predicted non-pCR more accurately, early before the completion of NAC. HER2+ patients who received 2-3 cycles of NAC plus trastuzumab and still had residual malignancy on serial CNB might be suitable candidates for early treatment escalation or alteration.
The authors wrote this abstract by themselves, without the help of a third party.
Fudan University Shanghai Cancer Center.
Grants from the National Natural Science Foundation of China (81874113 and 81572583), the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (SHDC12010116), the Cooperation Project of Conquering Major Diseases in Shanghai Municipality Health System (2013ZYJB0302), the Innovation Team of Ministry of Education (IRT1223), and the Shanghai Key Laboratory of Breast Cancer (12DZ2260100).
All authors have declared no conflicts of interest.
Pathological complete response (pCR) is a commonly used endpoint in neoadjuvant trials for breast cancer (BC). A pooled analysis sponsored by FDA (Cortazar et al, 2014) showed pCR is a significant predictor of survival outcomes; however, it found little association between magnitude of difference in pCR rates and difference in survival between treatment arms in general BC or triple negative BC (TNBC). To reflect more recent evidence, this study aimed to update and focus the evaluation on the trial-level association between pCR and survival outcomes in TNBC.
Randomized controlled trials (RCTs) of neoadjuvant treatments for TNBC were identified through a targeted literature review (TLR) of publications all years through October 2018. RCTs that reported outcomes for both pCR and event-free survival (EFS) or overall survival (OS) in TNBC were included. Similarly as in Cortazar 2014, a weighted linear regression analysis on a logarithmic scale was performed based on odds ratios for pCR and hazard ratios for EFS/OS within each RCT. The coefficient of determination (R²) was used to measure the trial-level association between the treatment effects on pCR and survival. Scenario analyses were conducted to assess the impact of divergent study designs and pCR definitions across the RCTs.
Ten comparisons from 8 RCTs were identified by the TLR, which were all published after the Cortazar study. The primary analysis reported a moderate association between the improvement in pCR and EFS (R²=0.79). The R² between the improvement in pCR and OS was 0.42. Similar association was found in all scenario analyses.
Although uncertainty remains as to the validity of the trial-level surrogate, with availability of more TNBC-focused trials, this study demonstrated substantially stronger trial-level association between pCR and survival outcomes in TNBC compared with the findings in previous studies. With the increasing trend of TNBC-focused drug development, more robust evidence and sufficient amount of data may be available in the near future to address the uncertainty with respect to the association between pCR and long-term survival.
Merck & Co., Inc.
Merck & Co., Inc.
M. Huang, J. Zhao, A. Haiderali, V. Karantza: Employee: Merck & CO., Inc. C.Z. Qi, J. Xie, C. Gu: Employee: Analysis Group, which received funding from Merck & CO., Inc. to conduct this work. S. Ramsey: Consultant: Merck, AstraZeneca, Bayer, BMS, Genentech; Board of directors: LabKey A. Briggs, P.A. Fasching: Consultant of Merck & Co., Inc.
With the increased use of neoadjuvant chemotherapy (NAC), as well as increasing efficacy of systemic therapy, a substantial proportion of clinically node-positive patients may achieve a nodal pathologic complete response (pCR) with chemotherapy. Instead of axillary lymph node dissection (ALND), a novel surgical technique called targeted axillary dissection (TAD) including removal of sentinel lymph nodes (SLNs) and clip-marked node has been gaining acceptance in recent years. Logically, preoperative identification of patients with pCR or residual disease would allow for the optimization of axillary surgery for performing a TAD or proceeding to a ALND after NAC, thus sparing patients unnecessary procedures or expense. The aim of this study was to investigate the value of 18F-FDG PET/CT in tailoring axillary surgery by predicting nodal response among node-positive breast cancer patients after NAC.
Breast cancer patients with biopsy-confirmed nodal metastasis were prospectively enrolled. At least one 18F-FDG PET/CT scan was performed before NAC (a second one after two cycles with baseline SUVmax in axillary lymph nodes ≥ 2.5), among whom a subset of patients had underwent TAD. All the patients ultimately underwent ALND. The accuracy was calculated by a comparison with the final pathologic results.
Table. Accuracy of 18F-FDG PET/CT to Predict Ax-pCR in Overall Population and Different Subtypes Overall population ER-HER2+ subtype The rest subtypes No. of patients 111 31 80 Ax-pCR rate (%) 55.9 74.2 48.8 AUC (95%CI) 0.75 (0.65-0.84) 0.55 (0.31-0.79) 0.80 (0.70-0.91) P value <0.05 0.69 <0.05 Optimum cut-off (%) 78.4 79.9 76.2 Accuracy (%) 75.7 54.8 77.5 Sensitivity (%) 79.0 56.5 84.6 Specificity (%) 71.4 50.0 70.7 PPV (%) 77.8 76.5 73.3 NPV (%) 72.9 28.6 82.9 In this study, 133 patients were enrolled. With the optimum cut-off value of ≥ 2.5 for the baseline SUVmax and ≥ 78.4% for the ΔSUVmax, 18F-FDG PET/CT scans showed a moderate predictive value of axillary (Ax-pCR) with an area under the curve (AUC) of 0.75 (95% CI: 0.65-0.84) (Table). Explorative subgroup analyses indicated little predictive value for estrogen receptor (ER)-negative, human epidermal factor receptor 2 (HER2)-positive (HER2-enriched) patients (AUC=0.55). And the application of 18F-FDG PET/CT could spare 22 patients from unnecessary TADs or supplementary ALNDs and reduce 1 of 3 false-negative cases occurring in TAD among the non-HER2-enriched patients.
Application of the subtype-guided 18F-FDG PET/CT could accurately predict nodal response and aid in tailoring axillary surgery among node-positive breast cancer patients after NAC, which included identifying candidates appropriate for TAD or directly proceeding to ALND. This approach might help to avoid false-negative events occurring in TAD.
The manuscript was reviewed by Dr. William C. Wood, Division of Surgical Oncology, Department of Surgery, Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA, USA.
Fudan University Shanghai Cancer Center.
Has not received any funding.
All authors have declared no conflicts of interest.
Pathological complete response (pCR) of axillary lymph nodes (ALNs) is frequently achieved in patients with clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC), and ALN status is an important prognostic factor in breast cancer patients. Our goal is to develop a new clinical predictive model to assess the axillary lymph node pCR probability after NAC.
A retrospective series of 547 patients who had biopsy-proven positive ALNs at diagnosis and undergoing axillary lymph node dissection from 2007 to 2014 in National Cancer Center/Cancer Hospital of Chinese Academy of Medical Sciences. We analyzed the clinicopathologic features and developed a nomogram to predict the probability of ALN pCR. Univariate assessment was performed using a logistic regression model. A multivariate logistic regression stepwise model was used to generate a nomogram to predict ALN pCR in node positive patients Variables with P < 0.05 on multivariable analysis were included in the nomogram. The adjusted area under the receiver operating characteristic curve (AUC) was calculated to quantify the ability to rank patients by risk. Internal validation was estimated using 70-30 hold out validation method. Nomogram was validated externally with the prospective cohort of 167 patients from 2016 to 2018.
In retrospective study, there were 172 (31.4%) patients achieved axillary pCR after NAC. Multivariate analysis indicated that clinical nodal (N) stage (P = 0.002), hormone receptor (HR) status (P = 0.009) and clinical response of the primary tumor after NAC (P < 0.001) were significant independent predictors for axillary pCR. The NAC nomogram was based on these three variables. In the internal validation of performance, the AUCs for the training and test sets were 0.719 and 0.753, respectively. The nomogram was validated in an external cohort with an AUC of 0.734.
We developed a nomogram to predict the likelihood of axillary pCR in node-positive breast cancer patients after NAC. The predictive model performed well in prospective external validation. This practical tool could provide information to surgeons regarding whether to perform additional ALND after NAC.
ChiCTR1800014968.
Cancer Hospital, Chinese Academy of Medical Sciences.
Capital’s Funds for Health Improvement and Research (2016-2-4026); CAMS Innovation Fund for Medical Sciences (2016-I2M-1-001 and 2017-I2M-3-004); National Natural Science Foundation of China (81602343); Youth Research Fund of Beijing Tiantan Hospital (2017-YQN-09).
All authors have declared no conflicts of interest.
The aromatase inhibitor letrozole (Femarâ/ Femaraâ) and the aromatase inactivator exemestane (Aromasinâ) are currently widely used to treat estrogen receptor positive breast cancer in postmenopausal patients. Interestingly, exemestane may cause clinical disease stabilization following progression on non-steroidal AIs in patients with metastatic breast cancer indicating that additional effects, not necessarily related to estrogen-suppression, may be involved in the well-known “lack of cross-resistance”. The adipocytokine leptin has been shown to enhance the expression of aromatase via promoter II and I.3 using an AP-1 motif. In this study, we evaluated the serum levels of 12 adipokines relative to given treatment with aromatase inhibitors aiming for a direct head-to-head comparison between letrozole and exemestane in vivo.
The NEO-LET-EXE-trial is a neoadjuvant, randomized, open-label, intra-patient cross-over trial. Postmenopausal women with ER+, HER-2 negative, locally advanced breast cancer were enrolled. Blood specimens obtained at baseline, after 2 months and 4 months of treatment were available from 39 patients. All patients were randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) for 2 months followed by another 2 months on the alternative aromatase inhibitor. The serum levels of twelve adipokines were assessed using the Luminex xMAP technology (multiple ELISA).
Serum levels of leptin were significantly decreased during treatment with exemestane compared to treatment with letrozole (P < 0.001), regardless whether exemestane was given as first or second therapy. Furthermore, we observed a strong trend towards a reduction of serum levels of adiponectin during treatment with exemestane (P = 0.059). No significant changes in serum levels of the other adipocytokines were registered during treatment with aromatase inhibitors.
Our results suggest distinct influences of exemestane on serum leptin but also adiponectin levels that may contribute to the clinical well-document positive effects of exemestane following progression on non-steroidal AIs like letrozole.
Akershus University Hospital.
The South-Eastern Norway Regional Health Authority.
All authors have declared no conflicts of interest.
The role of neoadjuvant chemotherapy (NACT) in the treatment of early stage breast cancer is well established. Guidelines differ in their recommendation for staging work-up prior to NACT. Our institutional guidelines recommend CT thorax abdomen and pelvis scan for all such patients and we sought to evaluate the rate of metastatic disease by breast cancer stage.
All cases identified for potentially curative NACT by the Multidisciplinary Team between 1/1/15-31/12/17 were included. Clinical records were reviewed. Those without a CT, inoperable when referred, with a diagnosis other than breast cancer or with loco-regional recurrence were excluded. Rates of metastases by tumour size (greatest by MRI, USS and mammography), lymph node stage (MRI and USS), receptor status and multifocality were calculated.
185 patients were identified and 22 were excluded (no CT scan (6), inoperable (5), referred for adjuvant therapy (7), locoregional recurrence (3) and angiosarcoma (1)). 104/163 (64%) patients had a normal CT scan. 7/163 (4%) patients had definite metastases identified on their staging CT and 52/163 (32%) had an equivocal scan with further imaging required. Following additional imaging a further 10 patients had metastatic disease confirmed giving an overall incidence of of 10% (17 patients). The incidence of metastatic disease by stage (M1/total), (N + = node positive): T0N+ 0/1; T1N0 0/11; T1N+ 0/12; T2N0 1/42 (2%); T2N+ 9/53 (17%); T3N0 1/8 (12.5%);.
The incidence of metastatic disease detected on imaging during work-up for NACT was 10%. The rate of metastatic diagnosis increases with T stage in patients with clinical N0 disease. Staging can be omitted in patients T1/2N0 at diagnosis. Omission of staging CT scans in the T1-2N0 cohort would have reduced the imaging frequency across all modalities by 30% when both initial and additional imaging are considered.
Sacha Howell.
Has not received any funding.
All authors have declared no conflicts of interest.
Neoadjuvant chemotherapy plus anti-HER2 treatment is increasingly becoming the treatment of choice for all but the lowest risk HER2+ early and locally advanced breast cancer (BC). Patients achieving a pathological complete response (pCR) have substantially better outcomes compared with non-pCR. We evaluated the pCR rates following neoadjuvant systemic therapy in our HER2+ BC population and determined the influence of tumour and patient characteristics, and adverse events on pCR rates, disease free survival (DFS) and overall survival (OS).
We retrospectively identified patients with early and locally advanced HER2+ BC who received neoadjuvant treatment from January 2013 to December 2017 and underwent subsequent surgery. pCR was defined as ypT0/is N0. Demographics, patient and disease characteristics, pathological responses, toxicities, dose delays and reductions were recorded. Statistical analysis was undertaken using Chi-squared, Kaplan Meier and Log-rank tests.
300 patients were identified. Median age was 51 years (range 25-78) and 286 (95.3%) patients had performance status (PS) 0. 11 (4.0%) patients had clinical stage I, 189 (63.0%) stage II and 100 (33.0%) stage III disease. 204 (68.0%) had grade 3 disease and 282 (94.0%) ductal histology. 185 (61.7%) patients had ER+ disease and 115 (38.3%) ER- disease. 155 (52.0%) patients were treated with chemotherapy plus Trastuzumab. 143 (48.0%) patients had chemotherapy plus Trastuzumab and Pertuzumab. pCR rate in the overall population was 54.3% and significantly better in the ER- compared with the ER+ subgroup ( 68.7 vs 45.4 %; p < 0.001). Patients on dual anti-HER2 blockade achieved higher pCR rates compared with those on Trastuzumab (56.6 vs 52.2%) although the difference was not statistically significant (p = 0.448). pCR rates were not influenced by age, PS, dose reductions or dose delays but were significantly lower in case of chemotherapy early discontinuation. With a median follow-up of 23 months, median DFS and OS were not reached.
In our analysis, pCR rate was similar to published data in the literature and was higher in the ER-/HER2 positive subgroup.
The Breast Unit, The Royal Marsden Hospital.
Has not received any funding.
All authors have declared no conflicts of interest.
Neoadjuvant concurrent chemoradiation (CTRT) is not widely practised in breast cancer. We present our experience with the use of neoadjuvant CTRT in patients with locally advanced breast cancers (LABC) treated at our centre.
The study included all consecutive female patients with inoperable stage III LABC treated at our centre from December 2015 to June 2016. Data were collected retrospectively from the patients’ case records. The impact of neoadjuvant CTRT on pathological complete response and survival was analysed. All patients received 2 cycles of Paclitaxel 3 weekly (175 mg/m2/dose) with External beam radiotherapy (EBRT) delivered at 46 Gy in 23 fractions given over 5 weeks.
The study included 100 patients with a median age of 49 years among whom 9/100 (9%) had IIIA disease, 73/100 (73%) IIIB and 18/100 (18%) had IIIC disease. Hormone receptor-positive disease was observed in 36/100 (36%) patients, triple negative in 24/100 (24%) and Her2 neu positive disease in 40/100 (40%) patients. All patients were operable after completing the planned neoadjuvant treatments. Ninety-one out of 100 (91%) patients underwent modified radical mastectomy whereas 9/100 (9%) did not consent for surgery. pCR was observed in 12/21 (57.1%) patients with triple-negative disease, 11/34 (32.3%) patients with hormone receptor-positive disease and 16/36 (44.4%) patients with Her2 neu positive disease. Most common morbidity observed was grade 3 skin reactions. No grade 4 skin toxicity was observed. The 2-year event-free survival (EFS) and overall survival (OS) for the entire cohort was 88 % and 73.1 % respectively.
Neoadjuvant CTRT is well tolerated and is associated with higher pCR rates than what has been reported with neoadjuvant chemotherapy alone. However, further prospective studies with longer follow-up are required to confirm our findings.
Cancer Institute, Chennai, India.
Has not received any funding.
All authors have declared no conflicts of interest.
The prognostic and predictive value of the androgen receptor (AR) in triple negative breast cancers (TNBC) remains controversial. We assessed the impact of AR in TNBC on core needle biopsy (CNB) and remaining tissue after neo-adjuvant chemotherapy (NACT) by menopausal status which affects the androgen/estrogens relation and pathological complete response (pCR) rate.
We retrospectively evaluated all consecutive TNBC patients receiving NACT between 2000 and 2017 treated in a single center with sufficient remaining diagnostic CNB material. AR-expression was assessed by immunohistochemistry using the ≥1% as per recommendation of ASCO/CAP guidelines for estrogen receptor. AR was correlated with baseline demographics and clinic-pathological characteristics, including stromal tumor infiltrating lymphocytes (sTILs), pCR (pT0-is, N0), AR-expression in remaining tumor, and metastasis for outcome using the Fine and Gray model for statistical analysis. We explored whether results differ by menopausal status.
71 women were eligible (median age 51.0 yrs; 35 postmenopausal), 6.7 yrs median follow-up. AR-pos was seen in 32%. pCR, reported in 39.8% (45.7% in pre- and 33.3% in postmenopausal) predicted metastasis; 3.5% if pCR; 37.3% if no-pCR. AR on CNB did not correlate with age, menopausal status, BMI, sTILs or pCR. AR-status on CNB was not associated with metastasis. 14% of 43 patients with no-pCR following NACT were AR-pos; this predicted a poor outcome. The difference in median TTM by AR was 4m longer if AR-pos but this was not significant. A total AR-score for proportion of cancer cells staining ≥34% was more frequently observed in postmenopausal patients (27%), as compared to the premenopausal ones (5.7%). This discrepancy might possibly explain the 12.3% higher pCR rate in premenopausal patients. % pCR by AR-expression (cut-off ≥1%) and menopausal status.
% pCR All % Premenopausal % Postmenopausal % All patients 39.4 45.7 33.3 AR-neg 39.6 41.6 37.5 AR-pos 39.1 54.5 25.0
AR-expression in TNBC does not affect pCR nor DDFS but was associated in our series with lower pCR in postmenopausal women. AR in residual TNBC following NACT predicted a worse outcome.
University Hospitals Leuven.
Funds of Friends for Cancer Research Leuven.
A. Smeets: Research grant to the institution: Merck, MSD Belgium. H. Wildiers: Personal: travel support: Roche, Pfizer; Institution: Consulting fees, Honoraria: Roche, AstraZeneca, Amgen, Lilly, Novartis, AbbVie, Vifor Pharma, Pfizer, Celldex therapeutics, Janssen-Cilag TRM Oncology, Puma Biotechnology, Orion Corp.; Research grant: Roche. P. Neven: Speaker’s fees, consulting fees, research support: Roche (all provided to his institute); Advisory board: Novartis, AstraZeneca, Lilly, Pfizer (all consulting fees are provided to his institute). All other authors have declared no conflicts of interest.
Breast cancer is the most common cancer in Indian women. Triple negative breast cancer (TNBC) is associated with poor prognosis at any stage of diagnosis. It is an aggressive disease with a 5-year survival rate of 77% compared to 93% for other subtypes. Prevalence of TNBC in India is higher compared to western populations, making it an important target for early detection and treatment. Potential superiority of dose-dense chemotherapy in comparison with conventional regimen has been recently demonstrated in a meta-analysis in 2017 across various subsets of breast cancer. Aim of this study was to analyse survival outcomes in TNBC treated with dose dense chemotherapy at a tertiary care centre in India.
Retrospective analysis of patients diagnosed with TNBC stage I-III in last 8 years treated with 2 weekly dose dense AC regimen (adriamycin at 60mg/m2and cyclophosphamide at 600mg/m2 for 4 cycles followed by 2 weekly Paclitaxel at175 mg/m2 for 4 cycles or weekly Paclitaxel at 80 mg/m2 for 12 cycles) with growth factor support in adjuvant or neoadjuvant (NACT) setting. Locally advanced breast cancer (LABC) was defined as T > 5cm and ≥N2 disease. Kaplan–Meier method and log rank test were used to estimate survival functions.
97 patients with ER, PR and Her2neu receptor negative status were evaluated. Median age at diagnosis was 44 years (range 26 - 68 years). 56.7% had stage II disease, 36% stage III and rest stage I (7.2%). Disease free survival (DFS) rate ± SE at 2 years and 5 years was 90% ± 3% and 75% ± 5% respectively. Overall survival (OS) rate ± SE at 5 years was 82% ± 6%. 24 patients received NACT out of which 12 (50%) patients had pathCR. The DFS rate did not differ significantly between adjuvant and neoadjuvant subgroups. Early breast cancer and LABC subgroups had a statistically significant difference in DFS rates (p = 0.0002).
To our knowledge, this is the first study in India to evaluate survival outcomes of dose dense therapy in TNBC. The improved DFS (75%) and OS (82%) in this high risk subgroup are very promising, especially in patients with early disease. We advocate use of dose dense regimen in all patients of TNBC in curative setting.
Manipal Hospital.
Has not received any funding.
The author has declared no conflicts of interest.
Breast cancer is the most common tumour diagnosed in women worldwide and is the second leading cause of cancer death. The use of trastuzumab or Herceptin®, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2) together with chemotherapy has changed the natural history of breast cancers overexpressing HER2. There is mounting evidence that responses differ according to hormone receptor (HR) status. The behaviour of so called “double positive” tumours and how they respond to existing therapies are relevant clinical questions. Late recurrences and risk of death is characteristic of this subtype. HER2 is overexpressed in 25% of all breast cancers. In nearly 50% of these there is co-existence of oestrogen receptor (ER) and progesterone (PgR) expression. Neoadjuvant treatment combining chemotherapy and trastuzumab is standard of care. Pathological complete response (pCR) rates are consistently inferior in HER2 positive patients who are ER positive compared to those with ER negative disease. This review addresses the role for adding endocrine deprivation therapy (EDT) in the neoadjuvant setting.
A computer-based literature search was conducted using the Cochrane library, PubMed and Embase. Results reported at international meetings and ClinicalTrials.gov were also included. Publications were restricted to studies investigating the addition of EDT in the neoadjuvant setting with pCR reported as an outcome of interest.
This systematic review included eight studies. pCR rates were reported on 1,232 women with HER2 positive breast cancer with or without co-existence of ER. The treatment paradigm was wide ranging across the studies with dual anti-Her2 therapy being adopted in favour of chemotherapy free regimens or chemotherapy combined with either single or dual anti-HER2 therapy. pCR rates ranged from 8% to 46.1% in this subtype when EDT was added. The addition of EDT to trastuzumab and chemotherapy in the neoadjuvant setting likely represents a worthwhile, safe and cost-effective approach.
The evidence is compelling to warrant further clinical trials to better identify distinctive subtypes and optimise targeted therapy for HER2 and HR positive breast cancer.
Martina A Smith.
Has not received any funding.
All authors have declared no conflicts of interest.
Pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) has been proposed as a surrogate endpoint for of long-term clinical benefit, such as disease-free survival, event-free survival, and overall survival in patients (pts) with early breast cancer (BC). The association between molecular subtypes, clinicopathological features, and pCR rate in early BC pts treated with NAC were examined.
We retrospectively analyzed data of 208 pts undergoing NAC. Luminal A was documented in 12 pts, Luminal B in 42 pts, Her-2+ in 38 pts (Her-2+ ER-/PR- = 12; Her-2+ ER+ and/ or PR+ = 26) and triple negative breast cancers (TNBC) in 116 pts. Pathological complete response was defined as the complete disappearance of the invasive cancer in the breast and absence of tumor in the axillary lymph nodes.
The pCR rate of the entire cohort was 45%. At 4 years 95% of pts who attained a pCR were disease free compared to 78% of pts who did not (log rank test Chi2 =10.775, p < 0.01). Among TNBC subtype, at 4 years 95% of pts who attained a pCR were disease free compared to 77% of pts who did not (log rank test Chi2 =7.525, p < 0.01). On univariate analysis factors associated with higher pCR included molecular subtype (TNBC 58%, Her-2+ ER-/PR- =75%, Her-2+ ER+ and/or PR+ = 46% and Luminal A + B was 11%, Chi2 =37.03, p < 0.00000), primary tumor size (T1=62% vs. T2=46% vs. T3=16% vs. T4=18%, Chi2=15.16, p < 0.00168), nodal disease (N0=53% vs. N1=39%, Chi2=3.76, p < 0.05), age (< than 50 years = 55% vs ≥ 50 years = 39%, Chi2 = 5.05, p < 0.02) ER receptor status (neg=60% vs. pos=21%, Chi2=30.08 p < 0.00000), PR receptor status (neg=58% vs. pos=16%, Chi2=30.1 p < 0.00000), Ki67 (>40=59% vs.14-39=36% vs. <14=6%,Chi2=22.09 p < 0.00060) and stage (I = 80% vs. IIA=49% vs. IIB=40% vs. III=22%, Chi2=22.09 p < 0.0004). Menopausal status, ethnicity, extra-nodal spread and lympho-vascular invasion were not associated with a higher pCR rate. In a logistic regression model Ki-67 as a continuous variable (p < 0.02) and TNBC subtype (p < 0.04) retained its significance; while tumor size, stage of disease, nodal status, ER and PR lost significance.
TNBC molecular subtype and high Ki67 are associated with a higher pCR rate in early BC pts undergoing NAC.
The Medical Oncology Centre of Rosebank.
Has not received any funding.
All authors have declared no conflicts of interest.
Although ER+/HER2− BC has better overall prognosis than other subtypes, a high-risk subpopulation is characterized by high-grade tumors, decreased sensitivity to ET, higher responsiveness to CT, and worse prognosis. A meta-analysis of prospective studies on neoadjuvant chemotherapy (NAC) to treat stage I to III BC showed that increased pathologic complete response (pCR) rates at surgery were associated with improved survival in triple-negative BC, HER2+ BC, and high-grade HR+/HER2− BC. Patients with vs without pCR after NAC for high-grade HR+/HER2− BC had a 90% vs 60% 5-year event-free survival (EFS) rate, respectively. Thus, increased pCR rates after NAC may have a substantial impact on the survival of patients with high-risk, early-stage HR+/HER2− BC. KEYNOTE-756 (ClinicalTrials.gov, NCT03725059) is a global, randomized, double-blind, phase 3 study of pembrolizumab (pembro; vs placebo) + NAC followed by pembro (vs placebo) plus ET as adjuvant treatment for patients with high-risk, early-stage ER+/HER2− BC.
Patients with cT1c-2 cN1-2 (tumor size ≥2 cm) or cT3-4 cN0-2 grade 3, invasive, ductal ER+/HER2− BC will be stratified by lymph node involvement (pos vs neg), tumor PD-L1 status (pos vs neg), ER positivity (≥10% vs < 10%), and anthracycline dosing schedule (every 3 weeks [Q3W] vs Q2W), then randomized 1:1 to neoadjuvant treatment with pembro 200 mg Q3W or placebo combined with paclitaxel (80 mg/m2 Q1W) for 4 cycles followed by doxorubicin (60 mg/m2) or epirubicin (100 mg/m2), each with cyclophosphamide (600 mg/m2), Q2/3W for 4 cycles. After definitive surgery (± radiation therapy, as indicated), patients will receive adjuvant treatment of pembro (200 mg Q3W) or placebo for 9 more cycles combined with ET, which can be given for up to 10 years. Coprimary endpoints are pCR rate (ypT0/Tis ypN0) and EFS. Secondary endpoints include pCR rates (ypT0 ypN0 or ypT0/Tis, and using all 3 definitions in the PDL1+ subpopulation), overall survival, and safety. Enrollment is currently ongoing.
Rajni Parthasarathy, PhD, and Diane Neer, ELS, MedThink SciCom.
NCT03725059.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
F. Cardoso: Consulting: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Teva. L. Jia, K. Hirshfield, V. Karantza: Employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and may hold stock/stock options in Merck & Co., Inc., Kenilworth, NJ, USA.
In TNBC neoadjuvant chemotherapy (NACT) is associated with increased pathological complete response (pCR). Thus, patients with a pCR have a favourable prognosis. However, patients with residual disease have a substantially increased risk of recurrence compared to those with other subtypes of breast cancer (Liedtke 2008, Loibl 2017). Blockade of PD-L1 binding by atezolizumab has resulted in relevant anti-tumor efficacy (Adams 2017, Schmid 2017).
GeparDouze (NCT03281954/NSABP B-59/GBG96) is a phase III, double blind, placebo-controlled trial evaluating neoadjuvant administration of atezolizumab with NACT followed by adjuvant atezolizumab in patients with high risk TNBC. Accrual will be 1,520 randomized patients stratified by region (North America; Europe), tumor size (1.1-3.0 cm; > 3.0 cm), epirubicin or doxorubicin/cyclophosphamide (EC; AC) schedule (q2w; q3w), and nodal status (positive; negative). Patients are randomized 1:1 to receive atezolizumab 1200 mg or placebo IV every 3 weeks concurrently with sequential regimens of weekly paclitaxel 80 mg/m2 IV for 12 doses and every 3 week carboplatin AUC of 5 IV for 4 doses followed by AC/EC every 2-3 weeks (per investigator discretion) for 4 cycles. Following surgery, patients resume atezolizumab 1200 mg or placebo IV every 3 weeks as adjuvant therapy for 6 months. Radiotherapy based on local standards is co-administered with atezolizumab/placebo. Patients with centrally-confirmed ER-neg, PR-neg, HER2-neg invasive breast cancer by ASCO/CAP guidelines can be enrolled. Primary tumor must be stage T2 or T3 if cN0 or cN1 with negative biopsy or T1c, T2, or T3 if cN1 with positive biopsy or cN2 or cN3. Co-primary endpoints are event-free survival and pCR (ypT0/Tis ypN0). Main secondary endpoints include pCR breast, overall survival, distant disease-free survival, safety and toxicity. GeparDouze is performed as an academic collaboration between NSABP and GBG.
NCT03281954; NSABP B-59; GBG96.
NSABP and GBG.
Genentech/Roche.
S. Loibl: Grant: Roche; Grants: Pfizer, Celgene, Amgen outside of the submitted work. C. Jackisch: Personal fees: Roche; Personal fees: Celgene, during the conduct of the study. P. Rastogi: Grants: Genentech/Roche, during the conduct of the study; Other: AstraZeneca, Other: Genentech/Roche; Other: Lilly, outside the submitted work. P.C. Lucas: Grants: Genentech, during the conduct of the study; Other: Amgen; Personal fees: Bayer/Loxo, outside the submitted work. C. Denkert: Shareholder and co-founder: Sividon Diagnostics; Honoraria/consultation: Teva, Novartis, Pfizer, Roche, Amgen, MSD, Daiichi, Celgene, AstraZeneca; Patent application: EP18209672 - Cancer immunotherapy. J. Costantino: Grants: Genentech, during the conduct of the study. N. Wolmark: Service contract between NSABP Foundation, Inc. and Genentech/Roche during the conduct of the study. C. Geyer: Grants: Genentech/Roche, during the conduct of the study; Grants, non-financial support: AstraZeneca, AbbVie; Personal fees: Celgene; Grants, non-financial support: Genentech/Roche, outside the submitted work. All other authors have declared no conflicts of interest.
Hypofractionated radiotherapy (RT) is becoming a new standard in the adjuvant treatment for patients with breast cancer. However, data are lacking on late-term arm and shoulder morbidity with hypofractionation in patients with advanced stage disease who undergo mastectomy followed by local and regional nodal irradiation (RNI). In this study, we report late-term effects in arm and shoulder with 3 weeks of RNI with hypofractionation in patients with breast cancer.
Between January 1990 and December 2007, 1770 women with stage II and III breast cancer post mastectomy, prospectively treated with hypofractionated local and RNI were analyzed for late-term effects on arm and shoulder. RT dose was 35Gy/15#/3 wks to chest wall by two tangential fields and 40Gy in same fractions by a single incident field to supraclavicular fossa. Late-term toxicities were assessed with RTOG LENT SOMA scale. All late effects assessment scores were dichotomised as none/mild versus moderate/marked effects.
Median follow up was 10 years. Chemotherapy and hormonal therapy was given to 1136(63%) and 1381(74%) of patients, respectively. RNI was delivered in 1689(95%) of patients. Moderate/severe arm/shoulder pain was reported by 374(22%) patients. Moderate/severe difficulty in abducting arm was reported by 269(16%) patients. Moderate/marked arm edema was seen in 131(7.7%) of patients. Brachial plexopathy was not seen in any of the patients.
Hypofractionated local and RNI in 3 weeks was associated with modest arm and shoulder late-term effects. Table. Patients characteristics Characteristics Total=1770 n(%) Age ≤40 491 (28) >40 1279 (72) Menopausal Status Pre-menopausal 828 (47) Post-menopausal 942 (53) Tumor stage T1 906 (51) T2 659 (37) T3 34 (2) T4 171 (10) Histology Invasive Ductal Carcinoma (IDC) 1628 (92) Non-IDC 142 (8) Grade 1 2318 (18) 2 1134 (64) 3 318 (18) N Stage (pathological) N0 654 (37) N1 593 (34) N2 383 (22) N3 140 (8) Surgical Margins Negative 1562 (88) Positive 208 (12) Estrogen Receptor Status Positive 859 (62) Negative 530 (38) Unknown 381 Progesterone Receptor Status Positive 729 (53) Negative 632 (47) Unknown 409 Chemotherapy Yes 1136 (64) No 634 (36) Hormonal Therapy Yes 1381 (78) No 389 (22).
PGIMER, Chandigarh.
Has not received any funding.
All authors have declared no conflicts of interest.
Breast magnetic resonance imaging (MRI) has a high sensitivity (95-100%) in detecting invasive neoplasms. Controversy still exists whether preoperative staging with breast MRI has an impact on surgical outcomes. The aim of this randomized controlled trial is to evaluate the ability of MRI in selecting patients for breast conserving surgery (BCS).
BREAST-MRI is a randomized, open label, unblinded trial conducted at ICESP, São Paulo, Brazil. Patients were stratified for mammary density and randomized on a 1:1 basis. Sample size was calculated assuming a recurrence rate of 10% for conservative surgery and 1% for mastectomies for invasive breast cancer. All patients were female, older than 18 years old, diagnosed with breast cancer stage 0 to III and candidates for BCS were evaluated by physical exam, breast ultrasound (US) and mammography. Breast MRI were performed on a 1.5T MRI system (Signa HDxt®, GE Healthcare). Breast density on mammography were assessed using ACR BI-RADS®. The surgery was modified when MRI showed an increase of more than 50% of the tumor size. Primary end-point was accuracy of MRI and rate of mastectomies.
815 patients were eligible, 446 patients were included. MRI was performed in 49,1% (219) patients. Groups were similar according to clinical and tumor characteristics (Table). The MRI group showed surgical change management in 68 patients (31,1%). Surgical changes were made in the ipsilateral breast in 49 cases (72,1%), at contralateral breast in 13 cases (19,1%) and at both breasts in 6 patients (8,8%). MRI correctly modified the surgical procedure in 44 out of 55 patients (80%) for ipsilateral breast and 7 out of 13 patients (53,8%) from contralateral breast. There was no difference at the accuracy rate of MRI according to the mammary density (p 0,74). Conversion to mastectomy occurred in 19 patients at the ipsilateral breast.
Preoperative MRI changed surgical management in 31,1% of the cases, to either wide BCS or mastectomy, with an accuracy rate of 80%. However, it did not change reoperation rates.
NCT02798796.
ICESP.
Has not received any funding.
All authors have declared no conflicts of interest.
Baseline characteristics HRT: Hormone replacement therapy.MRI Group (n = 219) Control Group (n = 227) p Age (median) 57,3 57,9 0,45 Body Mass Index (kg/m2) 29,3 29,4 0,35 Nulliparity 0,52 Yes 20 (9,2%) 25 (11%) No 198 (90,8%) 202 (89%) Missing information 1 0 Menopausal status 0,26 Premenopausal 64 (29,4%) 56 (24,7%) Postmenopausal 154 (70,6%) 171 (75,3%) HRT 0,51 More than 5 years 2 (11,1%) 6 (26,1%) Less than 5 years 16 (88,9%) 17 (73,9%) Mammary density 0,68 A 12 (5,5%) 12 (5,3%) B 93 (42,5%) 99 (43,6%) C 101 (46,1%) 108 (47,6%) D 13 (5,9%) 8 (3,5%) Clinical Stage 0,28 0 28 (12,8%) 34 (15%) I 97 (44,3%) 108 (47,6%) II 91 (41,6%) 85 (37,4%) III 3 (1,4%) 0 Surgery 0,001 BCS 168 (76,7%) 226 (99,5%) Wide BCS 35 (16%) 0 Mastectomy 13 (5,9%) 1 (0,5%) NSM 3 (1,4%) 0 Re operation rates 0,646 Further wide local excision 12 (5,5%) 11 (4,8%) Mastectomy 5 (2,3%) 5 (2,2%) Chemotherapy 0,013 Yes 103 (49%) 83 (37,2%) No 107 (51%) 140 (62,8%) Radiotherapy 0,918 Yes 199 (95,2%) 209 (95%) No 10 (4,8%) 11 (5%) Hormone therapy 0,59 Yes 181 (86,6%) 196 (88,3%) No 28 (13,4%) 26 (11,7%) Follow-up (months) 23,6 (1-45) 23,6 (1-53) 0,99 Status 0,64 Local recurrence 0 1 (0,4%) Distant recurrence 4 (1,8%) 3 (1,3%) Breast cancer death 0 1 (0,4%) Any death 2 (0,9%) 1 (0,4%)
There is no definite consensus on the role of post-operative radiotherapy (RT) in breast cancer patients with 1-3 axillary lymph node positivity. EBCTCG meta-analysis and Danish trials (DBCG 82 b and c) showed improvement in loco regional control and overall survival (OS) with post operative radiotherapy in 1-3 node positive patients, but level I evidence is awaited [SUPREMO trial]. With this background we conducted this retrospective analysis to evaluate clinical outcomes of patients with 1 to 3 axillary node positive breast cancer.
From 1 January 2010 to 31 December 2014, a total of 474 patients with pT1-T2 pN1 breast cancer were identified from Hospital Registry. Clinical outcomes in terms of Disease Free Survival (DFS), Local Recurrence Rate (LRR), OS and patterns of failure were assessed.
Of the 474 patients, all of them except 3 were females, with a mean age of 52 years. 89% of the patients had >/=10 axillary lymph nodes dissected and around half of the patients studied had single node positivity. Adjuvant RT was given to 364 patients (76.8%) and 75.5% of them received conventional fractionation schedule. The median follow up was 77.4 months. At the time of analysis, 403 patients were alive without any evidence of disease. Forty-one patients died due to disease sequelae and 8 patients were alive with disease. The 5 year OS and DFS were 93% and 89.4% respectively. Eighteen patients (3.7%) had locoregional relapse. There was a significant difference in outcome in terms of OS and DFS in favor of single node positivity when compared with 2-3 node positivity (5 year DFS 94.4% vs. 83.5 %, p = 0.000017, 5 year OS 96.6% vs. 89.1%, p = 0.00023). There was no difference in OS and DFS between patients who received adjuvant RT and patients who did not.
76% of the patients received adjuvant RT and there was no statistically significant difference in the outcome between those who received adjuvant RT and those who did not. Patients with single node positivity had better DFS and OS when compared with patients with 2-3 node positivity. The ongoing prospective trial (SUPREMO Trail) may give us further insight into the exact role for RT in patients with 1-3 node positivity.
Regional Cancer Centre, Trivandrum, India.
Has not received any funding.
All authors have declared no conflicts of interest.
Triple-negative breast cancer (TNBC) shows different clinical course from ER-positive cancers. We designed multi-institutional retrospective study to analyze treatment outcomes after post-operative radiotherapy in TNBC.
We retrospectively reviewed 699 TNBC patients with post-operative radiation therapy from 6 institutions between 2008 and 2010. Median age was 49 (range, 24-80) and neoadjuvant chemotherapy was administered in 130 patients (18.6%). Breast conserving surgery was done in 634 (90.7%) and invasive ductal carcinoma was reported in 611 (87.4%). Two hundred and twenty five patients (36.5%) were stage I, 305 (43.6%) in II, and 67 (9.6%) in III. Lymphatic invasion (LI) was reported in 240 patients (34.3%) and extracapsular extension (ECE) was in 49 (7.0%). Patients were irradiated 45-50.4Gy with 25-28 fractions to the breast or chest wall followed by tumor bed boost with 10-16Gy with 5-8 fractions. Simultaneously, additional radiation fields were irradiated to supraclavicular or internal mammary lymph nodal areas. Adjuvant chemotherapy was done in 596 (85.3%).
In median 94 months (range, 7-192) after treatments, 594 patients (85.0%) were no evidence of disease, 31 patients (5.0%) with alive with disease, 3 patients (0.4%) with died due to other causes, and 67 (9.6%) death from the breast cancer. Local recurrence was reported in 33 patients (4.7%), and regional failure was in 31 patients (4.4%), respectively. Distant metastasis was in 78 patients (11.2%). 5-year OS was 91.4%, 5-year LRRFS was 92.3%, 5-year DMFS was 89.4%, 5-year DFS was 85.2%, and 5-year CSS was 91.8%. On univariate analysis, age, clinical/pathologic T stages, clinical/pathologic N stages, histologic grade, LI, and ECE were related to survival rates. On multivariate analysis, younger age (≤50), clinical/pathologic stages, and ECE were also related to the survival outcomes.
We could verify several prognostic factors including age, stage, and ECE related survival outcomes after post-operative radiation therapy in TNBC. Distant metastasis was also more common than loco-regional failures. Further detailed analysis, including more patients scheduled for enrolment, would be necessary.
Jin Hee Kim.
Has not received any funding.
All authors have declared no conflicts of interest.
Accelerated hypofractionated or conventional RT post BCS reoprted similar recurrence rates and cosmetic outcomes. Conventional RT delivers radiation dose of 50 Gy in 25 fractions in 5 weeks. Radiobiologic models suggests higher radiation doses over shorter period of time may produce similar outcomes. An accelerated, hypofractionated treatment also might be more convenient for patients and conserve resources, in developing countries where patient load is too much and the resources are limited.
100 patients were randomized to receive hypofractionated radiation with 40 Gy/15#/3 weeks and the control group receiving 50 Gy/25 #/5 weeks. Post radiation therapy all the patients were followed up regularly on monthly interval. Follow up assessment for quality of life made by EORTC questionnaire. All the patients in both study and control groups were assessed regularly and records maintained at weekly intervals with special attention to toxicity, physical examination, QOL scores and subjective evaluation were documented.
The patients in the study group as well as the control group were well matched in terms of age distribution (p value - 0.235).The difference in between both the arms regarding severity and incidence of dermatological toxicities was statistically insignificant (p value - 0.260) at the end of treatment. Radiation induced esophagitis was the main GI toxicity which increased towards the end of the treatment but statistically it was not significant in both the groups (p value - 0.356). Equal number of patients from study and control group showed grade I pulmonary toxicity after the follow up period of 6 months. The difference in both the group was statistically insignificant (p value -1.0).
The hypofractionated radiotherapy in post operative breast cancer patients is more relevant in the present context in our country where the case load is more and availability of the equipment is a major issue. So treating patients with hypofractionated RT will reduce the burden on the machine and will also reduce the number of the visits of the patient to the hospital. This short course RT has improved the compliance very much.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Complications to surgery have been implicated in recurrence in many cancer forms. Methods for breast reconstruction after mastectomy vary substantially in magnitude of surgical trauma. We have previously reported an impact of delayed reconstructive surgery on the relapse dynamics in breast cancer patients. In the current study, our aim was to determine the rate of complications after delayed breast reconstruction, and explore a potential link to oncologic outcome between these events as well as perioperative factors such as use of LMWH.
The study population consists of all patients who had delayed breast reconstruction at Haukeland University Hospital after mastectomy for breast cancer between 1977 and 2007, n = 312. Complications, relapses and deaths were registered from patients’ records. Survival was evaluated by the Kaplan-Meier method.
41% received implant surgery alone, the remaining had autologous reconstructions (28%), or combinations of implant and contralateral reduction (31%). In total 28% experienced complications > = grade 2 (Common Terminology Criteria for Adverse Events, CTCAE version 4.0). In the group receiving autologous flap reconstructions 56% had complications grade > =2. Patients with complications grade > =2 demonstrated a bimodal relapse patterns with a near doubling of the first peak at 18 months, compared to patients with none or minor (grade 1) complications. Overweight or obesity at the time of reconstruction was associated with an increase in relapses the first 18 months after reconstruction, but not with increased complications. Surprisingly, perioperative anticoagulation with LMWH was associated with reduced relapse-free survival.
In our material, complications were significantly more prevalent in patients undergoing extensive reconstructive procedures. This did not result in significantly reduced breast cancer specific or overall survival. The relapse dynamics, however, were affected. This suggests an accelerating effect on the escape of micrometastases from tumor dormancy as a result from an additional inflammatory response induced by the complication.
University of Bergen.
Has not received any funding.
S.A. Jensen: Consult cosmetic surgery: Sørlandet Privatsykehus AS. All other authors have declared no conflicts of interest.
The long-term effectiveness and cosmetic outcomes after intraoperative radiotherapy (IORT) delivered with Xoft® Axxent® Electronic Brachytherapy (eBx®) System in early breast cancer (EBC) is still under evaluation. This system is available in 11 countries around Europe. We aimed to investigate the experience of the European countries with this system and compare the outcomes with the first results in Bulgaria.
We search the PubMed, Scopus and ScienceDirect for clinical trials published before 2019, investigating the effectiveness of an IORT delivered with Axxent® eBx® system as a single radiation dose (20 Gy) in patients with EBC. Our search strategy included: “breast cancer, IORT, Axxent”, “breast cancer, IORT, electronic” and “Axxent, breast”. The identified final reports were compared to a prospective case series of 12 patients fulfilling the GEC- ESTRO low risk group criteria and treated at Department of surgery, Alexandrovska University Hospital, Sofia, Bulgaria.
We searched through 791 results and found 13 eligible studies (Ivanov (2011); Costa (2015); Dickler (2015); Hanna (2015); Zammit (2016); Chowdhry (2017); Hung-Wen Lai (2017); G. Proulx (2017); Olsen (2018); Osorio (2018); Lozares (2018); Silverstein (2018) and Syed (2018)), with a total of 3319 patients. Only Dickler reports results from 5-years follow up. Five of the studies were conducted in Europe. The first published European results come 4 years after the first results from US. Comparison of the outcomes of European studies with ours is shown on Table.
The European studies using the Axxent® eBx®system for IORT show excellent cosmetic results, low recurrence rate and convenience for both patients and medical team in terms of duration of treatment. Still, trials with larger number patients and longer follow up time are needed for conclusions on recurrence rates.
European studies evaluating the effectiveness of Axxent® eBx® system, single dose, 20GyStudy Country Patients (N) Median follow up (months) Cosmetic outcomes Recurrence, % Costa PT 30 18 excellent 3.3 Zammit UK 25 >12 excellent 0 Osorio ES 242 16 good x Lozares ES 150 x x 0 Syed USA / PT 1174 19.5 x 0.85 Vasileva BG 12 15 excellent 0
Mariela Vasileva-Slaveva.
Has not received any funding.
All authors have declared no conflicts of interest.
The dual technique with radio colloid and blue dye is the gold standard in sentinel lymph node biopsy (SLNB) to stage axilla in breast cancer. The objective of the present study was to assess the diagnostic performance of sentinel lymph node (SLN) biopsy using the indocyanine green (ICG) fluorescence method compared with that using the conventional method in detection of sentinel lymph nodes.
60 patients diagnosed with early breast cancer underwent the SLNB procedure using technetium‐99m radio colloid (R), methylene blue dye (MB), and ICG. All SLNs that were removed during surgery were labelled as hot, blue or/and fluorescent and sent for pathological examination. The detection rate of SLNs and positive SLNs, and the number of SLNs of ICG, MB+ R, ICG + MB, ICG + R were compared. Injection safety of ICG and MB was evaluated.
Sentinel Lymph Node was identified in all 60 cases. Total Sentinel lymph nodes removed was 145 (Mean=2, Range 2-5), ICG was able to identify more nodes than the dual dye technique. The identification rate with the dual dye technique was 95%, with blue dye alone 93.6% and with radioisotope alone 96.8% whereas with ICG alone was 100%, with ICG + MB was 96.6% & ICG + R was 96.6 %. 28(46.6%) out of 60 patients had positive nodes which was identified by both dual dye & ICG. None of the patients had any local or systemic reaction with ICG, 3 patients with blue dye had tattooing & staining of skin.
ICG is as effective as the dual dye for SLNB. In addition, as a near-infrared dye, it has the advantages of real-time visualization, lower cost, and wider availability, since no radioactive material needs to be handled. It can be a boon for developed countries & second tier centers of developing country where there is limited access to nuclear medicine department facility & the cost involved in its establishment. A combination of blue dye and ICG is useful dual approach when radioisotope is unavailable.
Manipal Hospital.
Has not received any funding.
All authors have declared no conflicts of interest.
The optimal local therapy for women with BRCA-associated breast carcinoma remains controversial, and still controversial is the prognostic role of controlateral prophylactic mastectomy (PCM). The aim of this study was to investigate the role of risk reductive surgery in BRCA patients.
The authors conducted a retrospective review of 374 women with breast cancer who were tested for BRCA1 and BRCA2 genetic mutations at the Breast Unit of ASST Settelaghi - University of Insubria Varese between 2006 and 2016.
Among the 374 women who underwent genetic testing for BRCA mutation, 70 were found to have a BRCA1 mutation and 58 BRCA2. Among the patients we analyzed 88 women with BRCA1-2 mutation undergoing breast surgery in our Institute. The median age was 44, the median follow-up was 104 months. The overall survival of the treated group was 89,7% at 10 years and down to 77% for a longer follow-up. Analyzing the survival curves in relation to the type of surgery performed, there has not emerged any statistically significant difference in terms of OS among patients treated with conservative surgery compared to patients treated with mastectomy. We analyzed the OS of the group undergoing a PCM compared to the group that underwent no reductive risk surgery. The curves demonstrate that at a median follow-up of 120 months, patients undergoing a PCM appear to have better prognosis although not statistically significant but the benefit is cancelled by going forward with the follow-up years. Survival of 92.9% at 120 months in the PCM group, survival of 87.5% for patients not treated with risk reductive surgery [Breslow (Generalized wilcoxon) p = 0.577].
In the recent literature PCM was shown to reduce the incidence of contralateral breast cancer, but there is insufficient evidence that PCM improves survival, and further studies are recommended.
Senology Research Center, Department of Surgical Sciences and Human Morphology, University of Insubria (Varese-Como), Varese, Italy.
Has not received any funding.
All authors have declared no conflicts of interest.
Biopsy has been the recommended for BI-RADS category 4A, 4B and 4C. However, the malignancy rate of 4A lesions is very low (2-10%). Therefore, the majority of biopsies of category 4A lesions are benign it would take unnecessary costs and make patients anxiety. This study aimed to establish a nomogram, incorporating ultrasound and mammographic as well as patients’ information, to predict the individual likelihood of malignancy of BI-RADS US 4A lesions in diagnostic setting of women with dense breast. To identify patients at lower risk of malignancy and thus avoid unnecessary biopsy.
Nomogram was based on an analysis of 418 BI-RADS US 4A patients with dense breast tissues treated at Sun Yat-sen Memorial Hospital. They also got physical examination and mammography. All patients were confirmed pathology by breast biopsy or surgical excision. Multivariate logistic regression was used to identify statistically significant variables (P < 0.05), and included in the nomogram. The predictive accuracy and discriminative ability were determined by concordance index (C-index) and calibration curve. Model was subjected to external validation using 97 patients from the second affiliated Hospital of Guanghzou medical university.
On multivariable analysis, independent risk factors were history of breast cancer, Ultrasound features (Margin, Shape, Direction, Lymph nodes), Calcifications of mammography, which were in nomogram. The calibration curves for probability of malignancy showed optimal agreement between nomogram prediction and actual observation. The C-index of nomogram for predicting malignancy in training cohort was 0.81 (95%CI: 0.73-0.89), validation cohort was 0.77 (95%CI: 0.58-0.95). In addition, it showed good performance in stratifying different risk groups of patients both in training and validation cohorts.
We developed a well discriminated and calibrated nomogram that can provide individual prediction of malignancy of BI-RADS US 4A with dense breast based on history of breast cancer, Ultrasound features (Margin, Shape, Direction, Lymph nodes), Calcifications of mammography. Our nomogram may help to identify patients at lower risk of malignancy and avoid unnecessary biopsy.
Sun Yat-sen Memorial Hospital, Sun Yat-sen University.
Guangdong, Science and Technique Department, 2017B030314026 and the National Natural Science Foundation of China (81272893).
All authors have declared no conflicts of interest.
The negative pressure therapy (NPWT) is usually used to treat difficult and chronic wounds. Among NPWT devices, some of them, like PICO, have a proven utility as a prophylaxis against surgical wound complications in high risk patients. PICO is a fixed intensity instrument, working with a continuous -80mmHg pressure over the wound.
In the MARIPI study 100 high risk patients have been enrolled, 50 of them received a PICO plaster directly in the surgical room. We have then evaluated the difference in incidence of surgical wound complications between the case and control groups.Patients have been considered eligible to our study in the period 01.01.2016 to 01.01.2017 due to one or more of these following risk factors: diabetes, heavy smoke (more than 10 cigarettes per day), previous radiotherapy in the thoracic fields, skin diseases, vascular or cardiac alterations.
After a deep results analysis, significant difference in the wound infection rate comes out: 1(4.3% ) in the PICO group vs 3 (13,0%) in control group. The same consideration can be made concerning the wound dehiscences: 2 (8.7%) in the PICO group, 6 in the control one (26,1%). (p = 0.093) The whole number of patients’ clinical checks was 113 in the PICO group and 150 in the control one (p < 0.001) Medications with negative pressure reduce the wound infection rate down to about 50 and the dehiscence rate of about 66%, and this can lead to a costs reduction even considering the cost of 200$ (about 130 €) for any PICO medication.
In our opinion, similarly to what may be found in the literature concerning other kinds of surgery, the use of PICO for risk reduction is justified in high risk patients. Further and broader randomized studies are in any case needed to better clarify the role of the therapies with negative pressure in breast cancer patients.
AUSL Romagna.
Has not received any funding.
All authors have declared no conflicts of interest.
The variety and clinical characteristics of BRCA1/2 and non-BRCA1/2 mutations in women with a suspicion of HBOC before the implementation of multi-gene panels in our referral population was unknown.
This is an exploratory study of all consecutive women tested at the HBOC Unit between 2016-2018. TruSight Cancer panel (Illumina) was used and 16 genes were analyzed: BRCA1, BRCA2, PALB2, ATM, CDH1, CHEK2, TP53, NBN, PTEN, STK11, BRIP1, MLH1, MSH2, MSH6, RAD51D and RAD51C. The main objective was to determine the prevalence of pathogenic mutations (PM) and variants of uncertain significance (VUS). Other secondary objectives were explored such as the distribution of the breast cancer (BC) subtypes and the pathological complete response (pCR) rates following neoadjuvant anthracycline/taxane-based chemotherapy in BRCA1/BRCA2/PALB2-PM BC.
451 women were tested. PM and a VUS were found in 60 (12.7%) and 42 (8.9%) patients, respectively. Among PM cases, 37 (62%) had BC and 23 (38%) had OC. The PMs identified in BC were BRCA2 (35.1%), BRCA1 (21.6%), PALB2 (24.3%), TP53 (8.1%), ATM (5.4%), BRIP1 (2.7%) and PTEN (2.7%). All women with PALB2 PM had BC. Within BRCA2-PM BC, the most common subtype was Luminal B (54%), followed by triple-negative (23%), Luminal A (15%) and HER2-positive (8%). Within cases with BRCA1-PM BC, the most common subtype was triple-negative (88%) followed by Luminal B (12%). Within cases with PALB2-PM BC, the most common subtype was Luminal B (56%), followed triple-negative (33%) and Luminal A (11%). Interestingly, within patients BRCA1/BRCA2/PALB2-PM BC (n = 30), only 1 (3.3%) case had HER2+ BC. Following neoadjuvant chemotherapy, 11 of 17 (58%) cases with BRCA1/BRCA2/PALB2-PM BC achieved a pCR. Within cases with OC, PM identified were BRCA2 (39.1%), BRCA1 (39.1%), TP53 (4.3%), BRIP1 (4.3%), CHEK2 (4.3%), RAD51D (4.3%) and MSH6 (4.3%).
Our in-house clinical guidelines detect >10% of tested cases with HBOC. Non-BRCA1/2 PM are found in 35% of the cases. BRCA1/BRCA2/PALB2-PM BC is associated with aggressive tumor biology and high chemotherapy sensitivity.
Hospital Clinic of Barcelona.
Has not received any funding.
A. Prat: Advisory role/lecture fees: NanoString Technologies, Roche, Pfizer, MSD, Novartis, Lilly; Funding: NanoString Technologies, Novartis; Scientific advisory role: Oncolytics Biotech. All other authors have declared no conflicts of interest.
Current UK national guidelines recommend reconstruction discussion for all women undergoing mastectomy for breast cancer. The decision for immediate reconstruction lies with the surgeon, based on patient’s choice, comorbidities and expected post operative adjuvant treatments especially radiotherapy which may affect reconstruction outcome. The aim of our study was to review surgeons’ decisions for immediate breast reconstruction and their accuracy of prediction for post mastectomy radiotherapy.
Prospectively collected 24 months data from a single oncoplastic breast unit was reviewed. All patients who had mastectomy for breast cancer with or without reconstruction were included. Reason for mastectomy, pre-operative tumour characteristics, reconstruction discussion, type of reconstruction and likelihood of postoperative radiotherapy were noted. Final outcome was the number of patients who had immediate reconstruction and needed post mastectomy radiotherapy.
Out of 173 patients who underwent mastectomy for invasive and in-situ breast cancer, 156 (90%) had a reconstruction discussion. Immediate reconstruction was offered to 130 patients and was accepted by 95 of them. Out of all immediate reconstructions, 53 (56%) were implant based and 42 (44%) had autologous reconstruction. Only 9 of these 95 patients required post-operative radiotherapy after MDT discussion. Statistical analysis showed surgeons were able to predict unlikelihood of radiotherapy in majority (90%) of immediate breast reconstruction patients (p = 0.001).
In a high volume breast reconstruction practice unit, we found that only a small number of our immediate breast reconstructions required post mastectomy chest wall radiotherapy. Surgeons are able to make appropriate reconstruction selection based on their predictability of radiotherapy for better-informed decision making and to potentially avoid the associated cosmetic problems.
Local Clinical Audit and Research Department.
Has not received any funding.
All authors have declared no conflicts of interest.
Biopsy proven axillary disease in breast cancer is a contraindication for sentinel node biopsy and is considered a predictor of heavier nodal disease. This may not hold true for early breast cancer with clinically negative axilla with a positive ultrasound biopsy. Our study aimed to identify a group of such patients with minimal involvement of 1-2 lymph nodes, who may benefit from sentinel lymph node biopsy and avoid axillary clearance based on Z11 criteria.
Ten years prospectively collected data of patients with clinically T1-2 N0 breast cancer was reviewed. All patients underwent axillary dissection for positive ultrasound biopsy. Primary outcomes were involvement of 1-2 lymph nodes or > 3 lymph nodes on final histology. Clinico-pathological and radiological factors including tumour characteristics and number of lymph nodes on ultrasound were recorded and analysed with binomial logistic regression model to predict higher lymph node disease of 3 or more lymph nodes on final histology.
One hundred and fourteen patients underwent axillary clearance for cT1-2N0 disease and positive ultrasound guided lymph node biopsy. Forty seven (41%) had only 1-2 lymph nodes positive in the final histology. None of the tested variables were found to have a predictive significance on binary logistic regression model.
It was noted that a substantial number of early breast cancer patients with ultrasound positive axillae show only 1-2 involved lymph nodes. We were unable to find any significant predictors for higher nodal disease. A larger prospective study and consideration of sentinel lymph node biopsy with ultrasound as an adjunct can be the next step forward to avoid axillary clearance in such patients.
Local Audit and Research Department.
Has not received any funding.
All authors have declared no conflicts of interest.
Intraoperative imprint and exfoliative cytology (IEC) or frozen section (FS) are margin assessment techniques to reduce reoperation risk. These techniques reduce the rate of positive margin on permanent section (PS) after breast conservation surgery (BCS), which lead to reduction of reoperation. The rate of positive margin using these techniques are reported accounts for 6–19% of BCS. However, previous studies reported only the single use of each method. The purpose of this study was to elucidate the efficacy of using IEC followed by FS as intraoperative margin assessment (IMA) in BCS regarding the positive margin rate of PS.
Four hundred and fifty-one women who were admitted to our institution and underwent BCS between January 2013 and November 2018, and participated in this study. At first, IEC was performed as IMA. When the margin was likely to be positive by IEC result, FS was added. Additional excision was performed in patients with positive margin FS. We have analyzed the rate of positive margin on PS based on our margin assessment techniques.
Of 451 patients, 121 (26.8%) patients were IEC-positive and 330 (73.2%) patients were IEC-negative. Among these 121 patients who were added FS, 87 (71.9%) patients were FS-positive. Also, 10 (3.0%) of 330 patients with IEC-negative had positive margin with PS. Of 34 patients with FS-negative, no PS-positive patients were found. Though 87 patients with FS-positive received additional excision, only 3 patients resulted in PS-positive. Overall positive margin rate on final pathology according to PS was 2.9% (13 of 451 patients).
Technique of IMA using IEC followed by FS improved positive margin rate of PS compared to that in the previous studies. Our techniques should contribute to reducing reoperation risk.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Worldwide, breast conservation has become increasingly accepted as the surgical management of breast cancer in clinical practice. Cancer care in India is also evolving tremendously with many cancer treatment centres following evidence-based practice hence the rates of breast conservation are expected to increase. Here, we are reporting the rate of breast-conserving surgery (BCS) at our centre.
A retrospective study of 401 patients who underwent breast cancer surgery at a tertiary care centre in South India from January 2015 to August 2017 were analysed to study the rate of BCS. All early breast cancers (EBC) were offered BCS. For large operable breast cancer (LOBC) and locally advanced breast cancer (LABC), neoadjuvant chemotherapy (NACT) followed by BCS was offered to these patients who wish to conserve their breast.
The mean age was 45 years. A total of 163 patients underwent BCS. Yearly, BCS rates were 38.8% in 2015, 36.7% in 2016 and 46.5% in 2017. Majority had EBC 310 (77.3%) of which 62.7% of T1 lesions (n = 51) had BCS, and 45.7% of T2 lesions (n = 258) had BCS of which 5 patients had to undergo NACT to preserve their breast whereas 100% Tis patient (n = 1) had mastectomy. Fifty patients had LOBC and only 2 (4%) patients had upfront BCS whereas 9 of them had to undergo NACT (18%). cT4 lesions had NACT followed by BCS in 2 patients.
The rates of BCS have been increasing in India over the past few years. The majority of the women presented with EBC which makes them suitable for BCS.
Manipal Hospital.
Has not received any funding.
All authors have declared no conflicts of interest.
Intraoperative assessment of sentinel lymph nodes for patients undergoing surgery for early breast cancer has the potential to reduce the need for delayed axillary lymph node dissection (ALND), significantly reducing patient morbidity, expediting adjuvant therapy, reducing length of hospital stay and cost of hospitalisation. This study aims to evaluate intraoperative frozen section in identifying cancerous involvement of sentinel lymph nodes in early breast cancer.
The frozen section and final histopathology reports of 104 consecutive patients undergoing surgery for early breast cancer with sentinel lymph node biopsy between May 2016 and June 2017 were assessed.
Intraoperative frozen section has a sensitivity and specificity of 89.7 (75.8–97.1%, p B 0.05) and 100%, respectively, with a negative predictive value of 94.1 (86.3–97.6%, p B 0.05) in identifying metastasis to sentinel node.
The sensitivity of frozen section is lowered by its inability to accurately pick up micrometastasis. However, frozen section is highly accurate in picking up macrometastasis with a sensitivity of 100%.
Manipal Hospital.
Has not received any funding.
All authors have declared no conflicts of interest.
In recent years, considerable success has been achieved in complex and combined treatment of breast cancer (BC). Reconstructive plastic surgery plays an important role in the rehabilitation of patients with breast cancer and it is currently considered as the causal treatment of mental disorders caused by loss of femininity and integrity of one’s own body. One-step breast reconstruction for cancer treatment makes it possible to use supplementary materials – synthetic and biological implants that can replace muscle autografts and thereby reduce trauma, blood loss, operation time, they help to avoid the defect of donor areas. The authors describe the state of the art at present and demonstrate the results of their own research.
From 2013 to 2018, 104 implant-based immediate reconstructive operations with mesh (N = 80) and ADM (N = 24) were performed in breast cancer patients after subcutaneous or skin-sparing, nipple-sparing mastectomies. The average age of patients is 47, 2 years old. Stage 0 of BC was diagnosed in 2% of patients, I – 30%, IIA – 33%, IIB – 16%, IIIA – 15%, IIIB – 2%, IIIC – 2%. Titanium meshes were used in 12 cases and polyester 3D meshes in 68 cases. The size of Implants ranged from 120 to 585 sm3.
Cosmetic result was rated as excellent in 67,3% cases, good in 19,2%, satisfactory in 7,7%, as very bad in 5,8%. The frequency of implant loss was 5,8% when titanium breast mesh was used and 0% with polyester mesh. Seroma was diagnosed in 1,9% when using pork ADM and 2,9% when using titanium mesh. Necrosis of a nipple was in 1,9% when using titanium mesh. Infection of the implant was recorded in 2,9% cases. A capsular contracture developed in 5,8% cases after radiotherapy.
Biological and synthetic materials are significantly important options for breast reconstruction. They are adequate substitutes for autologous muscle flaps if the patients for the operation are properly select.
The P.A. Herzen Moscow Cancer Research Institute – The Branch of the Federal State Budgetary Institution «National Medical Radiological Research Center» at the Ministry of Health Care of the Russian Federation.
Has not received any funding.
All authors have declared no conflicts of interest.
To evaluate relapses in patients with breast cancer (BC) who underwent radical subcutaneous mastectomy with simultaneous reconstruction.
From 2013 to 2017 radical subcutaneous mastectomies were performed with various types of reconstructions in 472 patients with BC. Reconstruction was carried out by autotissues (15%), as well as expanders, followed by replacement with endoprostheses, as well as a combination of endoprostheses with or without patch (85%). Distribution by patients’ cancer stage: 0 – 5,5%, I – 30,7%, IIA – 28,6%, IIB – 14,8%, IIIA – 13,8%, IIIC – 4,9 %, IIIB – 1,7%. The distribution by biological types of BC is as follows: luminal A - 165 (37%), luminal B - 84 (18,8%), luminal B her2 positive - 74 (16,6%), triple negative - 81 (18,2 %), her2-positive - 42 (9,4%).
The timing of relapse ranged from 0,8 to 5,5 years. In 1 case, a local recurrence was diagnosed simultaneously with distant metastases. A total of 9 patients were diagnosed with a relapse: in 4 cases a local and in 4 cases a regional relapse, and in 1 case a locoregional relapse. Treatment of BC recurrence was as follows: in two cases, polychemotherapy courses were performed, in 6 cases operations were performed - excision of the recurrence in the mammary gland (4), removal of the mammary gland (2), in 1 case - radiation therapy. Metastases were diagnosed in 21 (4,4%) patients. The overall 3 year survival rate was 97,8%. In 13%, relapses were diagnosed in stage IIIC of breast cancer, the lowest percentage of relapses was 0,7% in stage I and IIA. In the case of luminal type A, relapse was diagnosed in 1,8%, in the case of luminal B 2,4%, in the case of the triple negative type 2,5%, and in the case of luminal B her 2 positive - 2,7%. In a multicentric BC, relapse was diagnosed in 5,5%, in a monocentric tumor in 1,5% (p < 0,05).
1) relapses of BC were diagnosed in 9 (1,9 ± 0,6%) cases. 2) distribution of relapses by molecular-biological types of BC: luminal A – 1,8%, B – 2,4%, triple negative – 2,5%, luminal B her2-positive – 2,7%; 3) metastasis of BC was diagnosed in 21 (4,4 ± 0,9%) cases, in 50% metastases were detected in the brain and lungs; 4) 3-year overall survival of patients with BC was 97,8% (n = 269).
Rasskazova E.
Has not received any funding.
All authors have declared no conflicts of interest.
Young women with breast cancer have poorer prognosis, greater lifetime risk of local recurrence, contralateral recurrence, and distant disease, regardless of surgery received. Here we systematically review published evidence relating to the information requirements and preferences of young women diagnosed with early-stage breast cancer offered a choice between mastectomy and breast conservation surgery (BCS). Findings will inform the development of a surgical decision aid for young women.
Eight databases were searched to identify research examining information requirements of young women facing breast oncological surgery treatment decisions. Twelve studies met the inclusion criteria. Data were extracted and summarized in a narrative synthesis.
Findings indicate that young women prefer greater and more detailed information regarding treatment side effects, sexuality, and body image. Younger age of diagnosis leads to an increased risk perception of developing a body image and career. Information is required in a continuum throughout the treatment experience and not only at diagnosis when treatment decisions are made. Young women show differing levels of participation preferences.
Young women find decision-making challenging when the characteristics of diagnosis provide a surgical choice between mastectomy and breast conservation surgery. Efforts should be made to provide information regarding sexuality, body image, reconstruction, fertility and likelihood of familial predisposition. Further research is needed to identify the specific level and information requirements of this young-onset group. The low number of studies indicates a need to design studies targeting specifically this age group of breast cancer patients.
NWGH.
Has not received any funding.
The author has declared no conflicts of interest.
To improve our understanding of the molecular mechanisms underlying response to immune checkpoint inhibition, we monitored dynamic changes within the tumour microenvironment exposed to immune checkpoint inhibition by single-cell RNA sequencing (scRNA-seq).
In a window-of-opportunity setting, fresh tumor tissue was collected from breast cancer patients before and 10 days after a single dose of 200 mg Pembrolizumab monotherapy. Hematoxylin-eosin (H&E) staining to determine tumor infiltrating lymphocytes (TILs) and scRNA-seq was performed on fixed and fresh tumor tissue, respectively. Single cell suspensions were subjected to 10X Genomics scRNA- and T-cell receptor-sequencing using the Chromium Single Cell 5’ kit on an Illumina NovaSeq. Expression matrices were generated using CellRanger and analyzed by Seurat. Dimensionality reduction was applied by PCA.
Currently, 7 paired tumor samples have been analyzed. All were ER/PR-negative IDA, of which 3 were pre-treated with neo-adjuvant chemotherapy. On H&E slide, there were no notable differences in TILs comparing biopsies before versus after Pembro. By scRNA-seq, we did observe several prominent changes. First, there was a decrease in cancer cells versus an increase in immune cells after Pembro. Second, the increase in T-cells was due to an increased prevalence of exhausted CD4+ and CD8+ cytotoxic cells, as well as regulatory T-cells, which were all positive for PD1 expression. Cytolytic activity in these T-cell subpopulations also increased significantly, and this was accompanied by a specific increase in TCR clonotypes in these. Finally, in 3 out of 7 pairs such changes in T-cells were not detectable. In these post-treatment samples, a decrease in expression of MHC class 1 genes was observed specifically in cancer cells.
Our data suggest that scRNA-seq creates accurate maps of the tumor micro-environment and is capable of monitoring dynamic changes already induced by a single dose of immunotherapy. Particularly, in 4/7 patients changes in T-cells reactivity reminiscent of a clinical response to Pembrolizumab were noted. Other patients failed to display such reactivity presumably due to a failure in presenting neo-epitopes by MHC class 1 genes.
NCT03197389.
University Hospitals Leuven.
Investigator initiated study MSD Kom op Tegen Kanker Fonds Nadine de Beauffort VIB VIB Grand Challenge.
All authors have declared no conflicts of interest.
Tumor-infiltrating lymphocytes (TIL) have been associated with good clinical outcomes in HER2-positive (HER2+) and triple-negative (TN) breast cancer (BC) patients. Recently, we found that in 60% of BC, TIL are organized in tertiary lymphoid structures (TLS) in the stroma. We further identified a CXCL13-producing CD4+T follicular helper (Tfh) cell subpopulation associated with positive clinical outcomes in BC. We aimed to investigate how CD4+ Tfh cells, expressing the CXCL13 receptor CXCR5, contribute to immune response in BC TLS.
Prospectively collected fresh primary BC tissues were dissociated without enzymes to separate tumor supernatants and TIL and used for Immunoglobulin (Ig)/cytokines quantification and flow cytometric analysis/sorting. Matching formalin-fixed paraffin-embedded (FFPE) were used for spatial analysis.
In our BC cohort, around 15% CD4+ TIL, 13% CD8+ TIL and >95% B cell TIL express CXCR5 while confocal microscopy reveals that they colocalized in BC TLS. In some BC Tfh TIL (as activated tonsillar Tfh) express ICOS and PD-1 suggesting they are activated. RNA analysis on sorted Tfh TIL detected high expression of IL-21, INFg, and CXCL13. In an in vitro assay where Tfh TIL were activated with splenic B cells revealed that only ICOS+PD-1+Tfh TIL from TN/HER2+ BC are capable of inducing Ig secretion by B cells. mRNA analysis of sorted ICOS+PD-1+Tfh TIL confirms an activated, functional nature for the former with high levels of mRNA expression of IL-21, INFg, and CXCL13. We found that CXCR5+CD8 TIL expressing ICOS and PD-1 are related to high expression of CCL4, FASL, granzyme B and IFNγ. Indeed multiplex IHC analyses confirm the presence of the later in close contact with functional Tfh and B TIL. A high correlation between the presence of functional Tfh with activated CD8 TIL and with Ig secreted in the NANT from TN/HER2+ BC was observed.
We describe two distinct population of Tfh TIL. The CXCL13-producing Tfh that may recruit the CXCR5+Tfh TIL in BC TLS. Functional Tfh TIL probes to guide humoral and cytotoxic anti-tumor immunity in TLS. These data shed light on anti-tumor immune responses taking place in the TLS, whose functional activities may have important treatment implications, particularly for immunotherapy in BC.
Karen Willard-Gallo.
Fonds National de Recherche Scientifique Belgium/ Télévie.
All authors have declared no conflicts of interest.
Triple negative breast cancer (TNBC) account for about 30% of invasive breast cancers in the Indian population. TNBC is an inherently aggressive cancer with limited treatment options. Hence alternative lines of treatment are the urgent need of the day. Immune checkpoint inhibitors are a new class of drugs used in the treatment of various cancers, the advantage being long lasting response and reduced toxicity.PDL-1 is a ligand which is a part of this immunomodulating pathway.
Paraffin blocks of 201 triple negative breast cancer (TNBC) patients are tested for the expression of PDL-1 expression by immunohistochemistry. Clinicopathological features associated with PDL-1 expressing cancers were compared with PDL-1 negative cancers. 5-year Disease free survival (DFS)and pathological complete response (pCR) were compared between PDL-1 positive and negative TNBC patients.
201 blocks of TNBC patients were evaluated for expression of PDL-1 receptor with immunohistochemistry. 48.2% of patients were PDL-1 positive,51.7% were PDL-1 negative. The probability of 5-year disease free survival(DFS) of PDL-1 positive patients was 82% compared to 87.2% in PDL-1 negative patients. There was no statistical significant difference in 5-year DFS between PDL-1 positive and negative patients. There is no statistically significant association between PDL-1 positivity and clinicopathological factors like age, pathological tumor stage, pathological nodal status, grade, lymphovascular invasion and pathological complete response.
Expression of PDL-1 was approximately 50% in triple negative invasive breast cancers in the Indian population. Disease free survival is comparable between PDL-1 positive patients and PDL-1 negative patients. Factors like age, histological type, pathological tumor stage, pathological nodal status or lymphovascular invasion and response to chemotherapy were not significantly different between PDL-1 positive and negative patients.PDL-1 expression may serve as a predictive factor for response to treatment with immune check point inhibitors in the future.PDL-1 testing needs further standardization.
Scientific Review Committee, Regional Cancer Centre.
Regional Cancer Centre, Trivandrum, India.
All authors have declared no conflicts of interest.
Toll-like receptor -3 is a nucleic acid-sensing innate immune receptor that detects RNA released from narcotic cells in the tumor microenvironment. TLR3 is expressed on the endosomal compartments but the surface expression of TLR3 has also been reported in various cancers, including breast cancer from our group (Bandopadhya et al., 2015). TLR3 exclusively uses TRIF dependent pathway to mediate its effect on cellular apoptosis and hence used in different clinical trials. But, the outcomes of clinical trials using TLR3 agonists are not always favorable. In the present work, we have addressed the involvement of canonical MyD88 mediated pathway through cell surface to explain the anti-apoptotic effect.
Human breast cancer cells MDA-MB-231, MCF-7 and T47D were challenged with TLR3 ligand Poly (I:C) and MyD88 inhibitor (ST2825). Cell proliferation, BrdU incorporation assay, ELISA, Confocal Microscopy, Western blotting, Co-Immunoprecipitation, and immunohistochemistry were carried out to investigate the signaling cascade.
Poly (I:C) treatment enhances the cell proliferation, DNA content and cell viability while MyD88 inhibitor reversed the effect of Poly (I:C). The expression level of secretary IL-6 as well as nuclear localization of NF-kB (p65) was significantly increased with Poly (I:C) addition but the level was decreased with the addition of MyD88 inhibitor. The expression level of P-IRAK1, P-TAK1, IRAK1, TAK1, TAB1, TRAF-6, and Cyclin D1 had significantly increased with Poly (I:C) addition but the level was decreased with the addition of MyD88 inhibitor. The formation of TRAF-6, TAK1 and TAB1 complex also showed the same pattern.
The mechanistic process includes surface ligand bound TLR3 induces MyD88 dimerization, which promotes the early phase nuclear localization of p65, to up-regulate IL-6 production and finally promote Cyclin-D1 production. Elevated Cyclin-D1 can justify cellular proliferation than apoptosis which is independent of established TRIF meditated TLR3 signaling promoting apoptosis. Thus, this is the first time reporting the surface TLR3 might use MyD88 mediated canonical pathway. Thus our work can help to TLR3 ligand mediated immunotherapy that got set back earlier clinical trial.
Anupam Basu, PhD Molecular Biology and Human Genetics Laboratory Professor Department of Zoology the University of Burdwan Purbo Bardhaman - 713104.
Science and Engineering Research Board, Department of Science & Technology, Government of India.
All authors have declared no conflicts of interest.
In 3 Phase III trials, RIB (cyclin-dependent kinase 4/6 inhibitor) + various ET partners demonstrated longer progression-free survival (PFS) vs placebo (PBO) + ET in patients (pts) with HR+/HER2– ABC. Using pooled trial data from the MONALEESA–2 (ML-2; all patients), ML-3 (ET-naïve subgroup only), and ML-7 (NSAI subgroup only) trials, we further evaluate efficacy in ET-naive pts here.
ML-2 and ML-3 enrolled ET-naive postmenopausal pts with ABC to receive PBO or RIB + study-designated ET, letrozole (ML-2) or fulvestrant (ML-3). In ML-7, ET-naive premenopausal pts with ≤1 line of chemotherapy for ABC received RIB or PBO + goserelin + nonsteroidal aromatase inhibitor or tamoxifen. The primary endpoint was locally assessed PFS. Secondary endpoints included clinical benefit rate (CBR) and overall response rate (ORR).
Data were pooled from 1530 pts (including 34% with de novo metastatic disease) treated with RIB + ET (n = 820) or PBO + ET (n = 710). Median follow-up time for PFS was 15.1 (ML-2), 16.5 (ML-3), and 13.0 (ML-7) months. Addition of RIB to ET prolonged PFS vs PBO (median, 25.3 vs 15.6 months; HR, 0.57 [95% CI, 0.49-0.66]). The PFS benefit of RIB + ET over PBO + ET was observed in most pt subgroups, including those defined by age, race, baseline ECOG performance status, presence of visceral or bone metastases, de novo metastatic disease, and prior chemotherapy. ORR and CBR were both improved in the RIB arm vs the PBO arm, and the estimated probabilities of tumor response for RIB vs PBO were 16.0% vs 10.0% at 2 months, 35.2% vs 22.6% at 6 months, and 42.3% vs 28.8% at 12 months (Table).
The addition of RIB to several ET partners consistently demonstrated longer PFS and higher response rates vs PBO + ET in this pooled population. This very large data set (> 1500 pts) supports RIB-based ET as an option for a diverse population of pre- and postmenopausal pts with ET-naive HR+/HER2– ABC.
MediTech Media, funded by Novartis.
MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), MONALEESA-7 (NCT02278120).
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
D. Tripathy: Grants, personal fees: Novartis; Pfizer during the conduct of the study; Personal fees: Nektar Therapeutics, CellMax Life, Sellas Life Sciences, Polyphor Ltd, GlaxoSmithKline, Genomic Health, outside the submitted work. G.N. Hortobagyi: The work under consideration for publication - Novartis: Grant and personal fees; Relevant financial activities outside the submitted work - Consulting: Lilly, Pfizer. S-A. Im: Relevant financial activities outside the submitted work: AstraZeneca - Grant Spectrum, Novartis, Roche/Genetech - Advisory board member. S. Chia: Honorarium for advisory boards: Novartis, Hoffmann LaRoche, Pfizer, AstraZeneca, Genomic Health; My institution has participated in research studies: Novartis, Hoffmann La Roche, Pfizer, AstraZeneca, Genomic Health, Genentech, Merck, BMS. S.A. Hurvitz: Grants: Ambryx, Amgen, Bayer, OBI Pharma, Bimarin, Cascadian, Daiichi Sankyo, Dignitana, Genentech, Gsk, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, Puma, Roche, Seattle Genetics. A. Ridolfi: Employee: Novartis Pharmaceuticals Corporation. All other authors have declared no conflicts of interest.
CBR, clinical benefit rate; ET, endocrine therapy; ORR, overall response rate; NE, not evaluable; PBO, placebo; PFS, progression-free survival; RIB, ribociclib; TTR, time to response. a Proportion of patients with confirmed complete or partial response, or stable disease/non–complete response/non–progressive disease ≥24 weeks. b Percentage is the estimated probability of having an event at or prior to the specified time point based on Kaplan-Meier estimates.RIB + ET (n = 820) PBO + ET (n = 710) PFS, median, months 1-year PFS (95% CI), % 2-year PFS (95% CI), % 25.3 74.3 (71.0-77.3) 54.2 (49.7-58.4) 15.6 60.2 (56.4-63.8) 35.7 (31.5-40.0) ORR (95% CI), % 40.6 (37.2-44.0) 28.3 (25.0-31.6) CBR (95% CI), %a 78.5 (75.7-81.3) 70.1 (66.8-73.5) TTR (95% CI), %a 2 months 6 months 12 months 16.0 (13.6-18.8) 35.1 (31.8-38.6) 42.3 (38.9-46.0) 10.0 (8.0-12.5) 22.6 (19.7-26.0) 28.8 (25.5-32.4)
In the PALOMA-3 trial, palbociclib plus fulvestrant demonstrated a clinically meaningful improvement in overall survival compared with fulvestrant plus placebo in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer who had relapsed or progressed on prior endocrine therapy (Turner NC et al., NEJM 2018). Detailed analyses for first-line (1L) and later-line (2L+) therapy are still limited.
The prospective, multicenter phase 2 INGE-B trial was designed to generate efficacy and safety data on the combination of palbociclib with letrozole (1L) or fulvestrant (1L, 2L+) in accordance with the PALOMA trials and to generate so far lacking trial data on the combination of palbociclib with anastrozole (1L), exemestane (1L) or letrozole (2L+). This pre-planned interim analysis was conducted to evaluate data on pts receiving palbociclib plus fulvestrant as 1L or 2L+ therapy. The primary objective was the clinical benefit rate (CBR) in pts with measurable disease according to RECIST v1.1. Key secondary endpoints included the overall response rate (ORR), the CBR for all pts, and safety. Data were analyzed with descriptive statistics.
At the cut-off date of the interim analysis (Dec 17, 2018), 124 pts have been recruited from 03/2017 through 06/2018 at 47 sites across Germany to receive palbociclib plus fulvestrant (1L: 57 pts; 2L+: 67 pts). Of those, 54 pts treated in 1L were evaluable. Median age was 69.5 years, 96.3% of pts had an ECOG performance score of 0 or 1. 31.5% of pts had bone-only disease. The CBR was 58% (n = 21) for the 36 pts with measurable disease (RECIST v1.1) and 65% (n = 35) for all pts (investigator assessment). The ORRs were 36% and 30%, respectively. Grade 3/4 adverse events experienced by at least 10% of pts were neutropenia (n = 17, 31.5%) and leukopenia (n = 8, 14.9%).
This INGE-B interim analysis showed for the first time a remarkable clinical benefit for palbociclib plus fulvestrant as first-line therapy for pts with HR+/HER2- advanced breast cancer. No new safety signals emerged.
EudraCT-Nr. 2015-001603-32 29-JAN-2016.
Iomedico AG.
Pfizer Pharma GmbH.
A. Welt: Advisory boards: AstraZeneca, Novartis, Roche, Eisai, Pfizer, Amgen, Lilly; Fees: COCS GmbH, Iomedico AG, Interplan AG; Funding of scientific programs: Novartis; Stock ownership: None. D. Lüftner: Stock ownership: None; Membership on an advisory board or board of directors: Amgen, Novartis, Eli Lilly, Pfizer, Celgene, AstraZeneca; Corporate-sponsored research: Novartis. All other authors have declared no conflicts of interest.
This large study aims to explore in depth the impact of breast cancer (BC) subtype on metastatic behavior and long term outcome.
This is a retrospective single centre study of 5971 patients with newly diagnosed, unilateral first diagnosis of BC, diagnosed between 2000 and 2010. Surrogate BC subtypes were defined according to immunohistochemical criteria (estrogen receptor (ER), tumor grade, HER2), and the HER2+ subgroups were separately analyzed depending on trastuzumab (TRTZ) administration. The impact of BC subtype was evaluated in terms of first distant metastatic event behavior and breast cancer specific survival (BCSS), defined as time from first distant metastases (DM) till death due to breast cancer. Analysis was performed using the Kaplan-Meier method, logistic and Cox regression.
The cohort consisted of 5071 early BC pts treated with upfront surgery (EBC) of whom 621 (12,2%) developed DM, 592 early BC pts treated with neoadjuvant systemic therapy (NEO) of whom 196 (33.1%) developed DM, and 308 primary metastatic pts (META). Median FUP was 122,9 Mo (IQR 92-156). For EBC+NEO, DM rate per subtype was: LumA(grade 1-2) 8.1%, LumB(grade 3) 20.4%, ER+HER2+ without TRTZ 21.7%, ER+HER2+ with TRTZ 9.0%, ER-HER2+ without TRTZ 30.0%, ER-HER2+ with TRTZ 19.8% and Triple Neg BC (TNBC) 25.3%. Primary metastatic disease (META) rate per subtype was least common in TNBC (17,7%) and most common in ER+HER+ with TRZT (37,8%) and LumA (34,1%). There were major differences in site of first DM according to subtype. Median BCSS was worst for TNBC (12.0 mo) and best for LumA (46.7mo) and ER+HER2+ with TRZT(43.1mo). For pts with single organ DM, median BCSS was worst for brain localization (17.9mo), compared to skin (24.1mo), lung (25,0mo), liver (33,8mo), bone (38.7mo). Multiple sites of first DM had worse BCSS (³3 sites 20,5mo) compared to 2 sites (27,1mo) or 1 site (40.0mo). BCSS is longer in primary DM (META: 43,4mo) as compared to secondary DM (EBC+NEO: 27,9mo) but when looking at subtypes, this difference only seems important in LumA and LumB subtypes.
Tumor subtype influences the metastatic behavior and survival after development of metastatic disease.
University Hospitals Leuven.
Has not received any funding.
H. Wildiers: Travel support: Roche, Pfizer; His institution received consulting fees, honoraria: Roche and other companies; His institution received an unrestricted research grant: Roche. P. Neven: Speaker’s fees, consulting fees, research support: Roche (all provided to his institute); Advisory board: Novartis, AstraZeneca, Lilly, Pfizer (all consulting fees are provided to his institute). K. Punie: Consulting fees, travel support: Roche (all provided to his institute). All other authors have declared no conflicts of interest.
This study investigates efficacy and safety of intermittent versus continuous scheduling of chemotherapy over two treatment lines for patients within the Stop & Go trial.
Participants were randomized to two sets of four cycles (intermittent) or eight consecutive cycles (continuous) of chemotherapy in two treatment lines. First-line consisted of paclitaxel plus bevacizumab, second-line of capecitabine or non-pegylated liposomal doxorubicin. The primary endpoint of the present study was progression-free survival (PFS) of second-line treatment.
Characteristics at randomization were well-balanced. Patients with a good baseline performance status, only non-visceral metastasis, longer disease-free-interval, and HR-positive disease more often started second-line study treatment. For patients who started second line study treatment (n = 270; 131 vs. 139 in intermittent vs. continuous arm) median PFS in second-line was respectively 3.5 vs. 5.0 months with a Hazard Ratio (HR) of 1.04 (95%CI 0.69-1.57), and median OS in second-line was 10.6 vs.12.0 months, with a HR of 1.64 (95%CI 1.08 – 2.48). The median combined first- and second-line PFS for this population was 14.6 vs. 16.6 months with a HR of 1.59 (95%CI 1.04 – 2.45), and median OS measured from randomization was 20.3 vs. 23.0 months with a HR of 1.93 (95%CI 1.26 – 2.95). For all randomized patients (n = 420) median combined first- and second-line PFS was 12.7 vs. 13.9 months, with a HR of 1.21 (95%CI 0.9 – 1.63), and OS measured from randomization was 17.1 vs. 20.9 months with a HR of 1.37 (95%CI 1.03 - 1.54) for intermittent vs. continuous scheduling respectively. Selected baseline characteristics and first-line PFS duration were not significantly associated with second-line PFS in exploratory analyses. However, patients with longer first-line PFS more often started second-line study treatment (odds ratio 2.13; 95%CI 1.20 – 3.78) compared to patients with shorter first-line PFS. Details on safety will be presented at the meeting.
In conclusion, considering the overall survival benefits of continuous scheduling in both first- and second-line chemotherapy, we recommend this strategy for treatment of advanced breast cancer.
EudraCT 2010-021519-18; BOOG 2010-02.
Dutch Breast Cancer Research Group (BOOG).
F. Hoffmann-La Roche Ltd, The Netherlands TEVA Nederland, B.V.
F.L.G. Erdkamp: Honoraria, consulting/advisory role: Roche, Novartis. V.C.G. Tjan-Heijnen: Honoraria: E. Lilly, Pfizer; Funding for her institution: E. Lilly, Roche, Eisai, Pfizer, Novartis; Travel expenses: E. Lilly, Pfizer, Novartis, Roche; Consulting or advisory role: E. Lilly, Pfizer, Roche. All other authors have declared no conflicts of interest.
The phase III Stop&Go study randomized patients with advanced breast cancer to two times four intermittent cycles or to eight continuous cycles of first- and second-line chemotherapy, yielding inferior overall survival (OS) with intermittent scheduling. Here we report on the prospectively planned quality of life (QoL) analyses.
QoL was measured by RAND-36 questionnaires every 12 weeks during study treatment and follow-up. Physical and mental component scores were calculated and presented as T-scores with a mean of 50 and a standard deviation (SD) of 10 for the normal population, with higher scores representing better QoL. All patients who responded to baseline questionnaires with sufficient valid data were included. The primary objective was to describe the course of physical and mental QoL for both treatment arms, and to estimate differences in changes from baseline in physical and mental QoL between arms. These differences were estimated longitudinally with multilevel linear regression analyses with a follow up period of 30 months. An effect size of 0.5 SD (5 points) was considered clinically meaningful.
A total of 398 patients were included with a median follow-up of 11.3 months (IQR 5.6 - 22.2). Mean baseline scores were 37.9 and 38.3 for physical, and 44.7 and 42.5 for mental QoL for intermittent and continuous treatment respectively. Physical QoL declined linearly in the intermittent arm causing a clinically meaningful difference of 5.68 points at 24 months (p < 0.001), while scores in the continuous arm stabilized after a decline of ± 3.5 points at 12 months. Conversely, mental QoL was fairly stable and even improved by 1.86 (p = 0.012) and 2.53 points (p = 0.001) at 12 months for intermittent and continuous treatment. When comparing the arms for both components in changes from baseline, the maximum differences were 3.11 points (p = 0.069) for physical and 3.32 points (p = 0.057) for mental scores, both measured at 30 months and in favor of continuous treatment.
Intermittent chemotherapy was less effective and showed a trend for worse impact on QoL compared to continuous chemotherapy in advanced breast cancer.
EudraCT 2010-021519-18; BOOG 2010-02.
Dutch Breast Cancer Research Group (BOOG).
F. Hoffmann-La Roche Ltd, The Netherlands TEVA Nederland, B.V.
F.L.G. Erdkamp: Honoraria, consulting/advisory role: Roche, Novartis. V.C.G. Tjan-Heijnen: Honoraria: E. Lilly, Pfizer; Funding for her institution: E. Lilly, Roche, Eisai, Pfizer, Novartis; Travel expenses: E. Lilly, Pfizer, Novartis, Roche; Consulting or advisory role: E. Lilly, Pfizer, Roche. All other authors have declared no conflicts of interest.
CDK 4/6 inhibitors (palbociclib, ribociclib, abemaciclib) have been rencently introduced in the clinical management of ER positive metastatic breast cancer (MBC) patients, based on significant improvements in terms of progression free survival (PFS); however, no improvent in overall survival (OS) has been demonstrated in individual trials so far. The purpose of this analysis was to assess, across trials, the effect on progression free (PFS) and overall survival (OS) of the combination of endocrine therapy and CDK 4/6 inhibitors.
We searched literature databases to identify randomized controlled trials that compared endocrine therapy (ET) with ET plus CDK4/6 inhibitors in ER positive MBC. The main outcome measures for this analysis were OS and PFS. Log hazard ratios (HRs) for OS and PFS were pooled across the studies by inverse variance weighting. Primary analyses were done with a fixed effects model, since no heterogeneity was found among studies.
We found 7 randomised clinical trials including 3854 patients. Of these, 4 included only first line therapy and 3 allowed prior treatments for MBC. Overall, the addition of CDK4/6 inhibitors to ET was associated with a significant improvement in PFS (HR = 0.54, 95% CI, 0.49 to 0.59; P 0.001), without any remarkable heterogeneity (I2 = 0). In trials of first line therapy, the HR was 0.56 (95% CI, 0.49 to 0.63, P < 0.001); in trials including pretreated MBC the HR was 0.52 (95% CI 0.46 to 0.60, P < 0.001). OS data were reported by 3 out of 7studies (1354 patients); a statistically significant improvement in OS was detected (HR 0.79; 95% CI, 0.66 to 0.96; P 0.015). There were no differences in effects on PFS among subgroups defined by age, metastatic site and Disease Free Interval.
The addition of CDK 4/6 inhibitors to endocrine therapy in ER positive MBC was consistently associated with a 50% reduction in the rate of progression both in first and subsequent lines of treatment and this effect appears to be independent of age, site of metastasis and DFI. Overall survival data are available in 3 studies, showing that the PFS advantage translates into a clinically meaningful and statistically significant survival advantage.
Alessandra Gennari.
Has not received any funding.
A. Gennari: Advisory board: Novartis, Roche, Pfizer, MSD, Lilly. All other authors have declared no conflicts of interest.
BRCA testing rates, treatment patterns and outcomes were compared based on BRCA mutation status in HER2- adult women with ABC.
Oncologists extracted data from patient charts in adult women with HER2- ABC across the US and France, Germany, Italy, Spain and the United Kingdom (EU5) via the Adelphi Advanced Breast Cancer Disease Specific Program. Data drawn from 2015 and 2017 were merged across common variables. Patients were categorized into three mutually exclusive cohorts; BRCA mutations (BRCAm), wild type (BRCAwt), and unknown status (BRCAunk). Treatments received and 1st line duration of therapy was compared between BRCAm and BRCAwt using Fisher exact, Mann-Whitney tests, and t-tests.
The study included 6,161 adult women with HER2- ABC (4,611 hormone receptor positive [HR+/HER2-], 1,415 triple negative breast cancer [TNBC], 135 unknown hormone status). Overall, 28% of patients received ≥1 BRCA test at any point in their lifetime (23% HR+/HER2-, 41% TNBC). 235/6,161 (4%) patients were identified as BRCAm, 1,025/6,161 (17%) as BRCAwt, and 4,901/6,161 (80%) as BRCAunk. Within the HR+/HER2- cohort, patients with BRCAm were more likely to receive 1st line chemotherapy compared to BRCAwt (65% vs 49%; P = 0.005) and less likely to receive endocrine +/- targeted therapies (33% vs 49%; P = 0.003). TNBC treatments consisted primarily of chemotherapy and were similar between BRCAm vs. BRCAwt, (89% vs. 91%; P = 0.545). Mean duration among patients who completed 1st line treatment was numerically shorter for patients with BRCAm [Table].
1st line duration of therapy (mean months [SD]) based on BRCA status Includes HR+, TNBC and HR unknown patients.BRCAm (n = 34) BRCAwt (n = 282) P value HR+/HER2- 7.8[10.0] 11.4 [5.5] 0.648 TNBC 6.4 [6.1] 5.0 [2.9] 0.933 HER2-a 6.6 [7.0] 9.0 [13.4] 0.408
In this study of adult women with HER2- ABC, low BRCA testing rates were observed. Patients with BRCAm were significantly more likely to utilize chemotherapy relative to BRCAwt. Mean duration of 1st line therapy was numerically lower among patients with BRCAm. With the advent of new treatment options, additional studies are warranted to validate these findings.
Pfizer.
Pfizer.
A. Niyazov: Employee, stockholder: Pfizer; R.G.W. Quek: Employee, ownership interest: Pfizer. All other authors have declared no conflicts of interest.
EMBRACA, a randomized 2:1 open-label Phase 3 trial (NCT01945775), showed a significant improvement in progression-free survival with talazoparib (TALA) vs physician’s choice of chemotherapy (PCT) (HR = 0.54; 95%CI: 0.41,0.71; P<.0001) in pts with HER2-negative ABC and a gBRCAm. This analysis evaluated the hospitalization and SCM utilisation while accounting for TALA/PCT–treatment-emergent period in EMBRACA.
From EMBRACA safety population (while pts were on TALA or PCT), serious adverse event (SAE)-associated hospitalization rates (per 100 patient-years), number of pts with ≥1 platelet/red blood cell (RBC) transfusion(s) and 7 types of SCM (opiate, antiemetic/anti-nauseant, antidiarrheal, appetite stimulant, bone disease treatment, antianemic, immunostimulant) utilisation ratios (total duration of each SCM type/treatment-emergent period) were compared between TALA vs PCT-treated pts.
EMBRACA safety population consisted of 286 TALA and 126 PCT-treated pts. Lower rates of SAE-associated hospitalization were observed with TALA vs PCT-treated pts (39.5 vs 64.0 per 100 patient-years). Nine TALA-treated pts (3.1%) had ≥1 platelet transfusion(s) vs 0 PCT-treated pts; 109 TALA-treated pts (38.1%) had ≥1 RBC transfusion(s) vs 7 (5.6%) PCT-treated pts. Across all 7 other types of SCM, the mean SCM utilisation ratios for TALA-treated pts were lower than PCT-treated pts (Table).
SCM Type Talazoparib Mean SCM Utilization Ratio (SD) n = 286 Overall PCT Mean SCM Utilization Ratio (SD) n = 126 Antianemic 8.0 (40.6) 14.3 (26.6) Antidiarrheal 1.3 (1.8) 5.0 (14.7) Antiemetic/Anti-nauseant 5.5 (11.2) 5.9 (8.8) Appetite Stimulant 1.2 (2.1) 9.9 (12.6) Bone Disease Treatment 4.5 (4.8) 6.6 (6.1) Immunostimulant 0.1 (0.2) 0.8 (1.5) Opiate 6.2 (10.9) 13.7 (17.4)
Pts with HER2-negative ABC and a gBRCAm treated with TALA had lower SAE-associated hospitalization rates and lower SCM utilization ratios vs PCT. More TALA-treated patients had ≥1 platelet/ RBC transfusion(s) vs PCT. These results may support the favorable clinical and patient reported outcomes observed with TALA vs PCT-treated pts in EMBRACA.
Pfizer.
Pfizer, Inc.
J. Ettl: Consulting fees: Lilly, Novartis, Pfizer, Roche, Tesaro, Eisai; Contracted research: Celgene; Honoraria: Pfizer, Roche, Teva, Lilly, AstraZeneca; Travel support: Celgene, Novartis, Pfizer. R.G.W. Quek: Employee: Pfizer Inc.; Stock ownership: Pfizer Inc., Amgen Inc. S.A. Hurvitz: Grants: Ambryx, Amgen, Bayer, BI Pharma, Biomarin, Cascadian, Daiichi Sankyo, Dignitana, Genentech, GSK, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, Puma, Roche, Seattle Genetics; Travel: Lilly, Novartis, OBI Pharma. A. Goncalves: Travel/accommodation/meeting registration fees: Pfizer, AstraZeneca, Roche, Novartis, Amgen, Cellgene, MSD, Boehringer Ingelheim. H.S. Rugo: Research funding to the University of California: Eisai, Genentech, GlaxoSmithKline, Lilly, Macrogenics, Merck, Novartis, OBI Pharma, Pfizer, Plexxikon; Travel expenses: Lilly, Mylan, Puma. All other authors have declared no conflicts of interest.
CR1447 is a novel transdermal formulation of 4-OH-Testosterone with aromatase inhibiting properties and androgen receptor modulation. Phase I data demonstrated efficacy and a favorable toxicity profile. In this trial efficacy and toxicity cohort A (A) with estrogen-receptor positive disease and cohort B (B) with androgen-receptor positive triple negative metastatic breast cancer was investigated.
Based on the phase I data, a dose of 400 mg was topically administered on both thighs every day. Primary endpoint was disease control rate at week 24 (DC24). The goal is to show that disease control at 24 weeks (DC24) of > 30% (A) and >15 % (B). In (A) patients (pts) with a maximum of one line of endocrine therapy for advanced disease (AD) for at least six months without progression were eligible (N = 21). Eight pts were excluded because they did not fulfill these criteria. In (B) up to two prior lines of chemotherapy for AD were allowed.
After registration of 37 pts (A)=29 and (B)=8, accrual was stopped after an interim analysis due to futility in (A) and slow accrual in (B). DC24 was reached in 5 out of 21 eligible pts (24%) in (A) and 0% in (B). In (A) eight pat were ineligible due to amendment of inclusion criteria. In (A) median PFS of eligible pts was 5.1 months (m) (95% CI: 2.5-5.6) and 2.6 months (95% CI: 2.1-2.9) in non-eligible pts. In (B) median PFS was 2.5 m (95% CI 0.7-2.6). Median OS of eligible pts in (A) was 24.6 m (95% CI 22.9-NA) and in (B) 10.8 m (95% CI 3.3-10.9). QoL assessed by FACT-ES questionnaire at baseline, week 4 and 24 showed no deterioration under treatment. CR1447 had a favorable safety profile without treatment related grade 3-5 toxicities in stratum A. Most common treatment related toxicities were: hypertriglyceridemia (60%), aspartate aminotransferase increased (51%) and dry skin (46%).
CR1447 is an innovative endocrine therapy with a favorable safety profile. Despite not reaching the primary endpoint (DC24 in 30% of patients), the DC24-rate of 24% in the 2nd-line setting and one patient in prolonged PR are a signal of activity. Further evaluation in a truly endocrine sensitive population is warranted.
NCT02067741.
SAKK Switzerland.
Curadis, Erlangen, Germany.
All authors have declared no conflicts of interest.
Metastatic breast cancer is a complex disease that is traditionally treated using systemic therapy. There is mounting evidence that locoregional therapy (LRT), such as resection of the primary tumour and/or localised radiotherapy could be associated with improvements in survival. We aimed to conduct a meta-analysis to inform decision making.
Using the PubMed, Cochrane and Ovid SP databases, a literature review and meta-analysis was undertaken in order to assess whether LRT of the primary tumour in metastatic breast cancer prolongs survival.
43 studies were analysed for the impact of LRT on survival which shown a significant 33.3% reduction in mortality with LRT (HR = 0.667:95% CI 0.617-0.721) and 37.3% with resection alone (N = 41; HR = 0.623: 95% CI 0.586-0.661).
This is the largest meta-analysis regarding this question to date. LRT seems to improve overall survival in de novo disease and should be considered in selected patients after a multidisciplinary discussion.
London Breast Institute.
Has not received any funding.
All authors have declared no conflicts of interest.
Several cancer treatments available for patients with HR+/HER2- advanced or metastatic breast cancer (ABC/MBC) may be associated with prolonged corrected QT interval (QTc), which may increase the risk of life-threatening ventricular arrhythmias, such as Torsades de Pointes (TdP). Therefore, identifying risk factors for QTc prolongation is imperative to ensuring safe and effective therapy tailored to individual patients. This interim analysis characterizes QTc/TdP risk among women with HR+/HER2- MBC living in Italy and Germany included in the MARIA registry.
MARIA is an ongoing non-interventional, prospective, multicenter study that includes women in Italy and Germany initiating their first or second therapy in the HR+/HER2- ABC/mBC setting. Comorbidities collected at baseline were examined to identify patients with specific cardiovascular conditions associated with QTc/TdP risk (i.e., myocardial infarction, hypertension, and heart failure). QTc/TdP risk burden was summarized as the proportion of patients with any risk factor (comorbidity or medication), as well as comorbidity and medication risk factors only.
A total of 318 patients (mean age 61 [SD 12.3], 94.3% stage IV at enrolment) were included. Of these, 180 (56.6%) patients had at least one risk factor for QTc/TdP. There were 115 (36.2%) patients with at least one risk factor related to comorbidity and 123 (38.7%) patients with at least one medication-related risk factor for QTc/TdP.
The results of this study suggest that more than half of women with HR+/HER2- mBC enrolled thus far in the MARIA registry had at least one comorbidity or medication associated with increased risk of developing QTc prolongation or TdP. This analysis underscores the need for clinical decision-making that incorporates individual characteristics that may change the benefit-risk profile of cancer related treatments.
Pfizer Inc.
Pfizer Inc.
N. Harbeck: Honoraria: Lilly, Novartis, Pfizer; Consulting/lectures: Lilly, Novartis, Pfizer. E.H. Law, D. Mitra: Employee, stock ownership: Pfizer. M. Ajmera, K. Davis: Employee: RTI Health Solutions, who were paid consultants to Pfizer in connection with the development of this abstract. M. De Laurentiis: Honoraria: Pfizer, Novartis, Roche, Celgene, AstraZeneca, Eisai, Eli Lilly. All other authors have declared no conflicts of interest.
RIB (cyclin-dependent kinase 4/6 inhibitor) + various ET partners demonstrated longer progression-free survival vs placebo (PBO) + ET in patients (pts) with HR+/HER2– ABC in the Phase III MONALEESA (ML) studies. Here we present a safety analysis of pooled data from ML-2, ML-3, and ML-7.
Postmenopausal pts with ABC were enrolled in ML-2 (ET-naive) and ML-3 (≤ 1 prior ET) to receive PBO or RIB + study-designated ET, letrozole (ML-2) or fulvestrant (ML-3). In ML-7 (ET-naive; ≤ 1 line of chemotherapy for ABC), premenopausal pts received RIB or PBO + goserelin + a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (NSAI cohort only from ML-7 included here). Safety analyses included rate of associated RIB/PBO discontinuations and time to and duration of first event. Adverse events (AEs) were assessed via Common Terminology Criteria for AEs v4.03.
Data were pooled from 1883 pts in the safety set treated with RIB + ET (1065 pts) or PBO + ET (818 pts). Neutropenia and leukopenia were the most common all-grade exposure-adjusted AEs of special interest and the most common any-cause grade 3/4 AEs (≥10%). Fridericia’s corrected QT interval (QTcF) >480 ms occurred in 5% vs 1% of pts in the RIB vs PBO arms. A new QTcF >500 ms occurred in 1% vs < 1% of pts, respectively. In the RIB arm, the median time to first grade ≥2 event was 2 weeks for neutropenia and QT prolongation and 12 weeks for elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST). Median duration of these first events was 2-4 weeks. The rates of study treatment discontinuation due to AEs were 7% vs 3%, and the most common all-grade AEs that led to discontinuation were elevated ALT (4% vs < 1%) and elevated AST (2% vs 1%) in the RIB vs PBO arms, respectively.
AESI, adverse event of special interest; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ET, endocrine therapy; PBO, placebo; RIB, ribociclib. Includes neutropenia, decreased neutrophil count, febrile neutropenia, granulocytopenia, and neutropenia sepsis. Includes leukopenia, decreased white blood cell count, lymphopenia, and decreased lymphocyte count. Includes anemia, decreased hemoglobin, macrocytic anemia, and decreased red blood cell count.Exposure-adjusted any-grade AESI irrespective of causality, n (incidence rate per 100 patient-treatment years) RIB + ET (n = 1065) PBO + ET (n = 818) Any AESI 992 (561.4) 543 (131.0) Neutropenia 788 (196.6) 43 (5.1) Leukopenia 330 (34.9) 36 (4.2) Anemia 200 (18.2) 51 (5.9) Increased ALT 161 (13.8) 48 (5.7) Increased AST 150 (12.7) 51 (6.0) Prolonged QT 69 (5.6) 13 (1.5)
Addition of RIB to various ET partners demonstrated a consistent and manageable safety profile in pts with HR+/HER2– ABC.
MediTech Media, funded by Novartis.
MONALEESA-2 (NCT01958021), MONALEESA-3 (NCT02422615), MONALEESA-7 (NCT02278120).
Novartis Pharmaceuticals Corporation.
Novartis Pharmaceuticals Corporation.
D. Tripathy: Grants, personal fees: Novartis during the conduct of the study; Personal fees: Pfizer during the conduct of the study; Personal fees: Nektar Therapeutics, CellMax Life, Sellas Life Sciences, Polyphor Ltd, GlaxoSmithKline, Genomic Health, outside the submitted work. G.N. Hortobagyi: The work under consideration for publication - Novartis: Grant and personal fees relevant financial activities outside the submitted work: Lily and Pfizer: Consulting. S-A. Im: Relevant financial activities outside the submitted work: AstraZeneca; Grant: Spectrum, Novartis, Roche/Genentech - Advisory board member. S. Chia: Honorarium for advisory boards: Novartis, Hoffmann-La Roche, Pfizer, AstraZeneca, Genomic Health; My institution has participated in research studies: Novartis, Hoffmann-La Roche, Pfizer, AstraZeneca, Genomic Health, Genentech, Merck, BMS. S.A. Hurvitz: Grants: Ambryx, Amgen, Bayer, OBI Pharma, Bimarin, Cascadian, Daiichi Sankyo, Dignitana, Genentech, GSK, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, Puma, Roche, Seattle Genetics. A. Ridolfi: Employee: Novartis Pharmaceuticals Corporation. All other authors have declared no conflicts of interest.
As CDK 4/6i therapy becomes the standard of care in the early-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−), metastatic breast cancer (mBC), this study evaluated the safety and effectiveness of eribulin mesylate when used post-CDK 4/6i treatment.
This was a retrospective, observational cohort study. Providers from community oncology practices in the United States selected female HR+, HER2− patients with MBC who were treated with any CDK 4/6i from Feb/03/15-Dec/31/17, and who subsequently initiated eribulin post-CDK 4/6i treatment. Patients were assigned to 1 of 3 protocol-defined treatment groups: “on-label” was defined as eribulin post-CDK4/6i treatment, >2 prior chemotherapies in the metastatic setting, and treatment with an anthracycline and taxane prior to eribulin; “third-line” (3L) was eribulin following treatment with a CDK4/6i and any other regimen; “other” was neither on-label nor 3L. Adverse events (AEs), objective response rate (ORR) per RECIST v1.1 guidelines, and time to progression during eribulin treatment were compared to findings from the registrational EMBRACE trial.
395 Patients were selected by 45 providers: on-label n = 135 patients, 3L n = 111, and other n = 149 (n = 121 with second-line eribulin [“other-2L”]) (Table). Based on target lesion measurements, the ORR in the on-label cohort was 26.7%, or twice that observed in EMBRACE (13%). Time to progression was similar to the EMBRACE median progression-free survival (PFS) estimate. Reported grade 3/4 AE rates were lower than in EMBRACE (neutropenia=8.1% vs 45%; peripheral neuropathy=0.5% vs 9%).
The results shown here for eribulin post-CDK4/6i were similar to those in the EMBRACE study. Longer follow-up will be needed to fully evaluate its influence on PFS and OS.
Per provider report. Response Evaluation Criteria In Solid Tumors version 1.1. Among patients with progression (55 patients). 60 Deaths. Includes 28 “other non-2L”.Parameter All¶ On-label 3L Other-2L n = 395 n = 135 n = 111 n = 121 Stage IV at diagnosis, % 63.5 57.8 57.7 76.9 Visceral metastases, % 87.3 92.6 91.0 86.8 Easter Cooperative Oncology Group-performance status ≥ 2, % 23.0 20.7 18.9 23.1 Mean duration of CDK 4/6i treatment (months) 11.0 10.1 9.9 12.9 Still receiving eribulin,% 77.5 84.4 85.6 67.8 Median duration of eribulin (months) 3.8 2.7 4.2 6.1 AE (grade 3/4)*, % Neutropenia 8.1 6.7 10.8 7.4 Any febrile neutropenia 1.3 0.7 0.9 2.5% Peripheral neuropathy 0.5 0.0 0.9 0.8 Diarrhea 0.0 0.0 0.0 0.0 Discontinuation due to toxicity, % 0.8 1.5 0.0 0.0 ORR†, % 30.6 26.7 26.1 42.4 Median time to progression (months)‡ 3.7 2.7 4.2 5.1 12-Months survival from eribulin start§, % 73.3 54.3 77.5 88.4
Tarah Connolly of Oxford PharmaGenesis, Newtown, PA, USA.
Eisai, Inc.
Eisai, Inc.
K. Alexis, D. Chatterjee R. Knoth: Employee: Eisai, Inc, Woodcliff Lake, NJ. B.A. Feinberg, D. Nero, T. Miller, J. Laney, J. Kish: Employee: Cardinal Health Specialty Solutions, Dallas, TX. All other authors have declared no conflicts of interest.
The WHO report revealed that breast cancer (BC) topped the list among various types of cancers in women in Bangladesh. The prognosis of metastatic breast cancer depends on certain factors, like surgery, radiotherapy, chemotherapy, hormonal receptor content of the tumor or associated illness such as diabetes mellitus and obesity. Among the associated illness, diabetes mellitus is one of the most common metabolic disease worldwide, which is linked to an increased risk of developing breast cancer and an even higher risk of recurrence and dying from this disease. In this context, we studied diabetic and metabolic disease related growth and metabolic factors in breast cancer patients for the better prognosis of BC.
A total of 180 mastectomy patients were purposively taken in the present study. Data were collected from retrospective information. Anthropometric and biochemical parameters were taken by standard methods. Growth and metabolic factors were determined by enzyme-linked immunosorbent assay (ELISA) method.
Serum level of insulin-like growth factor 1 (IGF1) was found to be significantly higher (p = 0.001) in ER and PR negative breast cancer than their positive counterparts. Patients who had lymph node positive and Her2 borderline showed a significant reduction in serum adiponectin level (p < 0.05) and this association was retained after adjusting the confounding variables. Furthermore, delayed treatment, IGF-1, ALP, sleeping hours were significant predictors for metastasis of breast cancer patients in Bangladesh. The Diabetic-BC patients treated with both insulin and oral drug was found to be negatively associated with metastasis breast cancer while comparing with Diabetic-BC patients treated with only oral drugs (p < 0.05). However, BC metastasis did not any have an association with serum fasting insulin or insulin resistance. Obesity also did not show any relation with BC prognosis.
Serum IGF-1 and adiponectin may have an association with invasiveness and metastasis of breast cancer. Diabetes treatment management may also be related to breast cancer prognosis; however, this study result is unable to reveal its mechanism.
Salima Akter, Department of Medical Biotechnology, Bangladesh University of Health Sciences (BUHS), Dhaka, Bangladesh.
The World Academy of Sciences (TWAS).
All authors have declared no conflicts of interest.
Limited information is available on the effect of BRCA1/2 mutations on patient reported outcomes (PROs). This multi-country study assesses the impact of BRCA1/2 mutation status on patient demographics, cancer-related and breast cancer specific PROs in women with human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC).
Oncologists extracted data from patient charts in adult women with HER2- ABC across the US and the United Kingdom, Spain, Germany, France and Italy (EU5) via the Adelphi Advanced Breast Cancer Disease Specific Program in 2017. A subset of patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) and the breast cancer module QLQ-BR23. Patients were categorized into 2 mutually exclusive cohorts; BRCA1/2 mutations (BRCAm) and BRCA wild type (BRCAwt). Differences in patient demographics were compared using t-tests and Pearson’s Chi-squared tests. PROs were compared utilizing inverse probability weighted regression adjustment across multiple potential confounders.
Overall 199 patients participated; (BRCAm n = 37, BRCAwt n = 162). Patients with BRCAm were significantly younger (50.3 vs. 55.4 years old), [P = 0.018] and more likely have a family history of breast or ovarian cancer (43% vs. 22%), [P = 0.003] relative to BRCAwt. Significantly worse scores in role functioning (44.9 vs. 57.9), [P = 0.002] and dyspnea (47.7 vs. 37.0), [P = 0.012] were observed in patients with BRCAm relative to BRCAwt. No statistically significant differences in other EORTC PRO scales were observed.
In this study of adult women with HER2- ABC, patients with BRCAm were significantly younger and more likely to have a family history of breast or ovarian cancer than BRCAwt. Patients with BRCAm reported significantly worse role functioning and dyspnea suggesting that BRCAm targeted treatment options leading to PROs improvements in these patients are needed.
Pfizer.
Pfizer.
A. Niyazov: Employee, stockholder: Pfizer. R.G.W. Quek: Employee: Pfizer Inc.; Stock ownership: Pfizer Inc., Amgen Inc. All other authors have declared no conflicts of interest.
There are currently few reports on the pattern of use and value of Pertuzumab in the real-world setting. Our study describes the clinical efficacy and treatment costs of Pertuzumab in HER2-positive metastatic breast cancer (MBC) treated in a tertiary cancer centre in Singapore.
A retrospective study of consecutive HER2-positive MBC patients seen from 1st January 2011 to 31st December 2017 at National Cancer Centre Singapore (NCCS) was conducted. Demographic and clinical data were extracted from medical records. Clinical characteristics of patients who received Pertuzumab were compared with those who did not. Billing data during the treatment period of all patients was also collected.
A total of 329 patients were included: Median age of diagnosis was 58 years where 196 (64.5%) were of Chinese ethnicity. Invasive Ductal Carcinoma (IDC) was diagnosed in 268 (88.2%) patients, and 168 (55.3%) had estrogen receptor (ER) and/or progesterone receptor (PR) positive disease. Bone was the most common site of metastasis which was observed in 167 (54.9%) of patients, while 225 (68.4%) patients had visceral metastases. Forty-nine (14.9%) patients received Pertuzumab, 30 of whom received it as first-line therapy. With an median duration of follow-up of 21 months, there was a statistically significant difference in the median overall survival (OS): 52 months (95% CI 32.7-71.3) versus 33 months (95% CI 28.5-37.5) (Log Rank p = 0.013) for Pertuzumab versus non-Pertuzumab groups, respectively. Two (4.1%) patients in the Pertuzumab group experienced grade 3 (G3) cardiotoxicity. The median treatment cost of the Pertuzumab group was SGD$152,283 compared to SGD$63,130 for the non-Pertuzumab group. The median percentage of total chemotherapy costs per patient in the Pertuzumab group spent on Pertuzumab was 49.8%.
This study shows that pertuzumab use in the treatment of metastatic breast cancer is associated with a significant improvement in survival and a low incidence of serious cardiotoxicities. However, the proportionate cost of Pertuzumab therapy remains high and further cost-effectiveness studies should be conducted.
National Cancer Centre Singapore.
Has not received any funding.
All authors have declared no conflicts of interest.
Gastrointestinal (GI) symptoms, including diarrhea and vomiting, are often reported by patients with advanced or metastatic breast cancer (ABC/mBC) and may affect patient care experience, health-related quality of life (HRQoL), and subsequent treatment decisions. This study characterizes the prevalence of GI symptoms and HRQoL among patients with HR+/HER2– ABC/mBC enrolled in the MARIA registry.
MARIA is an ongoing prospective, multicenter, non-interventional study collecting clinical and patient-reported data from patients receiving 1st or 2nd line endocrine therapy or chemotherapy for HR+/HER2- ABC/MBC in Italy and Germany. Single-item responses from the Functional Assessment of Cancer Therapy Endocrine Subscale (FACT-ES) were used to categorize patients into any/no symptom groups for both diarrhea and vomiting at baseline, 3-, and 6-months among patients with a visit and FACT-ES measurement. The FACT-General (FACT-G) measure was co-administered and scored to assess HRQoL at each visit. Independent t-tests examined differences in mean FACT-G scores between patients with and without symptoms for diarrhea or vomiting at baseline, 3-, and 6-months.
A total of 311 patients were included in the analysis. Diarrhea was reported among 17%, 28%, and 17% of patients at baseline, 3-, and 6-months, respectively. The prevalence of vomiting symptoms was 17%, 16%, and 17% at baseline, 3-, and 6-months, respectively. Mean differences [standard error] in FACT-G scores between patients reporting diarrhea and patients without were -5.0 [2.4] at baseline, -8.5 [3.7] at 3-months, -6.5 [2.9] at 6-months (all p-values <0.05). Mean FACT-G score differences [SE] between patients reporting vomiting and those who did not were -13.4 [2.3] at baseline, -17.6 [4.3] at 3-months, and -15.6 [2.6] at 6-months (all p-values <0.001).
At least 1 in 6 patients with ABC/mBC reported diarrhea or vomiting at each point of follow-up. Group-level mean HRQoL scores were lower among patients reporting GI symptoms, regardless of the point in time. GI symptoms should be taken into consideration during treatment selection.
Pfizer Inc.
Pfizer Inc.
E.H. Law, D. Mitra: Employee, stock ownership: Pfizer. M. Ajmera, K. Davis: Employee: RTI Health Solutions, who were paid consultants to Pfizer in connection with the development of this abstract. N. Harbeck: Honoraria: Pfizer, Lilly, Novartis; Consulting Pfizer, Lilly, Novartis. M. De Laurentiis: Honoraria: Pfizer, Novartis, Roche, Celgene, AstraZeneca, Eisai, Eli Lilly. All other authors have declared no conflicts of interest.
Her2 overexpressing breast cancer patients are at a high risk for developing brain metastases. We analysed the group of Her 2 overexpressing patients and studied disease and treatment related characteristics of those with and without brain metastases.
We retrospectively analysed 102 Her 2 overexpressing breast cancer patients who received treatment in our centre from 2013 to 2017, out of which 20 patients (19.6%) were found to have brain metastases. Descriptive data was accumulated from electronic medical records. Survival plot was calculated from Kaplan Meir and compared between groups using Log Rank test.
The median age of our study population was 52 years. The median overall survival(OS)of the Her 2 overexpressing cohort was 24.0 months. The 1year, 2year and 3year OS of the cohort without brain metastases was 95%, 90.6% and 82% respectively. Breast cancer specific median survival of the Her 2 overexpressing cohort after diagnosis of brain metastases was 5.06 months (Range 0.1- 17.64 months). It was observed that post development of brain metastases, 6 out of 20 patients (30%) had a survival beyond 6 months (Range 6.3 to 17.6 months) and 4 out of 20 (20%) had survived beyond 12 months. Two patients had undergone stereotactic radiosurgery and both of them survived beyond 1 year. On univariate analyses it was found that presence of estrogen receptor positivity was associated with a better outcome, which was statistically significant (P = 0.038). We also observed that Breast Specific Graded Prognostic assessment (BS-GPA) score of more than 2.5 had a trend towards better outcome(P = 0.49). Three out of 4 patients, who survived beyond 1 year after development of brain metastases had a BS-GPA score more than 2.5. Age, menopausal status and number of extracranial metastases were not found to have an impact on survival.
Estrogen positivity and BS-GPA score of more than 2.5 are associated with improved survival in patients of Her2 overexpressing breast cancer with brain metastases. This subgroup of patients also benefits with novel approaches like stereotactic radiosurgery for better control of intra cerebral disease.
HCG Manavata Cancer Centre.
Has not received any funding.
All authors have declared no conflicts of interest.
Triple negative breast cancer (TNBC) accounts for 15–20% of breast cancer diagnoses. As novel targets and therapies for TNBC emerge, a comprehensive overview of the current landscape of evidence on the approved or developing treatment options was needed.
We followed Cochrane guidelines for systematic literature reviews (SLR). Population of interest was adult female patients with TNBC receiving any pharmacological treatment. Studies of interest were randomized controlled trials (RCTs) or comparative non-randomized clinical trials (non-RCTs). Outcomes included survival, disease and pathological response, and adverse events. A search from January 2003 to July 2018 was performed on MEDLINE®, Embase, the Cochrane Central Database of Controlled Trials, and the US and European clinical trials registries. Conference proceedings from ASCO, ESMO, and SABCS covering the period from 2016 to end of 2018 were also reviewed.
Eighty-nine publications corresponding to 77 unique trials met the eligibility criteria for this review. The 72 RCTs and 5 comparative non-RCTs were predominantly open-label phase 2 or 3 trials. Immune checkpoint inhibitors, including nivolumab, atezolizumab, durvalumab, and pembrolizumab, were evaluated in 5 trials. Targeted therapies, primarily VEGF inhibitors (n = 12) and PARP inhibitors (n = 7), were evaluated in 40 trials. Thirty-two trials evaluated chemotherapy alone, with the majority assessing chemotherapy combinations of 2 or more subclasses. Thirty-five trials reported treatments on metastatic or advanced TNBC, 31 on neoadjuvant and 11 on adjuvant therapies. Overall survival (n = 32) and progression-free survival (n = 30) were the most commonly reported efficacy outcomes. Safety outcomes were reported in 39 trials.
Targeted therapies, followed by chemotherapy in forms of combinations of 2 or more subclasses, composed most trials in TNBC, with immunotherapy being rarely used thus far. The trials were mainly conducted in metastatic or advanced setting, followed by neoadjuvant and adjuvant settings. Comparison across different TNBC treatment options warrants further investigation as the growing evidence base evolves.
Bristol-Myers Squibb.
Bristol-Myers Squibb.
A.Z. Fu, N. Kumar, C. Davis: Employee: Bristol-Myers Squibb. Y. Kuang, M.S. Fazeli: Employee: Doctor Evidence LLC.
Endocrine therapy is the preferred treatment for patients with hormone receptor (HR)-positive metastatic breast cancer (MBC). While visceral metastasis is a negative prognostic factor, few studies have distinguished between the prognoses of metastases at different visceral sites.
In total, 398 patients receiving fulvestrant 500 mg at a single center over a 6-year period were analyzed. Logistic regression models identified the prognostic factors associated with progression-free survival (PFS). Kaplan-Meier analysis compared the PFS of patients with lung and liver metastases.
Baseline visceral metastases were present in 233 patients, including 138 with lungw/o liver metastases (lung metastases without liver involvement), 51 with liverw/o lung metastases (liver metastases without lung involvement) and 41 with lung and liver metastases. The median PFS was 6.8 months (5.6 and 9.2 months for visceral and nonvisceral metastases, respectively, P = 0.028). Patients with lungw/o liver metastases had longer PFS than those with liverw/o lung metastases or lung and liver metastases (9.6, 3.7 and 3.2 months, respectively, P < 0.001; liverw/o lung versus lungw/o liver hazard ratio (HR) 1.70; lung and liver versus lungw/o liver HR 2.85). Patients with liver metastases experienced significantly worse PFS than those without liver involvement (3.7 versus 9.2 months, P < 0.001). PFS benefits were observed in patients with longer disease-free intervals, no liver metastases, and no previous chemotherapy.
Fulvestrant treatment benefitted patients with lungw/o liver or nonvisceral metastases. It is important to differentiate liver from lung metastases when treating HR-positive/HER2-negative MBC with endocrine therapy.
Fudan University Shanghai Cancer Center.
Has not received any funding.
All authors have declared no conflicts of interest.
According to GLOBOCAN 2018, breast cancer is the most common cancer among women in Haiti. However, its trend throughout the years has not yet been studied. This study aims to present the four-year epidemiological trends of breast cancer managed by a cancer program in Port-au-Prince, Haiti.
A retrospective study was conducted on patients with breast cancer aged 18 years old (y/o) or more of the cancer clinic of Innovating Health International from January 2014 to December 2017. The chart review focused on variables such as age, gender, year of diagnosis, staging, estrogen receptor (ER) status and outcome. A systematic comparison between the years, age and ER status was performed. Overall mortality and loss to follow-up rates were also estimated.
Six hundred and sixty-two (662) cases of breast cancer, among them 659 women and 3 men, were selected for the study period, respectively 114 in 2014, 131 in 2015, 159 in 2016 and 258 in 2017 (p < 0.001). The mean age of the cohort was 50.7 years [20 –94], decreasing from 52.3 years in 2014 to 50.2 years in 2017 (p = 0.2). Patients under 40 y/o represented 21.4%% of this cohort, with the proportion increasing from 15.2% in 2014 to 24.5% in 2017 (p = 0.051). 92.3% of the staged patients (n = 595) had advanced breast cancer (stages IIB to IV). 30.8% of the patients had metastatic cancer, and the proportion decreased from 38.9% in 2014 to 25.7% in 2017 (p < 0.001). There was a higher proportion of MBC among Patients ≥ 40 y/o (32.5%) versus those < 40 y/o (24.6%) (p = 0.07). Of the patients with known ER status (n = 325), 56.9% were ER-positive, 52.4% among the < 40 y/o versus 58.1% among the ≥ 40 y/o (p = 0.41). The overall mortality rate was 35.5%, 35.5% among the <40 y/o versus 35.6% among the ≥ 40 y/o (p = 0.98). 14.8% of the patients were lost to follow-up. ER-negative patients were significantly more likely to die than ER-positive ones (Odds Ratio=1.91, p = 0.007).
There were a significant increase of breast cancer admissions and a decrease of metastatic cases from 2014 to 2017, due to a combination of increased awareness, incidence and referral. The breast cancer population became younger throughout the years, with more ER-negative cases among the < 40 y/o subgroup. ER-negative status was significantly associated with mortality.
Joseph Bernard Jr.
Has not received any funding.
All authors have declared no conflicts of interest.
In cohort studies, estimated incidence of breast cancer (BC) brain metastases (BM) is about 5%. This number seems to be increasing, due to longer survival. We intend to characterize the population of breast cancer patients treated in a single institution who developed BM in a 10-year-period.
Retrospective descriptive study revising clinical charts of BC patients with BM, diagnosed between January 2008 - January 2018. Data on patient and tumour characteristics, treatments and outcomes were analysed using IBM SPPS statistics.
From 217 patients with metastatic BC in our institution, 21 developed BM (9,7%), all females. Median age at diagnosis was 45 years (28-66), the majority were de novostage IV (38,1%) patients. Only one patient presented BM at diagnosis. The most frequent molecular subtype was Luminal B (38,1%), followed by HER2 + (33,3%). Median time to BM were 30 months (0-143). Time to BM was not associated with molecular subtype (pearson χ2 = 63, p = 0,37) nor with age at diagnosis (pearson χ2 = 357, p = 0,252). Eleven patients had a single lesion at presentation, of whom 5 were submitted to surgery and 1 to stereotaxic radiotherapy. Nine patients had multiple lesions at CNS presentation. Sixteen patients received whole-brain radiotherapy. Two patients had meningeous carcinomatosis (MC) as exclusive CNS manifestation, while other 3 patients developed MC after previously diagnosed BM. Four patients received intrathecal therapy: 1 with methotrexate (Her 2 -) and 3 with trastuzumab (Her 2 +). Median survival after MC was 1,4 months. From the 21 patients with BM, 12 (57%) died within a median of 8,5 months (0-50). Nine patients are still alive with a median follow-up time since BM of 28 months (9-156).
Within a 10-year period, we found a prevalence of BM of 9,7% in our institution, which is higher than published data. Noteworthy, 9 patients are still alive after BM management. As expected, MC was rare (5 patients), and prognosis was poor. The 4 patients treated with intrathecal therapy seem to have had limited benefit. In conclusion, BM are a relevant problem in BC with low survival and more effective treatments are needed.
Marta Vaz Batista.
Has not received any funding.
All authors have declared no conflicts of interest.
P is approved in the EU and US as 1st-line therapy in combination with docetaxel and trastuzumab (H) for HER2-positive mBC based on phase III results (CLEOPATRA). Data in later lines are very limited. In Switzerland, national regulations allow physicians to use P in this setting. We identified P-naïve patients (pts) treated with ≥2nd-line P+H in Switzerland to gain insight on clinical outcomes with P beyond 1st line.
Physicians from major Swiss oncology centres retrospectively completed a questionnaire for each pt providing data on treatment details, safety and survival.
The analysis included 35 pts with HER2-positive mBC. Most pts (95%) had invasive ductal carcinoma, 69% had oestrogen- and/or progesterone receptor-positive tumours, 49% were stage IV at 1st diagnosis and half had received prior H. Median age was 49 (range 35–87) years. The most common metastatic sites were bone (64%), liver (43%) and lymph nodes (43%). Analysis of the earliest line of P is shown below.
In this small retrospective analysis, median overall survival was similar to that reported with 1st-line P in CLEOPATRA. Diarrhoea was generally unproblematic and low grade; cardiac safety was as expected. These data support P in later lines if not used in the 1st line.
Jennifer Kelly (Medi-Kelsey Ltd), funded by Roche Pharma (Schweiz) AG.
Dr Biskup and Dr Vetter.
Roche Pharma (Switzerland) provided administrative support for this analysis.
A. Müller: Honoraria: Roche Switzerland, Novartis, Pfizer, Amgen, Tesaro; Consulting/advisory role: Roche Switzerland, Novartis, AstraZeneca, Pfizer, Amgen; Expert testimony: Roche Switzerland; Travel/accommodation expenses: Roche, AstraZeneca, Pfizer, Novartis. C. Leo: Honoraria: Pfizer, AstraZeneca; Consulting/advisory role: Pfizer, AstraZeneca; Travel/accommodation expenses: Roche. C. Uhlmann Nussbaum: Stock: Roche; Consulting/advisory role: Sanofi, Boehringer Ingelheim, Roche. D. Koychev: Consulting/advisory role: Roche, Novartis, Takeda, Pfizer; Travel/accommodation expenses: Novartis, Roche, Takeda. A. Schreiber: Honoraria: Amgen, Roche, Pfizer, MSD, BMS, Lilly, Celgene, Merck; Travel/accommodation expenses: Amgen, Roche, Pfizer, MSD, BMS, Lilly, Celgene, Merck. C. Taverna: Consulting/advisory role: Celgene, Amgen, Janssen; Research funding: Celgene. D. Thorn: Honoraria: Roche; Consulting/advisory role: Roche; Travel/accommodation expenses: Roche, Amgen, Teva, Novartis, Celgene. M. Vetter: Employment: Roche (family member); Honoraria: Roche, Novartis, Pfizer; Consulting/advisory role: Roche, Novartis, Pfizer; Research funding: Roche. All other authors have declared no conflicts of interest.
Grade (G) 3/4 adverse events (AEs) were reported in 14% of pts. Only 1 pt discontinued therapy because of P-related toxicity. The most common AE (irrespective of cause) was fatigue (all-G 46% of pts; G3 11%). Congestive heart disease occurred in 14% (6% G3), nausea in 14% (all G1), myelosuppression in 12% (6% G3), diarrhoea in 9% (all G1) and vomiting and mucositis each in 3% (G2). By 12 Sep 2017, 20 pts (57%) had died. Median overall survival was 6.2 (95% CI 3.9–11.6) years.Treatment Treatment line All pts 2nd 3rd ≥4th (n = 14) (n = 6) (n = 15) (n = 35) P + H + chemotherapy, n (%) 12 (86) 5 (83) 12 (80) 29 (83) Taxane 8 (57) 4 (67) 7 (47) 19 (54) Vinorelbine 3 (21) 1 (17) 2 (13) 6 (17) Gemcitabine 0 0 1 (7) 1 (3) Carboplatin 0 0 1 (7) 1 (3) Anthracycline 1 (7) 0 1 (7) 2 (6) P + H + endocrine therapy, n (%) 1 (7) 0 0 1 (3) P + H, n (%) 1 (7) 1 (17) 3 (20) 5 (14) Median P duration (range), months 6 (2–30) 6 (2–60) 11 (2–40) 6 (2–60) Reason for stopping treatment, n (%) Disease progression 10 (71) 4 (67) 9 (60) 23 (66) Toxicity 2 (14) 1 (17) 2 (13) 5 (14) Missing 1 (7) 1 (17) 2 (13) 4 (11) Ongoing 1 (7) 0 2 (13) 3 (9)
The aim of this study was to determine the safety and efficacy of intrahepatic Mitomycin C (MMC) infusion in patients with advanced metastatic breast cancer (mBC) resistant to systemic chemotherapy with liver dominant metastatic disease. We determined factors influencing overall survival.
We retrospectively analysed patients with mBC, treated with MMC infusion between 2000 and 2017. Hepatic response was measured by comparing CT scans after MMC infusion with baseline CT scans according to response evaluation criteria in solid tumours (RECIST) 1.1. Toxicities were registered by the common toxicity criteria for adverse events (CTCae) version 5.0. Overall survival (OS) and hepatic progression free survival (hPFS) were evaluated using Kaplan Meier estimates. After univariable analysis, a stepwise forward multivariable (MV) prediction model was developed to select independent pre-treatment factors associated with OS.
We included 176 patients who received a median of 4 prior lines of systemic therapy for mBC. The median time from diagnosis of mBC to first MMC infusion was 36.9 months (SD 35.6). RECIST evaluation of liver lesions (n = 132) after 1-3 of MMC infusions showed a partial response rate of 20%, stable disease of 57% and progressive disease in 23%. CTCae toxicity grade 3 and 4 were reported in 17.5%. Median PFS was 5.5 months and median OS was 7.8 months. Significant independent baseline predictors of worse OS on MV analysis included amount of prior systemic chemotherapy (HR = 1.2 CI;1.1-1.3), prior liver ablation (HR = 5.9 CI;1.8-19.4), higher liver tumour burden (HR = 2.4 CI;1.5-3.7), elevated levels of bilirubin (HR = 2.18 CI;1.3-3.8) and ALT (HR = 1.5 CI;1.01-2.09).
MMC infusion was safe and effective in patients with advanced mBC. MV analysis showed a worse OS in patients with increased amount of prior systemic chemotherapy, prior liver ablation, higher liver tumour burden and elevated levels of bilirubin and ALT.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Metastatic disease remains a major cause of mortality in breast cancer and previous studies have shown that arylamine N-acetyltransferase 1 (NAT1) is associated with increased cancer spread and poorer outcomes in breast cancer patients. However, the mechanism remains largely unknown. NAT1 alters cancer cell survival and invasive capacity in vitro. Since breast cancer cell invasion has been associated with increased matrix metalloproteinase 9 (MMP9) expression, we investigated the effects of NAT1 on MMP9 expression and activity in a range of cancer cells.
NAT1 gene deleted cell-lines (Breast cancer: MDA-MB-231, T47D; Colon cancer: HT29; Cervical cancer: HeLa; Prostate cancer: 22Rv1) were generated using CRISPR/Cas9 technology. In vitro invasion was determined by fluorescent gelatin degradation assay on coverslips, visualised by confocal microscopy and quantified using ImageJ. Gene expression was quantified by real-time RT-PCR and protein expression in cells and growth medium was determined by Western blot analyses. siRNA was used to silence Hif-1α expression. ChIP-qPCR was performed to measure acetylation level of histones at specific motifs in the MMP9 promoter.
NAT1 deletion (KO) resulted in the up-regulation of MMP9 mRNA and protein level in the highly invasive MDA-MB-231 cells as well as T47D cells but not in the poorly invasive lines HT-29, HeLa or 22Rv1. Activity of the MMPs in a gelatin degradation assay showed an 8-fold increase in the MDA-MB-231 KO compared to parent cells. Hif-1α, a transcriptional factor for several MMPs, also increased significantly following NAT1 deletion. These changes were rescued by ectopic expression of NAT1 in the MDA-MB-231 KO cells. Inhibition of Hif-1α with siRNA decreased MMP9 mRNA and protein levels. ChIP-qPCR analyses on the MMP9 promoter region revealed that both acetyl-histone H3 (AcH3) and acetyl-histone H4 lysine12 (AcH4K12) levels increased on the SMYD3 binding site, but not on the proximal or distal AP-1 binding sites.
NAT1 negatively regulates MMP9 transcription via HIF1-α and by altering histone acetylation level at the SMYD3 binding site. These observations may, in part, explain the poor outcome of breast cancer patients with low or negligible NAT1 expression.
University of Queensland.
National Health and Medical Research Council of Australia.
All authors have declared no conflicts of interest.
Since its approval in Europe in November 2016, the CDK4/6 inhibitor palbociclib (PA) has been widely used for treatment of hormone receptor-positive (HR+) metastatic breast cancer (MBC). This study evaluates as a quality assurance measure the treatment with PA at the breast center of the University of Munich (LMU).
Patients (pts) who started PA-treatment for HR+ MBC between 9/16-9/18 (n = 75) were retrospectively included. Data were obtained from pt medical files in 12/18 (54.7 % still under ongoing therapy). Statistical analyses were performed using Chi-squared-test and Kaplan-Meier-estimates.
Median age was 62 years; the main localization of metastases was bone (77.3 % of all pts, lymphatic 41.3 %, liver 36 %). 72 % received PA as 1st or 2nd line therapy for MBC, most had a history (adjuvant or in MBC) of at least one endocrine therapy (78.7 %) or chemotherapy (64.4 %). Most pts (50.7 %) received fulvestrant (letrozole 44 %, exemestane 5.3 %) and a starting dose of 125 mg PA (77.3 %). Dose reduction (DR) to 100 or 75 mg PA occurred in 52.1 % and 24 % of all pts - mainly due to grade 3 neutropenia (shown in 64 % of all pts, reason for 86.7 % of 1st and 88.9 % of 2nd DR). Main non-hematological complications were fatigue (41.3 %) and gastrointestinal symptoms (40 %), especially in the first therapy cycles with improvement over time. Complications and need for DR did not significantly correlate with localization of metastasis, therapy line or prior therapies. 45.3 % stopped PA-therapy during the observation period, mainly (85.3 %) due to progression. Median progression-free survival (PFS) estimated by Kaplan-Meier was 16 (95 % CI 9.1 - 22.9) months. Estimated median PFS was significantly shorter in pts with liver metastasis (7 months, without liver metastasis median not reached, p = 0.01), if PA was used in 3rd line or later (9 vs. 18 months, p = 0.01) and in pts receiving fulvestrant compared to letrozole (11 months, in letrozole therapy median not reached; p = 0.04).
Our data show that in daily clinical use, PA is a well-tolerated therapy for MBC with grade 3 neutropenia as the main complication. Pts with liver metastasis should be monitored carefully as progression seemed to occur earlier in this group.
Department of Obstetrics and Gynaecology, Breast Center and CCC Munich, University Hospital, LMU Munich.
Has not received any funding.
A. Hester: Research grants: The “Walter Schulz Stiftung”; Speaker, advisory board honorarium: Roche, Germany; Travel and accommodation costs, honorarium for symposium: Pfizer. T. Degenhardt: Honoraria for consultant activity: Pfizer; Travel support: Celgene S. Mahner: Research support, advisory board, honoraria, travel expenses: AstraZeneca, Clovis, Medac, MSD, PharmaMar, Roche, Sensor Kinesis, Tesaro, Teva. N. Harbeck: Honoraria for consulting / Lectures: Novartis, Lilly, Pfizer. R. Wuerstlein: Honoraria, consulting: Agendia, Amgen, AstraZeneca, BI, Carl Zeiss, Celgene, Daiichi-Sankyo, Eisai, Genomic Health, GSK, Hexal, Lilly, MSD, Mundipharma, NanoString, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PBYI, Riemser, Roche, Sandoz/Hexal, SGEN, Tesaro, Teva. All other authors have declared no conflicts of interest.
This large-scale retrospective study was conducted to evaluate the effectiveness and safety of eribulin for the treatment of metastatic breast cancer in real-world settings in Korea.
Patients who received eribulin between Jun 2014 and December 2016 at 14 hospitals in Korea for treatment of locally advanced or metastatic breast cancer were analyzed in this study. The Primary endpoint was progression-free survival(PFS) rate at 6 months. The Secondary endpoints included PFS, overall survival (OS), time to treatment failure(TTF), overall response rate (ORR) and hematologic adverse events.
In total, 398 patients’ medical records have been collected and were included in safety analysis set(SAS). Median age was 53 years old and the median number of previous chemotherapy regimens for advanced disease was 3 (range, 0-14). A median of 5 cycles of eribulin (range, 1-34) were administered. Among SAS, 360 patients’ records were included in full analysis set(FAS) and have been analyzed for the evaluation of efficacy. The PFS rate at 6 months was 37.78% and the median PFS, OS and TTF was 134, 631, and 120 days, respectively. The best overall response was confirmed as complete response (CR) 0.83%(3/360), partial response (PR) 17.22% (62/360), stable disease (SD) 31.39%(113/360) and progression disease (PD) 50.56%(182/360). We were able to collect only hematologic adverse events and in total, 65.08%(259/398) hematologic adverse events have been reported. The most frequent treatment-emergent adverse events were neutropenia (56.8%) and Anemia (11.3%).
The efficacy and safety of eribulin in Korea, in a real world setting, was consistent with previous Asian studies, with no other notable hematologic adverse events observed.
NCT03437083.
Eisai Korea Company.
Eisai Korea Company.
All authors have declared no conflicts of interest.
Neratinib is an oral small-molecule irreversible pan-HER tyrosine kinase inhibitor in late stage clinical development for advanced HER-2 positive breast cancer. Prophylactic loperamide (4mg qds Day 1, tds days 2-14, bd days 15-28 then prn) and budesonide (9mg od for 28 days) are required to reduce the incidence and severity of diarrhoea.
Patients enrolled within the Puma Biotechnology Neratinib Managed Access Program between 01/01/2016 and 01/06/2018 with advanced HER2 positive breast cancer were identified for this retrospective analysis. Data were collected from electronic patient records. The primary endpoint was progression free survival (PFS). Secondary objectives were overall survival (OS), response rate (RR, RECIST v1.1), clinical benefit rate (CBR) and toxicity graded by CTCAE v4.0.
We identified 29 patients, median age 54 years (IQR: 50-61) who received a median of 4 (range 1-6) prior lines of therapy for advanced breast cancer. 15 patients (51.7%) received neratinib 240mg/day as monotherapy (one with sc trastuzumab), 14 (48.2%) in combination with capecitabine 1500mg/m2/day for 2 weeks of a 3 week cycle. Median follow-up was 8.5 months (IQR: 5.1 – 11.6). Median PFS was 7.4 months (95%CI 3.5 – 17.9) and was significantly longer with combination therapy than monotherapy (17.9 (3.5-NR) vs 5.8 months (2.0-10.2), P = 0.043). Median OS was not reached but was not significantly different in the two treatment cohorts. The RR in monotherapy patients was 33% compared to 57% in combination patients. Two combination patients had complete responses which remain ongoing at 17 and 25 months. The CBR was 47% and 79% respectively. Grade 3-4 toxicities were reported in 4 patients (13.8%). Dose delays were required in 19 patients (65.5%), dose reductions in 4 (13.8%) and discontinuation in 4 due to pneumonitis (n = 1); nausea and vomiting (n = 2) and diarrhoea (n = 1). Any grade diarrhoea was reported by 15 patients (51.7%) despite prophylaxis, as above. There was no grade 3-4 diarrhoea.
In this cohort of heavily pre-treated HER2 positive advanced breast cancer patients, neratinib demonstrated durable anti-cancer activity with a manageable toxicity profile both as monotherapy and in combination with capecitabine.
The Royal Marsden NHS Foundation Trust.
Neratinib was provided by Puma Biotechnology free of charge within a Managed Access Programme; they did not provide any other funding towards this study.
S.R.D. Johnston: Advisory boards, consultancy work: Puma Biotechnology. M. Parton: Honoraria for lecture: Pfizer. A.F.C. Okines: Research funding: Pfizer; Honorarium/speakers bureau: Roche. All other authors have declared no conflicts of interest.
CD146 or Mel-CAM, a member of the immunoglobulin-like CAM family, is activated through a dimerization of its ligand, leading to a cascade of signal transduction events. While CD146 is a promoter of melanoma and prostate cancer, its role in BC remains nascent and controversial. However, we have recently reported that CD146, a negative transcriptional target of CD44-HA downstream signaling, suppresses breast tumor cell invasion; this has prompted us to generate the hypothesis that CD146 acts as a tumor suppressor in BC via its downstream transcriptional targets.
To test this hypothesis, we developed both in vitro and in vivo tetracycline (tet On)-inducible system of CD146 using MDA-MB-231 founder BC cell line. Our results demonstrated that induction of CD146 suppressed BC cell migration and invasion in vitro as well as tumor growth and progression in mouse breast xenograft model. Microarray gene expression profiling revealed latexin (LXN: a variant of Tissue Inhibitor of Metalloproteinases) as a novel potential CD146-downstream signaling transcriptional target, which was validated using various in vitro approaches.
To further validate our finding in vivo, immunohistochemical analysis of breast tumor tissues from both human and mouse (tet-inducible system) breast tissues showed that, while the expression of both CD146 and LXN were highly expressed in the early stages of BC (normal and benign tissues), it was lost in advanced stages (malignant and metastatic tissues). Pharmacological approach combined with luciferase assay revealed that NFκB activation via Akt pathway couples CD146 to the transcription of LXN in BC CD146inducible cells.
The present study discovers the main molecular players of a novel signaling pathway, CD146/LXN/Akt/N-κB, by which CD146 acts as a suppressor of BC progression.
Allal Ouhtit.
Qatar University.
All authors have declared no conflicts of interest.
Despite extensive research in systemic treatments for HER2 positive breast cancer brain metastases (BCBM), only limited benefits have been observed often at the cost of significant toxicities. Treatment failure is attributed to the limited capacity of drugs to cross the blood-tumor-barrier (BTB) or to resistance mechanisms in the brain lesion microenvironment. In this study we evaluate the radiolabeled drug CAM-H2 as a new systemic treatment for the irradiation of HER2 positive BCBM. Single domain antibody fragments (sdAbs) are small (15 kDa) heavy-chain-only antibody fragments. Due to their favorable pharmacokinetics, sdAbs are tested as targeting vehicles for the delivery of cytotoxic irradiation to cancer lesions inside and outside the brain. Here we measure the potential of CAM-H2 (131-Iodine conjugated anti-HER2 sdAb 2Rs15d) for targeting brain lesions with imaging and compare its therapeutic efficacy with Trastuzumab in a preclinical model.
Tumors were inoculated through intracranial injection of HER2+SKOV3.ip1 or MDA-MB-231Br (MDA) cancer cells. Biodistribution of radiolabeled 2Rs15d and Trastuzumab was evaluated through in vivoSPECT/CT imaging at 1h and 72h post injection followed by ex vivotissue radioactivity counting. Five groups of MDA-tumor-bearing mice were treated with either CAM-H2, Trastuzumab plus CAM-H2, unlabeled 2Rs15d, Trastuzumab, or PBS.
Mice treated with CAM-H2 and the combination of CAM-H2 plus Trastuzumab showed a significant increase (p < 0.05) in median survival compared to the Trastuzumab only, unlabeled 2Rs15d or PBS. The addition of Trastuzumab did not significantly prolong survival, compared to cold 2Rs15d or PBS. SPECT/CT imaging of CAM-H2 treated animals showed specific uptake in the brain lesions up to 2 days after administration.
CAM-H2 crosses the BTB and binds HER2 positive brain lesions. Treatment with therapeutic doses of CAM-H2 significantly increased survival compared to Trastuzumab. Systemically delivered cytotoxic irradiation conjugated to sdAbs has the potential to effectively treat cancer lesions inside the brain, with limited exposure to healthy brain. Clinical translation of CAM-H2 for treatment of BCBM is currently ongoing.
Vrije Universiteit Brussel.
Camel-IDS NV/SA.
M. D’Huyvetter: Ownership interest, employee: Camel-IDS NV/SA. B. Windhorst: Editor in chief: Nuclear Medicine & Biology; Editor: Journal of Radiolabelled Compounds & Radiopharmaceuticals T. Lahoutte: Holds ownership interest, consultant: Camel-IDS NV/SA; Member of the scientific advisory board: Ion Beam Applications; Member of the strategic committee: IRE; Preclinical contract research: Roche, Telix Pharmaceuticals. N. Devoogdt: Ownership interest, consultant for Camel-IDS NV/SA; Preclinical contract research: Roche, Telix Pharmaceuticals. All other authors have declared no conflicts of interest.
The PI3K/Akt/mTOR pathway is frequently activated in breast cancer (BC) and is implicated in resistance to endocrine therapy (ET). Addition of everolimus (EVE), an mTOR inhibitor, to ET improves cancer control compared to ET alone. However, in previous studies, the median progression-free survival (PFS) did not exceed 7 months (mo), responses were inconsistent and there was no efficient predictive biomarker of efficacy. We aimed to define a correlation between clinical, biological or histological features and EVE efficacy.
Retrospective analysis of metastatic breast cancer (mBC) patients treated with EVE in our centers between 2013 and 2018. Clinical characteristics (type of metastases), biological features (albumin levels, lactate dehydrogenase (LDH) and neutrophil/lymphocyte ratio (NLR)) and tumors features (estrogen or progesterone receptors, KI67, grade) were analyzed. In available tissue samples collected before EVE initiation, immunohistochemistry (IHC) for PTEN, cMET and pS6RP was performed. All these features were correlated with PFS.
There were 61 women, median age 59 yo, with mBC treated with EVE, and 35 tumor samples were available. Median PFS was 6,5 mo (1-32 mo). 3 tumor-related features were associated with poor prognosis (LDH >230 U/L, high NLR (>3) and visceral metastases). A score was made out of these 3 criteria : patients with a “high score” (HS) (2 or 3 criteria) had a low PFS compared to “low score” (LS) patients (0-1 criteria) (4 vs 11 mo, respectively; p < 0,001). Patients with IHC c-MET+ had a lower PFS in LS (4 vs 13,5 mo, p = 0,01) and HS patients (c-MET- PFS 8,5 mo vs 3 mo if c-MET+, p = 0,02). For HS patients with PTEN loss also had a shorter PFS (3 vs 5 mo, p = 0,003). Combining these criteria, PFS in LS PTEN-/cMET- was 10,5 mo and only 3 mo in HS PTEN+/cMET + (p < 0,001).
Visceral metastases, high NLR and high LDH were associated with lower PFS on EVE. They are useful, quick and economic scores to predict EVE efficacy in mBC patients. Additional histological characteristics such as PTEN and c-MET could help determine, within this population of patients, the ones who will and the ones who will not benefit from EVE treatment.
Emmanuel Seront - Hôpital de Jolimont.
Has not received any funding.
All authors have declared no conflicts of interest.
Since the introduction of trastuzumab-containing therapies, patients (pts) with HER2-positive breast cancers (BC) are experiencing longer progression-free (PFS) and overall survival (OS). However, the extending life expectancy of these pts is associated with an increased incidence of distance recurrences and, particularly, central nervous system (CNS) metastases. Aim of this study is the evaluation of factors which could affect prognosis from diagnosis of CNS metastatic disease to death.
Records of pts with HER2-positive BC treated at Humanitas Cancer Center between 2000 and 2017 were retrospectively reviewed. OS was estimated by Kaplan Meier method and differences between groups by log-rank test. Cox proportional Hazard model was used to estimate Hazard ratio (HR) with 95% confidence intervals (CI). Significance was set at a p value of 0.05.
Globally, 1171 pts with HER2-positive BC were retrospectively analyzed. 283 pts (24%) developed metastatic disease; 16 (6%) developed only CNS metastases, 174 (61%) other-than CNS metastases, 93 (33%) both. Among pts with CNS metastases, median age of diagnosis was significantly younger than median age of pts with other-than CNS metastases (51 years old, range 31-81 vs 57 years old, range 30-89, p = 0.012). The development of CNS metastases was associated with a worse prognosis, with an almost 5-fold increased risk of death compared with other-than CNS metastases (HR 4.7, CI 3.5; 6.4). Median time from diagnosis of CNS metastases to death was 13 months. The number of CNS metastatic lesions (single vs multiple lesions) was associated with a different 3-year survival (39% vs 18% p = 0.003). The administration of a brain radiation treatment had a favorable association with 3-year survival (p < 0.001). Pts who received the newest HER2-targetting therapies (pertuzumab and/or T-DM1 and/or lapatinib) had a 3-year OS of 30.6%, compared with 22.5% for those who did not receive the above mentioned treatments (p = 0.025).
Pts affected by HER2-positive BC who develop CNS metastases have a poor prognosis. A multimodality therapeutic approach shows an impact on survival, although limited. Still, greater efforts in understanding vulnerability of CNS metastases should be made.
Armando Santoro.
Has not received any funding.
R. Torrisi: Advisory board, fees as speaker: Celgene, MSD, Pfizer, Novartis, Lilly. A. Santoro: Advisory board, fees as speaker: Sandoz, Servier, Eisai, Roche, Novartis, Gilead, Pfizer, BMS. All other authors have declared no conflicts of interest.
Improvements in the systemic treatment of patients with metastatic breast cancer (MBC) and the inefficiency of many drugs in crossing the blood brain barrier have led to an increased incidence of symptomatic CNS metastasis. CNS metastases are clinically characterized by two distinct phenotypes, solid CNS metastasis and leptomeningeal metastases (LM). In addition to its poor prognosis, neurological impairment in LM is devastating. No major advances have been made in the treatment and diagnosis of LM, which remains challenging due to low sensitivity of CSF cytology and/or unequivocal MRI findings.
27 pts were diagnosed with breast cancer related LM and treated with IT therapy from 2008 - 2018 (GZA Hospitals Sint-Augustinus, Belgium). Conventional diagnosis was based on positive cytology on CSF and/or the combination of clinical signs and neuro-imaging findings. For a subset of pts (n = 12), circulating tumor cells (CTC) and CSF disseminated tumor cells (DTC) at time of LM diagnosis were enumerated, using the CellSearch platform (Menarini Silicon Biosystems).
The median OS from LM diagnosis was 27 months (4.5-128). Coexisting brain metastases are present in 37% of pts. The biochemical data matched the classic CSF findings of LM including a high protein concentration (75%, 9/12) and a low glucose concentration (42%, 5/12). CSF lactate was elevated (>2.2 mmol/L) in 100% (10/10). In 70% (7/10) CSF lactate was >3.5 mmol/L. Cytologic evaluation of the CSF demonstrated unequivocal malignant cells in 10/12 (83%). DTC enumeration in the CSF of these pts, however, revealed the presence of tumor cells 12/12 (100%). The cell count ranged between 10 - 3523 Epcam+cells/mL CSF.
Symptomatic LM in patients with MBC has a variable prognosis, with some patients experiencing prolonged survival. CSF lactate is a sensitive but aspecific marker of LM. Epcam-based DTC enumeration in the CSF is a robust tool to diagnose LM with apparently a superior sensitivity over conventional cytology. It furthermore has a broad dynamic range rendering it more suitable for treatment effect evaluation. This methodology should be considered in routine workup in MBC patients with suspected LM.
GZA Hospitals Sint Augustinus.
Has not received any funding.
All authors have declared no conflicts of interest.
BM in HER2-positive BC patients are increasing, without agreement on the appropriate treatment of this subgroup. The disrupted blood-brain barrier in the setting of BM may allow the penetrance of T-DM1, with little evidence of its efficacy in this situation.
HER2-positive BC patients treated with T-DM1 monotherapy at Ramon y Cajal Hospital (Madrid) from 2012 to 2017 were eligible. We differentiated patients without BM, stable BM (those with BM who had received local treatment for them and they were not in progression) and progressive BM (those who were in brain progression to a local treatment) at the beginning of T-DM1. We collected hormone receptors (HR) status, neoadjuvant treatment, number of previous treatments for metastatic BC, patients who received taxanes, pertuzumab or both, sites of metastatic disease, duration of T-DM1 and sites of progression. We analysed progression free survival (PFS) in total population and in both subgroups (patients with or without BM).
We identified 29 patients, 69% had positive HR, 45% had received neoadjuvant treatment and 55% had received 2 or more prior lines of treatment. Of total, 97% received taxanes and 38% received pertuzumab. Most patients had visceral disease. Patients received a median of 5 cycles of T-DM1, median duration of T-DM1 was 13 weeks and 4 remain on treatment at time of analysis. Before starting T-DM1, 28% had known BM (75% stable, the rest in progression). Only 10% of patients had cerebral progression during T-DM1. 19 patients had systemic progression during T-DM1, 2 of them with brain progression at same time, and 9 patients presented brain progression after finishing T-DM1. Median PFS was 21 months (m) in total population (confidence interval [CI] 95%: 12,58-28,94), 5 m in patients with BM (CI 95%: 3,88-6,50) and 24 m in those patients without BM when T-DM1 was started (CI 95%: 12,58-28,94). T-DM1 showed benefit in terms of PFS in patients without BM at the beginning of treatment in comparison with those with baseline BM (HR 0,297, p = 0,014).
T-DM1 seems to be an effective therapeutic option in unselected HER2-positive BC patients with BM, but these findings require a prospective validation.
Elena López Miranda, Roberto Martín Huertas.
Roche Pharma.
All authors have declared no conflicts of interest.
Breast to bone metastasis is a common event during breast cancer progression. The resultant lesions are painful and currently, despite medical advances, are incurable. Therefore, identifying the underpinning molecular mechanisms in the bone microenvironment is vital for the development of new therapies. Gene expression analysis and validation in human and murine specimens of bone metastases revealed matrix metalloproteinases, such as MMP-2, are highly expressed in the bone metastatic microenvironment. These data support the rationale for the development of a highly specific MMP-2 inhibitor for the eradication of active bone metastatic breast cancer.
Given that previous broad-spectrum MMP inhibitor (MMPI) trials were unsuccessful due to dose limiting systemic side effects, we utilized a novel chemical approach to synthesize bone seeking MMP inhibitors (BMMPIs) on a bisphosphonic backbone, with specificity for MMP-2 in the nanomolar range (IC50=140 nM). Based on our previous data about BMMPI’s ability to significantly reduce breast cancer growth in the bone microenvironment, we decided to investigate the role of BMMPI such as ML115 in preventing dissemination of cancer cells into the skeleton. Balb-c female mice (n = 10/group), pretreated for 7 days with vehicle, standard of care bisphosphonate (Zoledronate= 1 mg/kg) and BMMPIs (ML115= 1 mg/kg), were randomized and intra-cardiac injected with luciferase expressing 4T1 (2x105) breast cancer cell line. Tumor growth was assessed via luminescence quantitation overtime.
Our preliminary total body bioluminescent data suggest that pretreatment with ML115 can significantly reduce the amount of breast cancer cells homing into the bone, compared to vehicle and standard bisphosphonate. Cancer induced bone disease was measured ex vivo by μCT, Xray and histomorphometry. Ex vivo analysis also illustrated the significant beneficial effects of the BMMPIs in reducing the size of osteolytic lesions. We are currently measuring MMP activity in vivo and ex vivo via specific activatable MMP probes, in order to confirm BMMPI mechanism of action.
We predict that BMMPIs could be used as preventive treatment to impair breast cancer to bone metastasis in clinic.
H Lee Moffitt Cancer Center.
Susan G Komen Breast Cancer Foundation and American Airlines.
All authors have declared no conflicts of interest.
Breast cancer incidence in Nigeria has risen by > 120% since 2000. Its mortality rate (18.8 / 100 000 women / year) ranks highest in Africa. Studies have suggested that non-vigorous physical activity is associated with reduced risk of breast cancer. However, its role in breast cancer risk is yet to be established in sub-Saharan Africa. Increasing prevalence of behaviours associated with reduced non-vigorous physical activity has been reported across several countries in sub-Saharan Africa, including Nigeria. The purpose of this study was to investigate if there is an association between non-vigorous physical activity and breast cancer risk among Nigerian women.
The study was a multisite hospital based case-control design involving 379 histologically confirmed breast cancer cases and 403 controls. The participants were interviewed in-person between October 2016 and May 2017. Cases were selected from the oncology wards and controls from ophthalmology wards. Self-reported non vigorous physical activity (sum of occupational, household and transport physical activities) was summarised as both hours per week and metabolic equivalents hours per week (MET-hr / wk). Data were analyzed using multivariable logistic regression, adjusting for known confounders.
The result (in MET-hr/wk) showed a 40% [95 % confidence interval (CI): 0.40 - 0.89, p for trend = 0.032] reduction in breast cancer risk among women in the upper tertile of total non-vigorous physical activity compared to those in the lowest tertile of non-vigorous physical activity. This was stronger among younger [ odds ratio (OR) 0. 54, 95 % CI: 0.32 - 0.92], premenopausal (OR 0.46, 95% CI: 0.24 - 0.89) and lean women (OR 0.47; 95% CI: 0.25 - 0.88) compared to older, postmenopausal and overweight/obese women respectively.
Non-vigorous physical activity was associated with reduced risk of breast cancer among Nigerian women. This risk reduction was modified by age, menopausal status and body mass index. Conditions that promote increased participation in non-vigorous physical activity among women should therefore be encouraged with respect to breast cancer prevention in Nigeria.
Samuel Onyinyechukwu Azubuike.
National Open University of Nigeria.
All authors have declared no conflicts of interest.
Venous thromboembolism (VTE) is a common cause of mortality in cancer patients. This paper looks into prevalent characteristic of breast cancer in association with VTE, if any.
Hospital patient database were gathered from 2010-2015 with Venous Dupplex Scan or Computed Tomographic Pulmonary Angiography. Each result were reviewed for final conclusion bearing acute pulmonary embolism or acute thrombosis. Only the first VTE event after the diagnosis of cancer was considered.
There were 10,380 CTPA/Venous duplex scan performed for the year 2010-2015, where 916 (8.8%) had positive venous thromboembolism. Of the patients who had positive for venous thromboembolism, 208 (2%) had malignancy. Among all the malignancy-associated venous, majority 17.9% (n = 37) had breast cancer. Mean age for Breast cancer patients who had positive VTE was 60.9(46-84) with majority 64.8% having normal BMI. Most had VTE of lower extremities 75.67%, presented with swelling of extremities 48.6%. Twenty-one patients (57.7%) had VTE within one year of cancer diagnosis, 8(21.6%) had VTE more than two years from cancer diagnosis. Sixteen (43.2%) were alive for more than two years from VTE diagnosis, 14 (37.8%) died within 3 months to one years from VTE diagnosis. During the time of VTE diagnosis, active cancer management were chemotherapy 17 (45.9%), hormonal therapy 12 (32.4%), surgery 4(10.8%), while 4(10.8%) had VTE as the presenting symptom of cancer diagnosis. Among those receiving chemotherapy, 11(64.7%) had VTE during chemotherapy days while 35% had VTE with one month after completion of chemotherapy. Those with hormonal therapy 83.3% had aromatase inhibitor, while only 5.4% received tamoxifen.
Breast cancer patients with VTE have normal BMI, presenting as swelling of the lower extremity. VTE presented within one year of cancer diagnosis and were mostly alive for more than two years. Active cancer management during VTE diagnosis was mostly during chemotherapy and hormonal with aromatase inhibitor.
The authors.
Has not received any funding.
All authors have declared no conflicts of interest.
Triple negative breast cancer (TNBC) is commonly associated with a poor prognosis. Platinum-compounds (P) and low dose oral cyclophosphamide (mCy) have showed activity in TNBC, exerting a direct cytotoxic and possibly immunomodulating activity. Neutrophil (ANC) to lymphocyte (ALC) ratio (NLR), derived NLR (ANC/[White blood cells − ANC]; dNLR), platelet to ALC ratio (PLR), and high lactate dehydrogenase (LDH) level have been proposed as measures of inflammatory/immunosuppressive status, associated with poor prognosis. The aim of this study is to evaluate these biomarkers in TNBC patients treated with P+mCy combination.
We report an exploratory retrospective analysis on cohort of advanced TNBC patients treated in a phase II trial with the combination of cisplatin (60 mg/mq Q3W) and mCy (50 mg QOD). Clinical data, complete blood count, and LDH level at baseline were collected. NLR>2.5, dLNR>3, PLR>200, and LDH>ULN were considered as significant. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model.
A total of 47 patients treated from October 2011 to September 2015 were included. Median age was 55 years (26-77). More than 40% of the patients received the combination therapy as 2nd line, while 36% was heavily pretreated (>2 lines). Objective response rate and 6-month disease control rate were 23.3% and 57.9%, respectively. Median progression-free survival (PFS) and overall survival (OS) were 4.2 (2.9-5.4) and 12.7 (7.9-17.5) months, respectively. At univariate analysis, NLR>2.5 and PLR>200 were not associated with PFS and OS. dNLR>3 and LDH>ULN were associated with both reduced mPFS (1.8 vs 4.8 mo, HR 2.74, 95% CI 1.41-5.31, p=.003; 3.2 vs 5.8 mo, HR 2.19, 1.11-4.32, p=.023) and OS (4.2 vs 13.3 mo, HR 5.29, 2.22-12.6, p<.001; 5.7 vs 14.3 mo, HR 2.79, 1.26-6.15, p=.011). At multivariable Cox regression analysis, dNLR>3, but not LDH>ULN, was independently associated with PFS and OS.
dNLR confirmed a potential role to improve the selection of TNBC patients more likely to benefit from platinum-based and mCy regimens. Its validity, along with the implementation of new predictive biomarkers, warrants further studies for prospective validation.
Giuseppe Curigliano, MD PhD.
Has not received any funding.
All authors have declared no conflicts of interest.
The combination of palbociclib with hormone therapy significantly increases progression free survival (PFS) compared with hormone therapy in first and second treatment line of HR+ HER2- metastatic breast cancer (MBC). However, the activity and security of palbociclib in MBC patients progressing after multiple treatment lines, has not been tested in clinical trials.
Spanish compassionate use program of palbociclib enabled drug access to patients with HR+/HER2- MBC previously treated with at least 4 treatments for advanced disease and adequate organ function (bone marrow reserve, QTc interval and renal/liver function). Patients received palbociclib 125 mg once daily for 3 weeks followed by 1 week off alone or in combination with endocrine therapy (tamoxifen, fulvestrant, aromatase inhibitor and LHRH-agonists in premenopausal patients).
Between February 2015 and November 2017, 385 patients received treatment with palbociclib. Considering the dispersion of the centers that hindered the analysis, PALBOCOMP study has considered only those that included ≥ 3 patients in the compassionate use program. We report the results of the 70 first patients analyzed. The median age was 46.1 years (range 33.5–58.7 years) at the time of inclusion. 67 (95.7%) and 65 (92.9%) patients had received previous hormonal treatment and chemotherapy for advanced disease respectively. Concomitant hormonal therapy was fulvestrant in 55.7% patients and aromatase inhibitors in 34.3%. Best objective response was partial or complete response in 3 patients (4.3%), stable disease in 25 patients (35.7%) and progressive disease in 33 patients (47.1%) Evaluation of response was not available in 9 patients (12.9%) at the moment of the analysis. Median progression free survival was 5 months (95% CI 3.2-6.8 months).
Palbociclib in combination with endocrine therapy shows encouraging activity in heavily pretreated endocrine-resistant HR+ MBC.
Fundación para la Investigación Biomédica Hospital Clínico San Carlos.
Pfizer.
L. Manso: Consultant or advisory role: Pfizer, Tesaro, AstraZeneca, Roche, Novartis, Celgene; Research funding: Tesaro. Speaking: Roche, AstraZeneca, Novartis. M. Gonzalez: Advisory role: BMS, Pierre Fabre; Speaker: AstraZeneca. D. Malón: Advisory role: Roche, Novartis, Ipsen, Pfizer, BMS, MSD, Eisai; Travel expenses: Roche, Novartis, MSD, BMS. J.E. Ales: Travel expenses: Pfizer. F. Moreno: Advisory role: Roche, Pfizer, Novartis, AstraZeneca, Eisai; Travel expenses: Roche, Pfizer. All other authors have declared no conflicts of interest.
[Fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate (ADC) with a humanized HER2 antibody, topoisomerase I inhibitor payload, and cleavable peptide-based linker. In an ongoing phase 1 trial, [fam-] trastuzumab deruxtecan had a manageable safety profile and promising antitumor activity in HER2+ breast cancer (BC) previously treated with T-DM1 (confirmed objective response rate (ORR) of 54.5%; April 2018 data cutoff). The pivotal, phase 2 DESTINY-Breast01 trial in this population is ongoing.
This multicenter, open-label, phase 3 trial will assess the efficacy and safety of [fam-] trastuzumab deruxtecan vs T-DM1 in subjects with HER2 + (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-Breast03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive [fam-] trastuzumab deruxtecan (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, treatment will be in accordance with the approved label. The primary efficacy endpoint is progression-free survival (PFS) based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include overall survival (OS), ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety and health-related quality of life will also be assessed. The primary analysis for PFS will be performed when approximately 331 PFS events are observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects receiving ≥1 dose of study treatment.
Marie-Louise Ricketts, PhD; and Stefan Kolata, PhD of AlphaBioCom, LLC.
NCT03529110; release date May 18, 2018.
Daiichi Sankyo, Inc., Basking Ridge, NJ, USA.
Daiichi Sankyo, Inc., Basking Ridge, NJ, USA.
S. Verma: Consulting fees: Amgen, AstraZeneca, Eli Lilly, Novartis, Daiichi Sankyo, Roche, Seattle Genetics. J. Shahidi, C. Lee, K. Wang: Salaried employee: Daiichi Sankyo, Inc. J. Cortes: Consulting fees: Roche, Celgene, AstraZeneca, Cellestia Biotech, Biothera, Merus, Seattle Genetics; Fees for non-CME services: Roche, Novartis, Eisai, Celgene, Pfizer.
The combination of immune checkpoint blockade and chemotherapy has improved overall survival in a limited subset of patients (pts) with metastatic TNBC. The ectoenzyme CD73 found on the surface of tumor and stromal cells has immunosuppressive functions and is associated with poor prognosis in TNBC, thus blocking it with the monoclonal antibody oleclumab might enhance antitumor response of combined immunotherapy and chemotherapy.
The phase I studies the safety of the combination of paclitaxel (P; 80 mg/m2 IV weekly [Q1W] x 12), carboplatin (C; AUC 2 IV Q1W x 12), durvalumab (D; 1500 mg IV Q4W) and oleclumab (O; IV Q2W x 5, then Q4W; D/O until disease progression or unacceptable toxicity). The phase I will follow a de-escalation, modified 3 + 3 design testing 3 dose levels (DL0, -1, -2) of O in order to define the recommended phase 2 dose (RP2D). Starting doses were selected following the results of a phase I study in pts with metastatic solid tumors that determined a recommended dose of O both as monotherapy and in combination with D (corresponds to DL0). The RP2D of O will be used in combination with P, C and D in the phase 2 part. Regardless of the RP2D, DL0 of O will be used from week 17 onwards. The phase II openly randomizes pts in a 1:1 ratio to D, P and C with or without O. For D, P and C, the same doses and schedules as in the phase I will be used. The primary objective compares the efficacy of the two treatment arms by studying the clinical benefit rate (CBR; pts with complete/partial response and stable disease) at week 24. Sample size was planned assuming a CBR of 40% in the O-free arm (based on a phase Ib trial) and a CBR of 60% (as clinically meaningful benefit) in the O arm, requiring 68 pts/treatment arm (one-sided α = 0.1, 80% power). Assuming a 10% drop-out rate, 150 pts will be randomized. The trial has a translational research component with the collection of several blood/ tissue samples aiming at understanding mechanisms of sensitivity/resistance to D and O in TNBC. Recruitment for the phase I trial started in Jan 2019 with 3 pts enrolled so far. Clinical trial information: NCT03616886.
Sponsor Protocol Number: IJB-SYNERGY-012017, Issue date 30/06/2018.
Institut Jules Bordet, Bruxelles.
AstraZeneca/MedImmune.
C. Maurer: Travel grants: Mundipharma, Amgen. P.G. Aftimos: Honoraria: Synthon, Amgen, Novartis; Consulting/advisory role: Roche, Novartis, Macrogenics, Boehringer Ingelheim, Amcure; Travel grants: MSD, Roche, Amgen, Pfizer. M. Ignatiadis: Consultant/advisory role (honoraria): Celgene, Novartis, Pfizer, Roche, Seattle Genetics, Tesaro; Research grants to my Institute: Roche, Menarini Silicon Biosystems, Janssen Diagnostics, Pfizer; Travel grants: Pfizer. M. Piccart: Consultant/advisory role (honoraria): AstraZeneca; Research grants to my institute: AstraZeneca, Medimmune. All other authors have declared no conflicts of interest.
Patients with metastatic triple negative breast cancer (mTNBC) subtype have poor outcomes with a median overall survival (OS) of approximately 1 year. SGN-LIV1A, or ladiratuzumab vedotin (LV), is an investigational monomethyl auristatin E (MMAE)-conjugated humanized IgG1 antibody-drug conjugate (ADC) against LIV-1, a highly expressed transmembrane protein in breast cancer cells. LV mediated delivery of MMAE drives antitumor activity through cytotoxic cell killing and has been shown to induce immunogenic cell death (ICD). Preliminary results from an ongoing phase 1 study show that LV monotherapy is well tolerated and has encouraging antitumor activity in patients with mTNBC. Pembrolizumab, a checkpoint inhibitor that elicits antitumor activity by targeting the T cell inhibition pathway, showed limited response in the treatment of locally advanced/metastatic (LA/M) TNBC as monotherapy. Combining LV and pembrolizumab may result in synergistic activity through LV-induced ICD that creates a microenviroment favorable for enhanced anti-programmed cell death protein 1 activity.
SGNLVA-002 is a single-arm, open label Phase 1b/2 study of LV in combination with pembrolizumab as first line therapy for patients with LA/M TNBC (CT.gov: NCT03310957 EudraCT: 2017-002289-35). This study consists of 2 parts: dose finding and dose expansion, which are enrolling sequentially. Patients must not have had prior cytotoxic or anti-PD(L)1 treatment for advanced disease. Patients must have measureable disease per RECIST v1.1 and an ECOG score of 0 or 1. The dose finding phase was a dose de-escalation study and started at 2.5 mg/kg LV + 200 mg pembrolizumab every three weeks. The primary objective is to assess the safety/tolerability of LV+pembrolizumab, identify the recommended phase 2 dose of LV, and evaluate ORR by RECIST v1.1. The secondary objectives include evaluation of DOR, DCR, PFS, and OS. The first patient was enrolled in March 2018 and the study is currently enrolling in the US and EU.
Wendi Schultz and Amy Mackay, Seattle Genetics, Inc.
NCT03310957 EudraCT: 2017-002289-35.
Seattle Genetics Inc.
Seattle Genetics, Inc.
V. Boni: Research funding: Seattle Genetics, Inc.; Advisory board membership: Loxo Therapeutics, Ideya; Corporate board membership: ASCO, ESMO, SEOM, SOLTI. C. Alemany: Research funding: Seattle Genetics, Inc.; Speaker’s bureau: Alexion Pharmaceuticals, Inc. J.L. Meisel: Research funding: Seattle Genetics, Inc.; Consultancy: Puma, Pfizer; Honoraria: Total Health Conferencing; Travel expenses: Puma, Pfizer, Total Health Conferencing (travel to meetings). R. Sinha: Research funding: Seattle Genetics, Inc. D. Sterrenberg: Research funding: Seattle Genetics, Inc.; Speaker’s bureau: Puma Biotechnology, Tesaro. K.H.R. Tkaczuk: Grant info: Institutional grant support: Seattle Genetics, Inc.; Research funding grants, institutional grant support: Seattle Genetics, Inc. Y. Wang, Z. Wang: Employment, equity ownership: Seattle Genetics, Inc. H.S. Han: Research funding grants: Pfizer, Abbvie, TapImmune, G1 Therapeutics, Horizon, BMS, Novartis, Tesaro, Seattle Genetics, Inc.; Grant info: Department of Defense; Travel expenses: Pfizer.
There is no uniform standard of care for HER2+ breast cancer (BC) after disease progression on T-DM1. [Fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody, topoisomerase I inhibitor payload, and cleavable peptide-based linker. In an ongoing phase 1 trial, [fam-] trastuzumab deruxtecan showed promising antitumor activity in T-DM1-pretreated HER2+ BC (confirmed objective response rate [ORR] of 54.5%; April 2018 data cutoff). The pivotal, phase 2 DESTINY-Breast01 trial in this population is ongoing.
This multicenter, open-label, phase 3 trial will assess efficacy and safety of [fam-] trastuzumab deruxtecan in subjects with HER2 + (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC whose disease progressed on or after T-DM1 (NCT03523585, DESTINY-Breast02). Approximately 600 subjects will be randomized (2:1) to [fam-] trastuzumab deruxtecan (5.4 mg/kg IV q3wk) or investigator’s choice (trastuzumab/capecitabine or lapatinib/capecitabine). Randomization is stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. The primary efficacy endpoint is progression free survival (PFS) based on blinded, independent central review using RECIST v1.1; overall survival (OS) is the key secondary endpoint. Other secondary efficacy endpoints are ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Primary analysis for PFS will occur when approximately 372 PFS events are observed; providing 90% power to detect a hazard ratio of 0.70 in PFS (a 43% improvement in median PFS from 3.3 months with investigator’s choice to 4.7 months with [fam-] trastuzumab deruxtecan) with a 1-sided alpha of 0.025. An interim OS analysis is planned at the time of PFS analysis. Final OS analysis will occur when approximately 428 OS events have been observed. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all subjects receiving ≥1 dose of study treatment.
Marie-Louise Ricketts, PhD; and Stefan Kolata, PhD, of AlphaBioCom, LLC.
NCT03523585; release date May 14, 2018.
Daiichi Sankyo, Inc., Basking Ridge, NJ, USA.
Daiichi Sankyo, Inc, Basking Ridge, NJ, USA.
F. André: Fees: Pfizer, Lilly, AstraZeneca. J. Shahidi, C. Lee, K. Wang: Salaried employee: Daiichi Sankyo, Inc. I. Krop: Consulting fees: Daiichi Sankyo, Inc.
Tucatinib (ONT-380) is a highly selective small molecule inhibitor of HER2 kinase with nanomolar potency. Because tucatinib does not inhibit EGFR at clinically relevant concentrations, it potentially decreases EGFR-related toxicities (severe skin rash, diarrhea). In preclinical studies, tucatinib has demonstrated synergistic activity with T and is active in HER2+ models of brain metastases (BM). In a Phase 1b study, tucatinib showed encouraging antitumor activity when combined with C and T in pts with HER2+ mBC previously treated with ado-trastuzumab emtansine (T-DM1) and T. Objective responses were seen, including in pts with BM. The combination was well tolerated with low rates of Gr 3 diarrhea at the recommended dose (300 mg PO BID, equivalent to the single agent MTD). Tucatinib is being evaluated in an ongoing international randomized, double blind, phase 2 study in combination with C and T (HER2CLIMB).
HER2CLIMB is recruiting in North America, Europe, Israel, and Australia. The primary study objective is to assess the effect of tucatinib vs. placebo in combination with C + T on progression-free survival (PFS) based on independent central review. Additional objectives include PFS in pts with BM, overall survival (OS), objective response rate, and safety. To increase the power of key secondary endpoints, the sample size was expanded from 480 to 600 pts. The study population includes adult pts with progressive HER2+ locally advanced or mBC who have had prior treatment with T, pertuzumab, and T-DM1 but not TKIs. A contrast-enhanced brain MRI is required at screening. Pts with untreated or progressive BM may be enrolled if they do not require immediate local therapy. Pts with isolated CNS progression on study may continue study treatment after undergoing local CNS-directed therapy. Pts receive C (1000 mg/mg2 PO BID for 14 days of a 21-day cycle) and T (6 mg/kg IV once every 21 days after a loading dose of 8 mg/kg IV), and are randomized in a 2:1 ratio to tucatinib 300 mg PO BID or placebo. Safety is monitored by an independent Data Monitoring Committee.
Irene Chen (Seattle Genetics, Inc.) and Isabelle Murray (Seattle Genetics, Inc.).
NCT02614794.
Seattle Genetics, Inc.
Seattle Genetics, Inc.
E. Paplomata: Research funding grants: Novartis, Genentech, Corcept therapeutics, Seattle Genetics, Abbvie, Merck, Hoosier Cancer Research Network. T. Bachelot: Advisory board membership: Seattle Genetics, Roche, Novartis, Pfizer; Honoraria: Roche, Novartis, Pfizer; Research funding grants: Roche, Novartis, Pfizer, AstraZeneca; Travel expenses: Roche, Novartis, Pfizer, AstraZeneca. V. Mueller: Consultancy: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, Novartis, MSD, Daiichi-Sankyo, Eisai, Lilly, Tesaro, Nektar; Honoraria: Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Pfizer, Novartis, Roche, Teva, Janssen-Cilag. R.K. Murthy: Research funding grants: Genentech, Daiichi Sankyo, Oncothyreon/Seattle Genetics, EMD-Serono, Pfizer/Alliance foundation; Advisory board meetings, honoraria: Genentech, Puma, Daiichi Sankyo. A.F.C. Okines: Research funding grants: Pfizer; Speaker’s bureau: Roche. A.M. Wardley: Advisory board membership: Roche, Novartis, AstraZeneca, Lilly, Pfizer, Pierre Fabre, Amgen, MSD, NAPP, ACCORD, Athenex; Sponsorship for meetings: Roche, Daiichi Sankyo; Consultancy: Gerson Lehman Group Guidepoint Global, Coleman Expert Network; Corporate board membership: Director of Andrew Wardley LTD; Honoraria: Roche, Novartis, AstraZeneca, Lilly, Pfizer, Pierre Fabre, Amgen, MSD, NAPP, ACCORD, Athenex, Daiichi Sankyo; Speaker’s bureau: Roche, Novartis, AstraZeneca, Lilly, Pfizer; Travel expenses: Daiichi Sankyo. L.N. Walker: Employment: Seattle Genetics. A.M. Antunes De Melo e Oliveira: Consultancy: GSK, Puma Biotechnology, Roche; Research funding grants to the institution: AstraZeneca, Boehringer Ingelheim, Cascadian Therapeutics, Celldex, Genentech, GlaxoSmithKline, Immunomedics, Novartis, Seattle Genetics, Philips Healthcare, Piqur, Puma Biotechnology, Roche, Sanofi; Travel expenses: GP Pharma, Grünenthal, Novartis, Pierre-Fabre, Roche; Honoraria: Roche. All other authors have declared no conflicts of interest.
iBreast is an unique portable handheld non-invasive medical device which is developed in India to screen patients in rural and suburban areas. It employs a lead zirconate titanate piezoelectric cantilever sensor and can accurately detect abnormal areas by comparing the degree of deflection. Our tripled blinded study compares it with Clinical Breast Examination and Mammography and breast ultrasound.
1019 women visiting a tertiary Indian hospital, for annual health check were recruited. Each woman was examined by three independent methods, each blinded to the other two: iBreastExam (iBE), Clinical Breast Examination (CBE) by an expert clinician and Breast Imaging (mammography or breast ultrasound).
Out of 916 enrolled participants, 93 were confirmed by imaging to have at least one breast lesion. Clinical Breast Examination in comparison with imaging detected breast lesions with Sn = 65 %, Sp = 94 %, PPV = 52 %, NPV = 96 %, and iBreastExam reported Sn = 84 %, Sp = 94 %, PPV = 60 % and NPV = 98 %. In women below age 40 (314 participants), iBE detected breast lesions with Sn = 85 %, Sp = 93 %. All malignant lesions were identified by iBE, while one non-palpable malignant lesion was missed by clinician CBE.
The point-of-care Breast Imaging device (iBreastExam) performed with significantly better sensitivity, by 19 %, than CBE to detect breast lesions while reporting high specificity (94 %) and NPV (98 %). In younger women population under the age of 40 years, where the prevalence of dense breast is high, iBreastExam demonstrated high-performance characteristics. iBreast- Exam detected all malignant lesions in this study, while the clinician’s CBE missed to detect a non-palpable malignant lesion. iBreastExam can be a promising tool to provide clinically effective and standardized breast examinations in low-resource settings to detect breast lesions at early stages. The device can also be an effective screening tool for younger women with dense breasts.
Manipal Coprehensive Cancer Center.
Has not received any funding.
The author has declared no conflicts of interest.
To determine the incidence of breast cancer (BC) in BRCA mutation carriers (BRCA+) after ovarian cancer (OC) diagnosis, and to re-evaluate BC surveillance in BRCA+ with OC.
A consecutive chart review, from 2000 to 2017, of OC patients at three medical centers: one in the USA and two in Israel. Clinical data collected included demographics, BRCA mutation types, timing of BC diagnosis (before or after OC diagnosis) and family history of cancer.
Analysis revealed 284 BRCA+ with a median age at diagnosis of 55 years (range, 31.3-90) and median follow-up of 59.5 months (6-92); 209 patients were BRCA1 (73.5%) and 75 were BRCA2 (26.5%). The most common mutation was 185delAG (30.7%). Thirty-six patients (12.7%) were diagnosed with BC before OC. Fifty-four patients (20.5%) had a family history of BC and 187 (65%) were Ashkenazi Jews. Only 11 patients (3.89%) developed BC after OC diagnosis. Median time to BC after OC diagnosis was 109 months (29-93). There was a non-significant increase in BC after OC, and in BC prior to OC diagnosis, but there was no correlation of BC with family history.
The incidence of BC after OC diagnosis in the BRCA+ population was lower than expected. This finding may be attributed the high rate of OC mortality prior to BC development, OC chemotherapy treatment, or BC and OC clustering in families. Prophylactic bilateral mastectomy and/or MRI breast surveillance should be re-evaluated in this population and is possibly needed only in long survivors. Further investigation is warranted.
Local IRB.
Has not received any funding.
All authors have declared no conflicts of interest.
Despite weight gain and overweight have been related to an increased risk of recurrence and mortality in patients with EBC, the adherence to nutritional intervention is not entirely explored. Therefore, the aims of this trial were to evaluate the adherence to DG and the effectiveness of nutritional intervention in terms of BWC in patients with EBC undergoing treatment.
This prospective study included EBC patients addressed to receive neoadjuvant or adjuvant therapy; eligible patients received a nutrition evidence-based educational intervention by a skilled dietitian. Anthropometric and dietary assessments were performed. Adherence to DG was estimated through the validated Med-Diet 14-item questionnaire. Health-Related Quality of Life was analyzed with the EORTC QLQ-C30. Associations between variables and groups according to nutritional variables were analyzed (Chi-square test).
From February 2016 to December 2018, 204 patients were enrolled (median age 49 years). At baseline, 2.5% of patients were underweight, 41.7% were normal weight, 33.3% were overweight and 22.5% were obese. Moreover, 47.5% of patients gained ≥5% of their usual weight. Most patients reported significant nutritional impact symptoms (dyspepsia (51.5%) and constipation (62.3%)) and presented dietary patterns high in fat (median fat intake was 35.2%) and low in dietary fiber (median fiber intake was 17.2 g/day). A significant correlation between baseline BMI and tension was observed (p < 0.0001) as well as BMI and worry, irritability and depression (p < 0.0001, p < 0.0001 and p = 0.008, respectively). Six months after the intervention, the median adherence to DG was high (median Med-Diet score was 12). A high adherence to nutrition guidelines (defines as a Med-Diet score ≥10, 112 patients) significantly correlated with a weight loss ≥5% from the baseline weight (p = 0.005). Furthermore, the weight loss ≥5% was correlated with a lower rate of depression (p = 0.05).
These findings suggest that tailored nutritional intervention for women undergoing treatment for EBC may help to improve their adherence to the DG and finally to weight loss.
Luisa Carbognin.
LILT Verona.
All authors have declared no conflicts of interest.
Ionizing radiation can influence on cells of organisms through the chain of electric, physico-chemical, chemical and biological effects leading to different damages, genetic abnomalities and death. On 26 April 1986 the explosion of atomic reactor of the fourth power unit of Chernobyl Nuclear Power Station happened, having thrown into the atmosphere nearly 50 tons of nuclear fuel with the activity of 15-20 thousands of rentgen per hour. This disaster had detrimental outcome for people living in Ukraine and other countries, resulted to increase of morbidity and mortality from different diseases, especially oncological.
Analysis of data of National and regional cancer registries, statistical reports on the work done by the regional center and district hospitals of Cherkassy region on oncological patients in 1985, 2015 yy.
Number of new breast cancer (BC) cases in 1985 in Cherkassy region was 335 (man – 1, women – 334), in 2015 – 520 ( men – 4, women – 516). The number of BC cases increased by 35,6% ( by 25% in men, by 35,3% in women) in 2015 in comparison to 1985. Crude incidence rate per 100000 of population in 1985 was 21,87 ( men – 0,06, women – 21,8), in 2015- 43,8 ( men – 0,7, women – 80,2). So this rate increased by 49,9%. The number of cases of BC in women under 29 years old in 1985 was 2, in 2015 – 9 ( increased in 4,5 times), showing tendency to rise of incidence of this disease at a young age. Number of deaths from BC in 1985 was 164, in 2015 – 210, so this index increased by 22%. In 1985 stage distribution of new BC cases (according to TNM) was: I, II – 56,2%; III – 31,6%, IV – 12,2%. In 2015 this ratio was: I, II – 74,5%, III – 13,6%, IV – 11,3%. The number of BC cases detected during the preventive examination in 1985 was 25%, in 2015 – 42,8%. The percentage of morphologically verified BC in 1985 was 84,2%, in 2015 – 90,4%.
Chernobyl disaster and subsequent spread and influence of radiation led to increase of oncological diseases in Ukraine, including breast cancer. Despite the new advances in medicine the morbidity of BC in Cherkassy region continues to grow and Chornobyl disaster had a strong impact on this fact.
Cherkassy Regional Oncology Center.
Has not received any funding.
The author has declared no conflicts of interest.
With largely improved cancer survivorship in past decades, cancer survivors developed second primary breast cancer (BCa-2) are not uncommon. However, little is known about the prognosis of BCa-2. We therefore aimed to examine the risk of breast cancer-specific mortality among patients with BCa-2 compared with those with first primary breast cancer (BCa-1).
We included all women diagnosed with invasive breast cancer from January 1, 1990 to December 31, 2015 in US who were recorded in the Surveillance, Epidemiology, and End Results (SEER) program. BCa-2 was defined in patients with a previous diagnosis of non-breast primary malignancy in SEER. We estimated the hazard ratios (HRs) of breast cancer-specific and overall mortality among patients with BCa-2 compared with BCa-1, using COX proportional hazard models adjusted for demographic, tumor, and clinical characteristics.
883,881 and 36,313 patients were identified as BCa-1 and BCa-2, respectively. The median intervals from first primary malignancy to BCa-2 diagnosis was 4.75 years. Compared to BCa-1, women with BCa-2 were diagnosed with less aggressive tumor and received less treatment. BCa-2 patients were associated with increased risks of breast cancer-specific mortality (HR: 1.12; 95% CI: 1.08-1.15) and overall mortality (HR: 1.57; 95% CI: 1.54-1.59). The risk increase was particularly greater when the first malignancy was at distant stage, severer in prognosis, diagnosed within 2 years, or treated by chemotherapy/ radiation therapy. Stronger associations were also found among women with HER2 (+), PR (-), ER (-), and those with less aggressive tumor features.
Patients with BCa-2 have worse breast cancer-specific survival and overall survival, compared with their BCa-1 counterparts. These findings emphasize the needs for more active treatment and surveillance for cancer survivors who developed BCa-2.
West China Hospital, Sichuan University.
National Natural Science Foundation of China (grant number: 81872307), Swedish Research Council (grant number: 2018-00648), and Science and Technology Foundation of Sichuan Province (grant number: 2017SZ0005).
All authors have declared no conflicts of interest.
Chemotherapy for patients with early stage breast cancer (EBC) can be administered through either a peripheral vein or a central line (i.e. PICC or PORT) associated with different risks, benefits and costs. As the optimal type of vascular access is unknown, the feasibility of using a novel pragmatic trial model with integrated oral consent model to compare peripheral with central access was performed.
Patients with EBC receiving non-trastuzumab containing chemotherapy were randomised to either peripheral or central line insertion. Our primary feasibility endpoint would be met if > 25% of appropriate patients approached agreed to randomisation and if > 25% of physicians who agreed to participate in the trial approached patients. Other outcomes included rates of line-associated complications.
Of 159 patients approached, 150/159 (94.3%) agreed to randomization and 7/31 (22.5%) of physicians approached patients. 77 (51.3%) patients were randomized to peripheral and 73 (48.7%) to central access. For patients in the central access arm, PICCs were used in 72/73 (99%). Rates of complications in the peripheral vs central access groups were; thrombotic events (1 [0.67%] vs 3 [2.0%], p = 0.35), line infections (0 [0%] vs 1 [0.67%], p = 0.1084), phlebitis (1 [0.67%] vs 0 [0%], p = 0.35), and extravasations/infiltrations (4 [2.67%] vs 0 [0%], p = 0.1245). Overall, 4.67% (7/150) and 4.67% (7/150) of patients had a complication in the peripheral and central access arms respectively (p = 1.00). Among patients randomized to peripheral access, 9/77 (11.7%) subsequently required a central line.
The study did not meet both its a priori criteria to demonstrate feasibility as physician engagement was <25%. However, this prospectively performed randomised trial demonstrated that while the frequency of access-associated complications was similar, the different nature of events (e.g. thrombosis versus extravasations/infiltrations/phlebitis) means that more studies are needed. Importantly, these future studies will need to overcome the barrier of physician participation.
NCT02688998.
Mark Clemons.
Rethinking Clinical Trials (REaCT Program).
All authors have declared no conflicts of interest.
WSG (West German Study Group)-Protroca evaluated the efficacy and safety of primary and secondary prophylaxis (ppx) of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer (BC) patients (pts) receiving neo-adjuvant or adjuvant treatment in routine praxis.
Eligibility: histologically confirmed BC pts, age ≥18 years, prior or concurrent neo-adjuvant or adjuvant treatment with dose-dense chemotherapy (CT), or with moderate risk CT with risk factors (age >65 years, severe co-morbidities). Primary endpoint: occurrence rate of febrile neutropenia (FN) and/or severe infection (SI) (grade 3–4). Secondary endpoints: dose reductions of further CT or cycle postponement of CT after start of Lonquex® treatment, adverse events (AEs) and serious adverse events (SAEs) related to Lonquex® according to NCI-CTCAE Version 4.0. 47.3% (15.4%) and 38.7% (69.2%) of pts with primary (secondary) ppx received anthracycline (A)-containing dose-dense and A-containing conventionally dense regimen, respectively.
Of the 255 enrolled pts (2015–2017), 248 pts were evaluable for the intent to treat (ITT) set (222 and 26 pts with primary and secondary ppx, respectively). 5 pts of the ITT set receiving Lonquex® as primary ppx had FN grade 3–4 (2.3%). Regarding SI, 5 pts of the ITT population (2.0%) had an infection of grade 3–4; 4 pts got primary ppx (1.8%) and one received secondary ppx (3.9%). Dose reductions were only performed in 9.5% of pts (all of them receiving primary ppx). Postponement of CT cycles for >3 days was observed in 14.4% and 11.5% of pts with Lonquex® as primary and secondary ppx, respectively. 67.6% (84.6%) and 6.3% (11.5%) of ITT pts with primary (secondary) ppx exhibited AEs and SAEs, respectively. 10.8% (92/851 AEs) and 8% (2/25 SAEs of 851 AEs) of documented AEs and SAEs, respectively, were related to Lonquex®.
In WSG-Protroca, the application of Lonquex® was effective as primary and secondary ppx in the prevention of CT-induced neutropenia. Observed adverse drug reactions and AEs were in line with the Lonquex® summary of product characteristics and CT, respectively; no new toxicities were identified.
West German Study Group (WSG).
Teva Biotech GmbH.
R. Wuerstlein: Agendia, Amgen, AZ, BI, Carl Zeiss, Celgene, Daiichi-Sankyo, Esai, GE, GSK, Hexal, Lilly, MSD, Mundipharma, NanoString, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, Puma Biotechnology, Riemser, Roche, Sandoz, Seattle Genetics, Tesaro Bio, Teva. N. Harbeck: Honoraria for consulting: Amgen, Hexal. U. Nitz: Honoraria: Genomic Health, Roche. O. Gluz: Honoraria: Genomic Health, NanoString Technologies, Roche; Travel, accommodations, expenses: Celgene; Teva. All other authors have declared no conflicts of interest.
In British Columbia (BC), women taking adjuvant endocrine therapy (AET) for early breast cancer are followed by their oncologist for a variable length of time before discharge to their family physician (FP). Many women have physical and psychological needs beyond the scope of their FPs or the capacity of their oncologists to follow longitudinally. In addition, non-adherence to AET occur in over 40% of patients and is associated with increased mortality (Hershman, D Breast Cancer Res Treat 2011). We postulated that establishment of a dedicated service to assess and address symptoms and signs experienced while taking AET could improve quality of life (QOL) and potentially improve adherence.
With funding from the BC Cancer Foundation and in collaboration with the BC Women’s Hospital (BCWH), we established a transitional clinical service led by a Nurse Practitioner. Women taking AET are identified by their Medical Oncologists and referred to the ABCS, located at BCWH. All patients have baseline demographic and QOL assessment (FACT-B+4 and PROMIS sexual function and satisfaction V.2), to be repeated at 12 and 24 months. Adherence will be assessed and compared to BC Cancer historical controls using the provincial pharmacy database. The intent is to transition all patients back to their FPs.
The clinic opened April 2018. As of Jan 10th 2019: 237 patients were referred, 121 were seen (with the remainder scheduled through June) and 120 completed baseline assessments. Prevalent issues include upper body (shoulder, neck, breast) pain, fatigue, joint pain, insomnia, anxiety, depression, genitourinary and sexual concerns. Women have been referred to self-care (online) and multidisciplinary supportive care resources including dietician, exercise specialist, physiotherapist, counsellor, rheumatologist, sleep clinic, sexual health specialist and gynecologist. Informal feedback suggests high patient satisfaction with the service. Two patients have been discharged so far.
The ABCS was established to specifically address the needs of women on AET. Multiple baseline issues are being recognized and managed. It is too early to assess the objective impact of this service on adherence and QOL. This is planned with longer follow up.
BC Cancer and BC Women’s Hospital and Health Centre.
BC Cancer Foundation and BC Women’s Hospital and Health Centre.
T. Shenkier, C. Lohrisch: Advisory board: NanoString, Genomic Health. K. Gelmon: Research funds: AstraZeneca, BMS, Pfizer, Roche; Honorarium personal fund: AstraZeneca, Lilly, Novartis, Pfizer Genomic health, BMS, NanoString, Merck. S. Chia: Advisory boards: Novartis, Pfizer, Hoffman LaRoche. All other authors have declared no conflicts of interest.
Breast cancer survivors are at a higher risk of getting another breast cancer, as well as some other types of cancer. The most common second cancer is another breast cancer either at the same side or on the opposite side. Various factors are implicated in increasing the risk of second primary like hormonal therapy, radiation to the breast and axilla and chemotherapy. We aimed to asses the risk of second cancers in breast cancer survivors.
A retrospective audit was done at amrita institute of medical sciences by including patients with breast cancer treated between 2005 and 2015.
A total of 3470 breast cancers were included, 37.9%, 48.1% and 14% were EBC, LABC and MBC at presentation. 49 patients presented with second primary with a incidence of 1.4%. Median age was 51.4 years. The most common second primary was breast cancer 16 (Ipsilateral - 5, contralateral - 11), Ovarian cancer in 6 patients, Gastrointestinal malignancies in 12, endometrial carcinoma in 3, acute myeloid leukemia in 3 and thyroid carcinoma in 3 patients. The survival outcomes in patients with second malignancies were poor with 3 years overall survival of 38%. Majority (74%) of the patients received adjuvant chemotherapy with AC followed by Taxol including radiation (72%) as part of their primary treatment. Median time interval for development of second primary was 543 days.
Second primary in patients with breast cancer is not a rarity, these patients need to be on long term follow for early diagnosis and treatment. Genetic testing should be considered in patients with history of familial cancers, as genetic testing is not routinely practised due to logistic issues in our patient population, there is immediate need for diagnostics at a low cost to make it affordable to our patients.
Amrita Institute of Medical Sciences.
Has not received any funding.
All authors have declared no conflicts of interest.
Little is known about whether health insurance policies, particularly in developing countries, influence breast cancer prognosis. We aimed to examine the association between individual health insurance coverage plan among patients with invasive breast cancer in China and risks of breast cancer-specific mortality.
We included 7,436 women diagnosed with invasive breast cancer between January 1st, 2009, and December 31st, 2016, at West China Hospital, Sichuan University. The health insurance plan of each patient was classified into urban and rural schemes by insurance type, as well as low (0-69%) and high (70%-100%) reimbursement rate by the median. Cancer-specific mortality (i.e., death due to breast cancer) was the primary outcome, while overall mortality was the secondary outcome. Adjusting for multiple demographic and clinical covariates, we used Cox proportional hazards model, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer-specific mortality, contrasting rates among patients with a rural scheme or low reimbursement rate to that of those with an urban scheme or high reimbursement rate, respectively.
During the median follow-up of 3.1 years, we identified 372 deaths, of which 326 (87.6%) were due to breast cancer. Compared with patients insured by an urban scheme, patients under rural scheme were at 35% increased rate of cancer-specific mortality (95% CI 5% to 72%) after adjusting for demographics, tumor characteristics and treatment modes. Patients at low reimbursement rate were at 42% increased rate of cancer-specific mortality (95% CI 11% to 81%) as compared to patients at high reimbursement rate. Importantly, every increase of 10% at reimbursement rate was associated with 7% (95% CI, 2% to 12%) reduction in rates of cancer-specific mortality. Greater risk reductions were observed particularly in patients insured by rural scheme (28%, 95% CI 12% to 41%).
Our findings suggest that under-insured breast cancer patients in China face increased risk of cancer-specific mortality.
We would like to thank all staff members working on the Breast Cancer Information Management System (BCIMS) for their contributions to data collection and management. We also thank Dr. Bo Fu, Ms. Yan Li, and Mr. Pei Liu at the University of Electronic Science and Technology of China for data cleaning and zip code mapping.
West China Hospital, Sichuan University, Chengdu, China.
National Natural Science Foundation of China (grant number 81872307), Swedish Research Council (grant number 2018-00648), Karolinska Institutet Research Foundation (grant number 2018-01585) and the Key Research and Development Project of Sichuan Province of China (Grant No. 2017SZ0005).
All authors have declared no conflicts of interest.
Ireland has a mixed model of healthcare delivery with a public healthcare system funded by general taxation and a large private healthcare insurance system, covering 43% of the population in 2012 and 2016. We set out to examine disparities in outcomes among patients with breast cancer treated in a private hospital compared to national outcomes over a comparable period.
Medical records of patients diagnosed with early (Stage 1-3 as per AJCC version 5) breast cancer between 2010 and 2015 at Bon Secours Hospital, Cork, Ireland were reviewed. Staging was confirmed and 5-year disease specific survival (DSS) and overall survival (OS) were calculated. DSS was compared to 5-year net survival (NS) figures from the National Cancer Registry of Ireland (NCRI) for a comparable period (2010-2014).
DSS (Bon Secours) and NS (NCRI) are summarized in Table. 5 year survival figures are numerically higher in the private hospital compared with national data for each individual stage. Taking stages 1 to 3 combined, the 95% confidence intervals do not cross each other, indicating statistical significance.
Stage Bon Secours (DSS) NCRI (NS) DSS 95% CI NS 95% CI 1 100 96.5-100 98 97.2-98.9 2 95.2 90.6-97.1 90.9 89.9-91.8 3 89.5 70.5-96.5 71.5 69.2-73.9 1-3 combined 97 93.9-97.8 90.4 90.0-91.4
We found evidence of superior outcomes in patients with early breast cancer treated at a private hospital compared with national outcome figures. This was demonstrated in ‘all comers’ (stages 1-3 combined), and particularly in patients with stage 3 breast cancer. Potential reasons for this disparity include differences in socioeconomic status, health-seeking behaviours and/or underlying health status between the two populations included. Differences in extent or timeliness of access to therapies may also contribute.
Bon Secours Hospital Cork.
Has not received any funding.
All authors have declared no conflicts of interest.
Febrile neutropenia (FN) during adjuvant chemotherapy is associated with morbidity, mortality risk, and substantial cost. The optimal duration of filgrastim as primary FN prophylaxis in early stage breast cancer (EBC) patients is unknown. We compared the cost-effectiveness of 5, 7 or 10 days of filgrastim offered for primary FN prophylaxis.
We conducted a cost-utility analysis from the perspective of Canada’s health care system using a decision tree to evaluate the costs and quality-adjusted life years (QALYs) based on the results of the REaCT G study. In this study EBC patients who were to receive adjuvant chemotherapy were randomized to 5 versus 7 or 10 days of filgrastim as primary FN prophylaxis. Using EQ-5D-5L measures from patients at baseline, after one cycle and at the completion of chemotherapy, along with the cost of complications of febrile neutropenia and treatment-related hospitalization from the provincial database, we determined incremental cost-effectiveness ratio (ICER) for the 7 or 10 days of filgrastim compared to 5 days. Both deterministic and probabilistic sensitivity analyses were carried out.
From 464 patients on the REaCT G trial showed that 5 & 7 days compared to 10 days filgrastim were associated with lower costs and a slight decrease in QALYs. Compared to 5 days of filgrastim, 10 days was associated with an increase cost $3,763 and 0.019 QALYs with ICER of $198,052, and 7 days of filgrastim led to a rise in cost by $2,461 and QALYs by 0.004 with ICER of $615,250. The probabilistic sensitivity analysis showed that cost-effectiveness results were uncertain. At commonly willingness to pay threshold of $50,000/QALY, probabilities that 5, 7 and 10 days filgrastim are cost-effective were 48%, 35%, and 18%, respectively.
We conclude that shorter schedules of filgrastim provide cost savings with a slight decrease in QALY. The schedule of filgrastim prophylaxis that would be considered cost-effective depends on the willingness of the payer.
Mark Clemons.
REaCT Program and Cancer Care Ontario.
All authors have declared no conflicts of interest.
Insight in late treatment-related health problems following from breast cancer treatment is useful in anticipating on the (informational) needs of patients during follow-up. This study aimed to identify treatment-related health problems in breast cancer patients up to five years after diagnosis. Second, use of care associated to these health problems was identified.
876 surgically treated female patients diagnosed with early stage breast cancer (between 2012-2016) were asked to complete an online survey about current health problems and use of care. Multivariate logistic regression analyses were applied to determine the effect of patient and treatment characteristic on health problems.
404 patients responded (46%). Median age was 62.0 years (SD: 10.9). Apart from breast surgery, patients were treated with radiotherapy (72%), chemotherapy (49%), anti-hormonal therapy (57%), and axillary dissection (21%). Ninety-three percent experienced one or more health problems. Over 50% of respondents experienced fatigue, psychological problems, and health problems regarding the breast, and/or musculoskeletal, central nervous, and reproductive system. Treatment with chemotherapy was significantly (p < 0.05) associated with an increased risk of health problems, respectively fatigue (OR:2.00), and respiratory (OR:1.81), gastrointestinal (OR:1.87), central nervous (OR:3.40), and skin problems (OR:2.62). Use of health care for one or more health problems was reported by 64% of respondents.
Almost all patients experienced health problems up to five years after breast cancer diagnosis, with a range of complaints existing consistently present over time. Factors associated with the development of health problems are useful to better informing patients upfront and to target follow-up care.
Netherlands Comprehensive Cancer Organisation (IKNL).
Has not received any funding.
All authors have declared no conflicts of interest.
Breast cancer (BC) burden is increasing among women living with HIV (HIV+). Yet, data regarding epidemiology, BC presentation, treatment, and prognosis is still scarce, especially among HIV+ BC patients (pts) from developing countries.
This prospective cohort included BC patients diagnosed at the Maputo Central Hospital, Mozambique, from Jan-2015 to Mar-2017. Data on demographics, BC risk factors, co-morbidities, treatment, and survival were prospectively collected. Chi2 and t tests were used to compare categorical and continuous variables, respectively. Time-to-event outcomes were estimated using Kaplan-Meier methods. Survival estimates were compared using log-rank test and Cox proportional hazards models. All tests were two-tailed and results were considered significant if p-value was <.05.
Among 205 pts included, 98% were black and 52 (25%) were HIV+. HIV+ pts were younger than HIV- pts (median age: 44.5 vs 51.0 years respectively, p=.002), and most had stage III/IV BC (81% vs 71%, p=.204). Among HIV+ pts, 90% had a CD4+ cells count > 200/μL and 26% were diagnosed at the time of BC. Immunohistochemistry analysis was performed in 152 pts and showed that HIV+ pts had a higher proportion of triple-negative BC (TNBC) compared to HIV- pts (37.5% vs 20.5%, p=.029). Among pts with early BC (EBC), there were no significant differences in local treatments received; yet, HIV+ pts tended to receive a lower chemotherapy (CT) dose-intensity (DI) compared to HIV- pts (DI < 85%: 69.4% vs 50.0%, p=.057). Median overall survival (OS) was 31.0 months (m) in HIV+ pts and 34.0 m in HIV- pts (unadjusted hazard ratio [HR] 1.52, 95% confidence interval [CI] 0.92 – 2.51). In EBC pts, median disease-free survival was 27.0 m in HIV+ pts and 31.0 m in HIV- pts (HR 1.37, 95% CI 0.81-2.31).
Our results show that in Southeast Africa the proportion of HIV+ women among BC pts can be very high. These pts were diagnosed at a younger age and had a significantly higher proportion of TNBC compared to HIV- pts. They tended to receive lower CT DI, and their survival was worse as compared to HIV- pts, although not statistically different. This highlights the need for better understanding BC biology in HIV+ pts and to provide effective cancer care to this underserved population.
Faculty of Medicine, Eduardo Mondlane University, Mozambique.
NIH AORTIC BIG CAT grant (award number 59-210-6-004).
M.D.R.A. Brandão: Research grants to my Institute: Roche, Menarini Silicon Biosystems, Pfizer, Janssen Diagnostics. All other authors have declared no conflicts of interest.
Trastuzumab, a humanized monoclonal antibody significantly improves outcomes in Her2 neu positive breast cancer. The incidence of cardiotoxicity with trastuzumab is approximately 8-10%. The present study was designed to analyze the incidence and risk factors associated with trastuzmab related cardiotoxicity.
The present study was a single institutional retrospective analysis of the incidence of trastuzumab induced cardiotoxicity in nonmetastatic invasive breast cancer from January 2011 to December 2018. Trastuzumab induced cardiotoxicity (TIC) was defined as symptomatic heart failure or asymptomatic decline in left ventricular ejection fraction (LVEF) by > 10% or LVEF < 50%. Risk factors analysed were BMI (≥30 vs < 30), history of diabetes, hypertension, coronary artery disease (CAD) (yes or no), left sided radiotherapy (RT) and prior anthracycline (yes or no).
Data of 246 patients with Her2 neu positive breast cancer was collected. Of these, 117(47.5%) received trastuzumab. The median age at presentation was 51 years (range,28-72). Of 117 patients who received adjuvant trastuzumab TIC was seen in 16(13.6%) patients, asymptomatic LV dysfunction in 9.4% and symptomatic LV dysfunction in 4.2% patients. The median baseline ejection fraction of 65% (range, 56 - 72). The median time to development of TIC was 18.5 (range, 3-52) weeks and median trastuzumab cycle for TIC was 6 (range, 2-16). Presence of ≥ 2 risk factors (20%) had significant impact on incidence of TIC compared to < 2 risk factors (p = 0.04). 10 (62.5%) patients were rechallenged with trastuzumab and 6(37.5%) discontinued trastuzumab. Following rechallenge 1 patient developed asymptomatic decline in EF and 1 developed symptomatic heart failure and were stopped completely. No cardiacrelated mortality was seen.
Risk factors in relation to TICRisk factor TIC Present TIC absent p Value BMI ≥ 30 < 30 2 14 14 78 0.54 History of diabetes Yes No 3 13 21 80 0.88 History of hypertension Yes No 8 8 31 70 0.2 CAD Yes No 1 15 2 99 0.8 Left side RT Yes No 9 7 23 78 0.012 Prior anthracycline Yes No 13 3 65 36 0.29
Approximately 14% developed TIC which was higher in real-world population compared to that seen in clinical trials. Left sided RT to chest and presence of 2 or more risk factors had significant impact on development of TIC. Stringent monitoring of cardiac function to avoid cardiotoxicity and prompt resumption of trastuzumab following recovery may further improve outcomes in nonmetastatic breast cancer.
Nil
Nil
Department of Medical Oncology, NIMS, Punjagutta, Hyderabad, India.
Has not received any funding.
All authors have declared no conflicts of interest.
Male Breast Cancer (MBC) represents 1% of all breast cancers, as well as less than 1% of malignant neoplasm in male.
Describe male population with breast cancer (BC) in our institute from 2007 to 2017. Methods: Unicentric, retrospective and descriptive study with inclusion of all male individuals with diagnosis of invasive breast carcinoma. Data was obtained through clinical process review and analyzed with SPSS®.
There were included 66 cases of invasive male breast carcinoma with a median age at diagnosis of 66,5 years old, [24-88] and an initial ECOG PS of 0 in 73% (n = 48). Locally advanced disease was diagnosis on 47% (n = 30) of patients, meanwhile 44% of cases were early BC at the diagnosis. Stage IV disease occurred on 9% (n = 6), and 6 % (n = 4) of patients had bilateral BC. The most frequent molecular subtype was Luminal B-Like (67% n = 44), and cerB-2 overexpression occurred in 10,6% (n = 7). The most frequent symptom was breast lump (89% n = 59). At the time of diagnosis, clinical suspected axillary lymph nodes were detected on 68% of the cases and gynecomastia was present in 28%. The percentage of cases observed after 6 months of symptoms onset was 30%. Positive family history of neoplasms occurred on 71% of cases, including 26% with BC family history. Pre-existing neoplasia was observed in 20% of patients, namely prostate adenocarcinoma as the most frequent diagnosis. Near 53% of the cases were followed on familiar cancer risk appointment, with 4,5%, (n = 3) of cases positive for BRCA2 pathologic mutations. Neoadjuvant chemotherapy was performed in 33% (n = 22). Surgery was performed on 94% (n = 62) of the patients. The pathologic response rate was 90%. In adjuvant setting, 70% (n = 46) of patients received hormonotherapy and 47% (n = 31) radiotherapy. The median time to recurrence was 33 months, [11-147]. Near 23% (n = 15) of patients progressed and the most frequent secondary location was bone (60%). The median OS was 8 years, 95% CI[6,5 -9,5].
MBC is diagnosed later, presenting a more advanced stage, and the majority of patients had expression of hormonal receptors. Despite the late diagnosis, good disease control was achieved. This study in addition to being in accordance with literature reflects the importance of follow-up in family risk consultation.
Joana Cunha Carvalho.
Has not received any funding.
All authors have declared no conflicts of interest.
Tools to support clinical decision making regarding breast cancer (BC) are becoming more available to clinicians. NHS PREDICT is a freely available web-based tool for prognostication and assistance in BC management. Recent research shows doubt in using the tool for BC subtypes. There is fear over the possibility of over- or undertreatment of patients.
Ninety-four patients regardless of their ER (estrogen receptor), PR (progesterone receptor) and HER2 (human epidermal growth factor receptor 2) status were included in this study. Through using the platform NHS PREDICT 2.0 we evaluated through the pilot study the prediction of patients with newly diagnosed breast cancer. We evaluated the prediction of 10-year survival, benefit of surgical treatment, treatment with hormonal therapy, transtuzumab treatment and benefit of chemotherapy.
The median age at diagnosis was 60.10 years (SD 14.4). Patients were classified according to hormonal status: i) ER+ BC (n = 69), ii) ER+ and HER2+ BC (n = 8), iii) ER-, but HER2+ BC (n = 7) and iv) triple negative BC (n = 10). Overall 10-year survival for ER+, HER2- was 86.1 % (benefit of adjuvant chemotherapy adding 2.8 %), for ER- and HER2+ 83.7% (benefit of adjuvant chemotherapy adding 7.0 %) and for TNBC 77.4% (benefit of adjuvant chemotherapy 5.5 %). Overall data is represented in Table.
This pilot analysis estimates that overall survival was in accordance to available treatment data. TNBC 10-year survival was appropriate (decreased), but the tool estimated very low chemotherapy benefits for TNBC patients in comparison to other patient groups thus posing the risk of patient undertreatment.
The University Medical Center Maribor.
Supported through the Slovenian Research Agency Project (J3-9272).
All authors have declared no conflicts of interest.
Predict output on breast cancer subtypesBreast cancer subtypes 10-year age adjusted overall survival Mean age at time of diagnosis Benefit of surgical treatment on survival Benefit of hormonal therapy on survival Benefit of chemotherapy on survival Benefit of transtuzumab on survival ER+, PR+, Her2- (n = 69) 86.1 (SD 15.1) 58.7 (SD 13.2) 73.32 (SD 16.3) 3.71 (SD 2.8) 2.8 (SD 2.1) / ER+, PR+, Her2 + (n = 8) 88.9 (SD 11.0) 57.6 (SD 12.1) 64.9 (SD 20.9) 6.5 (SD 3.7) 4.7 (SD 2.8) 3.6 (SD 2.1) ER-, PR-, Her2 + (n = 7) 83.7 (SD 18.4) 56.3 (SD 19.9) 50.9 (SD 23.5) / 7.0 (SD 1.7) 7.0 (SD 2.0) ER-, PR-, Her2- (n = 10) 77.4 (SD 21.8) 62.5 (SD 17.7) 52.9 (SD 23.2) / 5.5 (SD 2.4) /
CIPN represents one of the main dose-limiting and quality of life-affecting factors of taxane therapy in breast cancer patients. Effective therapeutic and prophylactic measures against CIPN are still missing. Aim of this study is to develop a tool, which is capable of evaluating CIPN during chemotherapy and to proof its feasibility in clinical routine.
MEDLINE was searched for detection tools of CIPN. Tools were evaluated according to the following criteria: reliability, validity, objectivity, invasiveness, safety, feasibility in clinical routine and clinical significance of the test results. Outcome measures of the modified QST method were: Thermal detection and pain thresholds and the number of paradoxical heat sensations (with TSA-II-NeuroSensory Analyzer), Mechanical detection threshold (with von Frey hairs 0,25-512mN), Mechanical pain threshold (with pin-prick stimulators 8-512 mN) and Vibration detection threshold (with Rydel–Seiffer graded tuning fork 64 Hz). Ten breast cancer patients under taxane containing chemotherapy were evaluated via the modified QST-Measurement. All patients suffered from CIPN symptoms and had decreased scores in the FACT/GOG-NTx questionnaire.
21 detection tools were identified and evaluated. QST was chosen for conducting the feasibility study. All study patients completed the QST-measurement and were evaluable. QST detected abnormal Z-Values in nine out of ten symptomatic patients (Table).
QST-results H: hand, F:foot, -/ + = values lower/upper from normal z-values, CDT=cold detection threshold, WDT=warm detection threshold, TSL=thermal sensory limen, CPT=cold pain threshold, HPT=heat pain threshold, MPT=mechanical pain threshold, MDT=mechanical detection threshold, VDT=vibration detection threshold, PHS=paradoxical heat sensations.Pat.Nr. CDT WDT TSL CPT HPT MPT MDT VDT PHS H F H F H F H F H F H F H F H F H F 1 – – – – – – 2 3 – – – – – – 1/3 4 – – – 5 + – 6 + + 1/3 7 + – – – – 8 – – – – – + + – – – – 1/3 9 – – – – – – 3/3 10 + + – 2/3
QST is feasible to evaluate CIPN in clinical routine. The modified QST method can be used to evaluate CIPN in breast cancer patients who undergo taxane therapy.
Klinikum Rechts der Isar, Technische Universität München, Dr. med. Johannes Ettl.
Celgene.
All authors have declared no conflicts of interest.
PA has shown beneficial effects in the treatment of BC fatigue, nevertheless a significant portion of patients (pts) remain insufficiently physically active after BC. Currently most of BC pts has a smartphone and therefore mobile health (mHealth) holds the promise of promoting health behaviors uptake for many of them. Kiplin® developed an app-based mHealth group intervention aiming at engaging pts in group PA challenges while monitoring daily steps. The aim of this study was, through qualitative exploration, to 1) understand the feasibility of this challenge and 2) inform its development in pts with BC.
BC pts with fatigue (≥4/10 using a visual analog scale) and physically inactive (per WHO recommendations) were included. 2 independent pts groups (n1=5, n2=4; overall median age=47, range: 29-60) performed an initial focus group (FG) to understand barriers to PA and mHealth, followed by a 2 week Kiplin® challenge and a closing FG to obtain feedback on the mHealth experience. FGs lasted ≈60 minutes, were recorded, transcribed and anonymized. Emergent themes were identified by thematic content analysis using NVivo 12.
Three main themes regarding barriers to PA emerged: 1) physical barriers (e.g. late effects of treatment) (100%); 2) time barriers (e.g. work) (56%); 3) motivation barriers (33.3%). The main barrier to mHealth was lack of familiarity with technology (66.6%). All pts considered that the intervention was motivating (particularly due to the group effect), promoted personal organization to address time constrictions, subjectively it seemed to promote PA and decrease symptomatology. Technical simplifications (e.g. design changes, improvement of functionality) and information tools were provided for the second group addressing first group barriers which were not further identified. All pts would recommend such an intervention to other pts.
Kiplin®’s app-based mHealth group challenge was deemed feasible in these groups of BC pts with fatigue, being perceived as a promoter of PA engagement. This qualitative exploration aided the improvement of this intervention. Future interventional studies are warranted.
ID - RCB n°: 2017-A02062-51.
INSERM UMR 981.
Susan G. Komen (to Ines Vaz-Luis); Odyssea Organization (to Elise Martin).
All authors have declared no conflicts of interest.
Insomnia is a distressing and an enduring problem that affects between 25 and 59% of cancer patients during and after treatments. Despite its association with reduced quality of life, negative psychological symptoms and cancer-related fatigue, this major concern remains insufficiently assessed and managed in routine care. Cognitive-Behavioural Therapy for Insomnia (CBT-I) is considered as the non-pharmalogical gold standard treatment. However, one main limitation is the practical implementation of the intervention because of the lack of trained professionals in cancer care settings and geographic distances from therapeutics resources. The frequent presence of somatic comorbidities, such as fatigue or pain, can also complicate access to care. New technologies open innovative ways to facilitate access to targeted interventions, such as online attractive and easy-to-use programs.
Designed as close as possible to the usual care conditions, the monocentric pilot study SLEEP-4-ALL-1 mains, first, to determine the feasibility of a systematic self-screening for insomnia in a population of 400 French adult cancer outpatients with breast, colorectal, pulmonary or urological cancer, using the Insomnia Severity Index (ISI); second, to evaluate among patients with insomnia the acceptability of an online video-based CBT-I, validated in a Quebec breast cancer survivors sample by Savard’s team, with a mixed method approach (quantitative and qualitative). Inclusions are currently completed. SLEEP-4-ALL-1 study, funded by the French National Institute of Cancer (INCA), corresponds to the development phase of a multicentric randomized controlled trial (SLEEP-4-ALL-2) which aims to test an online stepped-care model in the treatment of persistent insomnia, that can provide patients and health professionals an efficient, easily available, replicable, and cost-effective therapeutic solution.
Gustave Roussy Cancer Center.
French National Institute of Cancer (INCA): Interventional Research in Public Health Call.
All authors have declared no conflicts of interest.