Background

The clinically used breast cancer markers are known to predict short-term survival, but whether these markers predict long-term (25-year) survival is unclear. We therefore aimed to determine whether the clinically used markers are long-term prognosticators and predictors of tamoxifen therapy benefit in patients with lymph node-negative and ER-positive/ HER2-negative breast cancer.

Methods

Secondary analysis of the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, randomizing postmenopausal lymph node-negative breast cancer patients to receive adjuvant tamoxifen therapy versus no adjuvant therapy. Distant recurrence-free interval (DRFI) by the clinically used markers was assessed by Kaplan-Meier and multivariable Cox proportional hazards analysis. Recursive partitioning analysis was performed to evaluate which markers best predict long-term survival.

Results

A statistically significant difference in 25-year DRFI was seen by tumor size (Log-rank, P<0.001) and tumor grade (Log-rank, P=0.019), but not by PR and Ki-67 status. Patients with smaller tumor size (T1a/b Hazard ratio [HR], 0.31; 95% CI, 0.17-0.55; T1c HR, 0.58; 95% CI, 0.38-0.88), and tumor grade 1 had a significantly reduced long-term risk (Grade 1 HR, 0.48; 95% CI, 0.24-0.95), compared to patients with larger (T2) tumor size and grade 3 tumors, respectively. A significant tamoxifen therapy benefit was suggested for patients with larger tumor size (T1c HR, 0.53; 95% CI, 0.32-0.89; T2 HR, 0.34; 95% CI, 0.16-0.73), lower tumor grade (Grade 1 HR, 0.24; 95% CI, 0.07-0.82; Grade 2 HR, 0.50; 95% CI, 0.31-0.80), and PR-positivity (HR=0.38, 95% CI, 0.24-0.62). Recursive partitioning analysis selected tumor size as the most important characteristic to predict survival, followed by trial arm for patients with larger tumors.

Conclusions

Our findings suggest that tumor size followed by grade are significant 25-year prognosticators of DRFI outcome. Further, a significant 25-year benefit from tamoxifen therapy was seen in patients with larger tumor size, lower tumor grade and PR-positive tumors.

Clinical trial identification

The trial center for the STO-3 trial was the Regional Cancer Center Stockholm-Gotland, in Stockholm Sweden. However, the start of the Stockholm Tamoxifen trial (STO-3) in 1976 was well before trial registration started in Sweden, therefore information on trial number is not available.

Legal entity responsible for the study

The authors.

Funding

Swedish Research Council and Swedish Cancer Society.

Disclosure

All authors have declared no conflicts of interest.

Background

BCI is a gene expression-based assay that reports a prognostic BCI score that significantly predicts risk of overall (10y), early (0-5y), and late (≥5y) distant recurrence (DR) in HR+, node-negative (N0) and node-positive (N1) breast cancer. The BCIN+ prognostic model was trained in the Trans-ATAC cohort, which evaluated primary adjuvant anastrozole versus tamoxifen. The current study optimized the BCIN+ prognostic model for late DR in N+ patients from the arm treated with 7.5 years of endocrine therapy in the translational cohort of the IDEAL trial.

Methods

Patients with 1 to 3 positive nodes (N1) in the 7.5-year endocrine treatment arm of the translational IDEAL cohort were used to examine cut-points for BCIN+ model across the range of 1 to 9 to classify patients into Low- and High-risk groups. Kaplan-Meier analysis was used to calculate the 15-year (post-diagnosis, 10-year post-randomization) late DR free interval (DRFI) as the primary endpoint. The cut-point was selected based on the classification of a low-risk group with <5% 15-year late DRFI. Initial validation of the optimized prognostic model was performed in a single institution retrospective cohort using Cox proportional hazards regression.

Results

241 N1 IDEAL patients (85% ≥ 55 y, 54% T1, 52% G2) were included. Evaluation of the BCIN+ prognostic model led to an adjusted cut-point, which classified 44 patients as BCIN+ Low Risk with a 15-year late DRFI of 3.2%, and 197 patients as BCIN+ High Risk with a DRFI of 19.0% (HR: 7.11, 95% CI: 0.97-52.17; p=0.024). Independent validation in a retrospective cohort of 349 patients (64% ≥55 y, 66% T1, 58% G2) showed that the optimized BCIN+ model was significantly prognostic for late DR (HR: 9.25, 95% CI: 1.27-67.45; p=0.007), and classified 66 and 283 patients as BCI Low- and High-risk with 1.6% and 15.2% 15-year late DRFI, respectively.

Conclusions

An optimized BCIN+ prognostic model was determined from patients in the randomized IDEAL trial, which was significantly prognostic for late DR in HR+ N1 patients. Additional studies in randomized N+ cohorts are required for further validation of this BCIN+ model optimized for late DR.

Clinical trial identification

BOOG 2006-05.

Legal entity responsible for the study

Biotheranostics, Inc.

Funding

Biotheranostics Inc.; Leiden University Medical Center Institutional Grant; Novartis.

Disclosure

G-J. Liefers: Advisory/Consultancy, Research grant/Funding (institution): Biotheranostics, Inc. Y. Zhang: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Biotheranostics, Inc. D.C. Sgroi: Advisory/Consultancy: Merrimack Pharmaceuticals; Licensing/Royalties: Biotheranostics, Inc. K. Treuner: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Biotheranostics, Inc. J. Wong: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Biotheranostics, Inc. C.A. Schnabel: Leadership role, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment, Officer/Board of Directors: Biotheranostics, Inc. All other authors have declared no conflicts of interest.

Background

Cyclin-dependent kinase 4 and 6 inhibitors like palbociclib (P) are a mainstay of treatment for ER+/HER2- ABC; however intrinsic or acquired resistance is a major clinical issue. We performed a mutational analysis on ctDNA samples from patients (pts) included in the c-TREnd study, the translational cohort of the TREnd trial (NCT02549430) which randomized pts to receive P alone or in combination with the endocrine treatment (ET) to which they had progressed in the previous line of ET.

Methods

Forty-six pts were enrolled in c-TREnd. Plasma was collected before treatment (T0), after the first cycle of therapy (T1) and at the time of progression (T2). Hybridization and capture were performed using the TruSight Tumor 170 Kit (Illumina). Single nucleotide variants (SNVs) were detected and annotated using LoFreq and Oncotator, and further refined by ABEMUS. Tumor Mutational burden (TMB) was the sum of silent and non-silent mutations. Tumor fraction (TF) was based on the dispersion of Copy Number Alteration (CNA) genomic profiles. Progression free survival (PFS) was estimated using the Kaplan–Meier method and compared with the log-rank test.

Results

Thirty-two pts (87 samples), 14 from the P arm and 18 from the P+ET arm, were included in the final analysis. The most frequently mutated genes at T0 were ESR1 (23%), PIK3CA (17%), AR, FGFR2 and TP53 (10%). At T0, mutations in ESR1, but not in PIK3CA, were significantly prognostic (median PFS – mPFS 3.7 mo vs 11 mo in ESR1 mut vs WT, p=0.015). A significantly worse mPFS was observed when a broader analysis of PI3K pathway (adding AKT1, PTEN, TSC1/2 and BRAF) was performed (mPFS 5.2 m in mut vs 10.8 m in WT, p=0.04). Mutations in AR tended to confer a better, although not statistically significant, mPFS (14.2 mo vs 5.5 in WT, p=0.29). At T2 we observed the emergence of 9 new mutations in 7 genes (ESR1, AKT1, ARID1A, BRIP1, CCNE1, MTOR and TP53). TMB and TF at T0 or TF change between T1 and T0 were not associated with PFS.

Conclusions

Mutations in ESR1 and in PI3K pathway genes were associated with worse prognosis in pts treated with P, while TMB and TF were not. Larger studies are needed to validate these observations.

Legal entity responsible for the study

Fondazione Sandro Pitigliani per la Lotta Contro i Tumori ONLUS.

Funding

Pfizer.

Disclosure

L. Malorni: Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Research grant/Funding (self): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Novartis. M. Benelli: Honoraria (self): Novartis. G. Curigliano: Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Veracyte; Advisory/Consultancy: Genomic Health; Honoraria (self): Ellipsis. A.M. Minisini: Advisory/Consultancy: Novartis; Advisory/Consultancy: MSD; Advisory/Consultancy: Pierre Fabre; Speaker Bureau/Expert testimony: SunPharma. E. Risi: Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Amgen; Honoraria (self): Lilly. A. Di Leo: Honoraria (institution), Advisory/Consultancy: Lilly; Honoraria (institution), Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Honoraria (institution), Advisory/Consultancy: AstraZeneca. L. Biganzoli: Advisory/Consultancy: Lilly; Honoraria (institution), Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Background

The prognoses of systemically treated, triple-negative breast cancer (TNBC) patients with a pathogenic tumor BRCA1 mutation (tBRCA1m) or BRCA1 promoter methylation (BRCA1 PM) have been widely studied. However, the prognosis for systemically untreated women remains unknown. This study investigates the prognosis of systemically untreated young N0 TNBC patients according to tumor BRCA1 status.

Methods

Dutch women aged < 40 years, diagnosed with T_anyN₀M₀ TNBC between 1989 and 2000 were selected from the Netherlands Cancer Registry. In that era, N0 patients were considered low risk and not given (neo)adjuvant systemic therapy. We analyzed tBRCA1m and BRCA1 PM using DNA from formalin-fixed paraffin-embedded tumor tissues. We built Cox and competing risk regression models, for invasive disease-free survival (iDFS), and distant recurrence-free survival (DRFS) with secondary primary tumors (SPTs) as competing events. Both models were adjusted for tumor characteristics and locoregional treatment.

Results

For 373 patients, tBRCA1m and BRCA1 PM status were available. Of these, 28% had pathogenic tBRCA1m, 36% had BRCA1 PM and the rest were classified as BRCA1 dual-negative. Compared to patients with BRCA1 dual-negative tumors, patients with BRCA1 PM had a favorable iDFS (adjusted hazard ratio [aHR] = 0.66, 95% confidence interval [CI] = 0.45 – 0.98) but similar DRFS (subdistribution hazard ratio [sHR] = 0.86, 95% CI = 0.50 – 1.46), while patients with tBRCA1m had poorer iDFS (aHR = 1.86, 95% CI = 1.30 – 2.65) and also similar DRFS (sHR = 1.04, 95% CI = 0.61 – 1.76). Furthermore, patients with BRCA1 PM had lower risk for SPTs (sHR = 0.38, 95% CI = 0.17 – 0.83), while patients with tBRCA1m had higher risk (sHR = 3.12, 95% CI = 1.79 – 5.45).

Conclusions

Although tBRCA1m and BRCA1 PM both cause BRCA1 gene inactivation, the iDFS differed significantly between systemically untreated young TNBC patients with these tumor types. This can be mainly attributed to substantially different risk for SPTs. Interventions to prevent SPTs, such as contralateral prophylactic mastectomy or secondary chemoprevention, should be considered for young tBRCA1m TNBC patients.

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

Dutch Cancer Society (KWF), A Sister's Hope, Vrienden UMCU, Agilent.

Disclosure

M. Kok: Advisory/Consultancy, Research grant/Funding (institution), Outside the submitted work, M. Kok is a advisory board member: BMS; Advisory/Consultancy, Research grant/Funding (institution), Outside the submitted work, M. Kok is a advisory board member: Roche; Research grant/Funding (institution), Outside the submitted work: AZ; Advisory/Consultancy, M. Kok is a advisory board member: MSD; Advisory/Consultancy, M. Kok is a advisory board member: Daiichi. S.C. Linn: Research grant/Funding (institution), Receives grants during the conduct of the study: ZonMw; Research grant/Funding (institution), Receives grants during the conduct of the study: A Sister's Hope; Advisory/Consultancy, Research grant/Funding (institution), Outside the submitted study: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Outside the submitted study: Cergentis; Advisory/Consultancy, Travel/Accommodation/Expenses, Outside the submitted study: IBM; Advisory/Consultancy, Research grant/Funding (institution), Outside the submitted study: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses, Outside the submitted study: Roche; Research grant/Funding (institution), Outside the submitted study: Eurocept-pharmaceuticals; Research grant/Funding (institution), Outside the submitted study: Novartis; Research grant/Funding (institution), Travel/Accommodation/Expenses, Outside the submitted study: Tesaro (now owned by GSK); Research grant/Funding (institution), Outside the submitted study and non-financial support such as study drug: Immunomedics; Research grant/Funding (institution), Outside the submitted study: Agendia; Travel/Accommodation/Expenses, Outside the submitted study: Bayer; Advisory/Consultancy, Travel/Accommodation/Expenses, Outside the submitted study: Daiichi Sankyo; Research grant/Funding (institution), Outside the submitted study: Genentech. All other authors have declared no conflicts of interest.

Background

Phosphatase and tensin homologue (PTEN) loss is associated with tumorigenesis, tumor progression, and therapy resistance in breast cancer. However, the clinical value of PTEN as a biomarker requires further studies. We seek to identify clinically relevant subtypes of breast cancer based on PTEN status and other clinicopathologic features.

Methods

A cohort of 608 breast cancer patients previously profiled for PTEN protein expression was included. Based on the expression on the neoplastic cells compared to the normal internal controls by IHC, cases were classified as PTEN-low (PTEN-L) or PTEN-retained (PTEN-WT). The former constituted the study group, while the latter the control group. Analysis of gene expression was performed on 3,929 patients from the METABRIC and MSK cohorts retrieved from cBioPortal. The Shapiro-Wilk test was used to analyze the normal distributions of continuous variables. Relationships between PTEN status and the clinicopathologic and molecular features of the patient population were assessed using Fisher’s exact test or Chi-squared/Wilcoxon rank-sum test. Survival curves were built according to the Kaplan-Meier method.

Results

Reduced expression of PTEN was significantly different at protein and gene levels, where the former was observed in 46.1% (n=280/608), while, not surprisingly, the latter in only 7.8% (n=308/3,929) cases. PTEN-L tumors were significantly enriched for in both HER2+ (n=63, 22.5%) and triple-negative (TN) (n=41, 14.6%) subtypes compared to PTEN-WT tumors (n=34, 10.4% and n=18, 5.5%, respectively; p<0.0001). When the relative expression of PTEN was decreased, both hormone receptor (HR)- and HER2 overexpression/amplification were significantly related to worse overall survival (OS) compared to the HR+/HER2- status (p<.0001). Of note, this condition was not statistically significant in the presence of a PTEN-WT expression. Moreover, PTEN-L protein expression but not gene expression was related to worse OS in HR+/HER2+ tumors compared to HR+/HER2- (p=0.002).

Conclusions

The combined analysis of PTEN protein and gene expression may provide additional data to perform a tailored risk assessment while evaluating patients with HR- and HER2+ breast cancers.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

N. Fusco: Speaker Bureau/Expert testimony: Merck Sharp & Dohme (MSD); Speaker Bureau/Expert testimony: Boehringer Ingelheim; Honoraria (self), Speaker Bureau/Expert testimony: Novartis. E. Guerini Rocco: Speaker Bureau/Expert testimony: Thermo Fisher Scientific; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Roche; Honoraria (self): MSD. All other authors have declared no conflicts of interest.

Background

BCI is a gene expression-based assay that reports a prognostic score for risk of overall (10y) and late (≥5y) distant recurrence (DR) in HR+ early-stage breast cancer. The current study optimized the BCI prognostic model for late DR utilizing N0 patients from the translational aTTom (Trans-aTTom) study.

Methods

N0 patients in the 5y tamoxifen arm of the Trans-aTTom cohort were used to examine BCI assay cut-points based on classification of a Low-risk group with >95% 15y (10y post-randomization) late DR free survival (DRFS) as estimated by Kaplan-Meier analysis. Validation was performed in an independent multi-institutional cohort using Cox proportional hazards regression.

Results

697 N0 patients (81% ≥55y, 71% T1, 44% G2) were included. A cut-point was determined with a 15y DRFS of 95.7% and 88.7% in the BCI Low- and -High Risk groups, respectively. At 10y and 20y post-diagnosis, patients were stratified as BCI-Low Risk (45%) with a DRFS of 98.0% and 92.9%, and as BCI-High Risk (55%) with a DRFS of 94.3% and 86.4% (HR: 2.16, [1.23-3.80]; p=0.006), respectively. Independent validation in 312 patients (47% <55y, 67% T1, 62% grade 2) showed that the optimized BCI model was significantly prognostic for late DR (HR: 2.16, p=0.006), stratifying BCI Low- (45%) and High-risk (55%) patients with 96.7% and 87.9% 10-year late DRFS, respectively. Table: 11P

Conclusions

In the current study, an optimized BCI prognostic model developed in the Trans-aTTom cohort was significantly prognostic for late DR in HR+ N0 breast cancer. Additional studies in cohorts with extended follow-up are required for further validation of this BCI late DR model.

Clinical trial identification

ISRCTN17222211; NCT00003678.

Legal entity responsible for the study

Biotheranostics, Inc.

Funding

Biotheranostics, Inc.; Breast Cancer Research Foundation; Ontario Institute for Cancer Research.

Disclosure

J.M.S. Bartlett: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Biotheranostics, Inc.; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: NanoString Technologies; Honoraria (self): Oncology Education; Advisory/Consultancy: BioNTech AG; Advisory/Consultancy: Insight Genetics; Advisory/Consultancy: OncoXchange; Advisory/Consultancy: Pfizer; Advisory/Consultancy: RNA Diagnostics; Research grant/Funding (institution): Agendia; Research grant/Funding (institution): Genoptix; Research grant/Funding (institution): Stratifyer GmbH; Research grant/Funding (institution): Thermo Fisher Scientific; Licensing/Royalties, Patent - Jan 2017: Methods and Devices for Predicting Anthracycline Treatment Efficacy: Other; Licensing/Royalties, Patent - Jan 2017: Systems, Devices and Methods for Constructi (Inst): Constructi. Y. Zhang, K. Treuner: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment: Biotheranostics, Inc. A.M. Brufsky: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Myriad; Advisory/Consultancy: Agendia; Advisory/Consultancy: Biotheranostics, Inc. D.C. Sgroi: Advisory/Consultancy: Merrimack Pharmaceuticals; Licensing/Royalties: Biotheranostics, Inc. C.A. Schnabel: Leadership role, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Licensing/Royalties, Full/Part-time employment, Officer/Board of Directors: Biotheranostics, Inc. D.W. Rea: Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self): Eli Lilly; Honoraria (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Research grant/Funding (institution): Roche; Advisory/Consultancy: Genomic Health; Advisory/Consultancy: MSD Oncology; Research grant/Funding (institution): Biotheranostics, Inc.; Research grant/Funding (institution): Celgene; Travel/Accommodation/Expenses: Eisai. All other authors have declared no conflicts of interest.

Background

Metaplastic breast cancer (MPBC) is a rare disease characterized by aggressive features and dismal prognosis after standard therapy. Herein, we report the molecular screening of the Milan National Cancer Institute case series for the evaluation of potentially druggable alterations.

Methods

A total of 49 MPBC cases treated with curative intent were identified. Primary tumors were profiled using Oncomine Comprehensive Assay Plus panel (Thermo Fisher Scientific) for copy number alteration (CNA), mutation, tumor mutational burden (TMB), and microsatellite instability (MSI) analyses, according to the manufacturer instructions.

Results

Sequencing results are presented for the first 34 pathological reviewed cases. Quality control metrics were met in 33 cases. In total, 94 unique genes harbored at least one mutation representing 24% of the panel. The median number of mutations indexed per patient was 3.5 (range 0-29). Notably, 25 cases showed actionable mutated genes, including PTEN, mTOR, FGFR3, FGFR4. Most of the cases showed low TMB, the median value being 4.5 (range 0-28). MSI status was high only in 2 cases. Common CNAs included 13q (10%), 5q (9%) and 17p (6%). Eight out of ten canonical cancer pathways (cell cycle, Hippo, MYC, NOTCH, PI3K, RTK-RAS, TGFβ and β-catenin/WNT) were altered by both mutational and CNA events occurring at different proportions, with mutational events involving up to 33%, and CNA involving up to 42% of genes of the altered pathway. In the Hippo and RTK-RAS pathways the two types of alterations were instead equally represented whereas the remaining pathways (β-catenin/WNT, TGFβ, PI3K, NOTCH, MYC and Cell cycle) were more affected by CNA than mutations. NRF2 and TP53 signaling pathways were instead activated by mutational events only.

Conclusions

Mutational and copy number alterations conveyed complementary information in MPBC cooperating in activation of cancer pathways.These findings suggest to further study the value of CNAs in MPBC biological processes, especially immunogenicity, which cannot be explained by the low TMB and MSI found. Extended data with matched immune profile will be presented at the meeting.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

Funding

Italian Ministry of Health.

Disclosure

All authors have declared no conflicts of interest.

Background

Different immunohistochemical programmed death-ligand 1 (PD-L1) assays and scoring methods in triple-negative breast cancer (TNBC) have been reported to yield variable results. We compared the analytical concordance and interobserver variability of four clinically developed PD-L1 assays assessing immune cell (IC) score and combined positive score (CPS) in TNBC.

Methods

Archival primary TNBC resection specimens (n = 99) were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3 and DAKO 28-8. PD-L1 expression was scored by four trained readers according to guidelines for IC-score and CPS on whole slide images by virtual microscopy.

Results

The mean PD-L1 positivity ranged between 53%-74% for IC-score ≥1% and CPS ≥1 with highest levels for SP263. The concordance between IC-score ≥1% and CPS ≥1 across all readers for each assay was >93%. Intra-class correlation coefficients (ICCs) revealed poor-to-good inter-reader agreement for each assay for IC-score (0.489-0.793, highest value for SP142) and moderate-to-good agreement for CPS (0.653-0.794, highest value for 22C3). ICCs for each reader (ranging from 0.226-0.595) uncovered poor-to-moderate inter-assay agreements on PD-L1-positivity for both scores. The concordance of all readers across the four assays was 86.8% for CPS ≥1 and 88.4% for IC-score ≥1%. Kappa scores for inter-reader agreement for each assay at IC-score ≥1% were 0.728-0.777 and for CPS ≥1 0.680-0.735. Evaluation of inter-assay agreement for each reader revealed kappa scores 0.446-0.596 at IC-score ≥1% and 0.492-0.587 at CPS ≥1.

Conclusions

We demonstrate a certain degree of concordance between IC-score and CPS for the assessment of PD-L1-positivity across different assays and readers. However, the four PD-L1 assays are analytically not fully concordant.

Legal entity responsible for the study

The authors.

Funding

MSD.

Disclosure

A. Noske: Travel/Accommodation/Expenses: Roche Pharma AG; Advisory/Consultancy: Myriad. D-C. Wagner: Travel/Accommodation/Expenses: Roche Pharma AG; Research grant/Funding (institution): MSD. K. Schwamborn: Research grant/Funding (institution): Roche; Research grant/Funding (institution): MSD. S. Foersch: Research grant/Funding (institution): MSD. K. Steiger: Research grant/Funding (institution): Roche Pharma AG; Research grant/Funding (institution): MSD. M. Kiechle: Honoraria (self): Celgene; Honoraria (self): AstraZeneca; Honoraria (self): Myriad Genetics; Honoraria (self): Teva; Shareholder/Stockholder/Stock options: Therawis Diagnostics GmbH; Shareholder/Stockholder/Stock options: Busenfreundin GmbH. D. Oettler: Full/Part-time employment: MSD. A. Hapfelmeier: Honoraria (institution): MSD. W. Roth: Honoraria (self): Roche Pharma AG; Honoraria (self), Research grant/Funding (institution): MSD. W. Weichert: Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis. All other authors have declared no conflicts of interest.

Background

Most breast cancers (BC) exhibit low immune infiltration and are unresponsive to immunotherapy. Hence, the urgency to find new mechanisms of immune activation, postulating receptor activator of nuclear factor kappa-Β ligand (RANKL) and its receptor RANK as potential immunomodulator. Our previous data demonstrated that RANK pathway inhibitors, such as denosumab, used for the treatment of bone metastasis, could also prevent and/or treat BC and regulate the tumour immune crosstalk. However, the population of breast cancer patients who may benefit from denosumab remains to be identified.

Methods

Patients with early-stage HER2-negative BC, candidates to tumour excision as first therapeutic approach are included. Patients are randomized 2:1 to denosumab: control (no treatment); experimental arm received 2 doses of 120 mg subcutaneous denosumab (once per week) before surgery (2-4 weeks later). Putative changes in tumour cell proliferation by Ki67 immunohistochemistry (IHC), cell survival by cleaved caspase 3 IHC (primary endpoints) and stromal tumour infiltrating lymphocytes (TILs) quantified in the haematoxylin and eosin by between baseline (biopsy sample) and surgery are evaluated. Specific antibodies will be used to characterize infiltrating immune populations. Denosumab driven gene expression changes in tumour samples will be analysed and tools such as CIBERSORT will be used to characterize the immune infiltrate.

Results

We present results from the first 36 patients enrolled out of 60. Clinical and tumour characteristics were well balanced between the groups. No relevant toxicities were reported. No clinically significant differences in Ki67 and cleaved caspase-3 were observed after denosumab treatment. Interestingly, a statistically significant increase in TILs was observed in the denosumab treated group (p=0.03, Paired t test) but not in the control group (p=0.80). A 33% of patients treated denosumab showed a ≥10% increase in TILs vs 0% in the control group (p =0.05).

Conclusions

Short term neoadjuvant denosumab increases TILs in early BC.

Clinical trial identification

NCT03691311.

Legal entity responsible for the study

The authors.

Funding

Amgen Juan de la Cierva. Postdoctoral contract. IJCI-2017-31564 Río Hortega (CM19/00148) Instituto de Salud Carlos III / Ministerio de Ciencia, Innovación y Universidades. ERC-Consolidator grant PLEIO-RANK European Research Council.

Disclosure

All authors have declared no conflicts of interest.

Background

Receptor subtypes of breast cancer, as defined by immunohistochemistry, are surrogates for molecular subtypes. Despite new emerging molecular tumour classifications, these receptor subtypes are well-known independent predictors of breast cancer death and remain widely used in clinics. Few studies have disentangled the combined influence of receptor subtypes, grade, size (T) and nodal status (N) on breast cancer survival in large groups of recently treated patients.

Methods

From the Cancer Registry of Norway, we obtained detailed clinical information on 24137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015. Of these, 17204 had non-metastatic breast cancer with known receptor status. Receptor subtype was defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status. Hazard ratios for breast cancer death up to 13 years after diagnosis were estimated using flexible parametric survival models and comparing combinations of receptor subtype, grade and TN status with adjustments for age, year and surgery type. Additional adjustment for adjuvant treatment was done on a subset of women with known treatment information.

Results

Receptor subtype, grade and TN status were strong predictors for breast cancer death, both independently and in combination. The combined effect of all factors was a 20- to 40-fold higher breast cancer mortality rate when comparing to women with the best outcome (ER+PR+HER2-, low grade, T1N0). In women with ER+HER2- subtypes and no nodal spread, a larger tumour size was associated with a significantly higher risk of breast cancer death. Women with ER+HER2- tumours also had an increased late (>5 years) mortality which was largely explained by intermediate/high grade and nodal spread. Women with ER+PR-HER2-, high grade, N+ tumours had particularly high mortality similar to triple negative breast cancer.

Conclusions

These results highlight the importance of thoroughly combining well-known tumour factors to describe the wide range of risks of dying from breast cancer, also among small, node negative tumours.

Legal entity responsible for the study

Cancer Registry of Norway.

Funding

Norwegian Cancer Society under Grant 161326.

Disclosure

All authors have declared no conflicts of interest.

Background

Ribociclib improves survival in hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (BC). Deeper understanding of the biology associated with ribociclib efficacy is needed, especially within the HER2-enriched (HER2-E) subtype given recent analysis of MONALEESA program. Here, we performed gene expression (GE) analysis with/without ribociclib monotherapy in BC patient-derived xenografts (PDX).

Methods

Eighteen PDXs representative of HR+/HER2- (n=11, 61%), HER2+ (n=6, 33%) and triple-negative (n=1, 6%) BC were treated with ribociclib monotherapy (75 mg/kg/day). The % change in tumor volume from baseline was calculated at day 35. RNA was obtained from flash-frozen tumors at baseline and day 12. PAM50 GE was analyzed by nCounter and associated with tumor response (as a continuous variable) using quantitative Statistical Analysis Microarrays (SAM). Differential GE during ribociclib treatment was identified using two-class paired SAM. All SAM used a false-discovery rate<5%.

Results

Baseline PAM50 subtype distribution was Luminal B (44%), HER2-E (33%) and Basal-like (B-L) (22%). HER2-E and Luminal B PDXs showed a statistically significant higher response to ribociclib (mean change in volume >40% and >140%), than B-L (>660%). Baseline GE analysis identified 6 genes highly expressed in responders (FOXA1, ERBB2, GRB7, MLPH, GPR160 and CXXC5), and 7 lower expressed genes (SFRP1, KRT17, MYC, CDH3, KRT5, MIA and KRT14). Paired GE analyses across PDXs identified 12 upregulated genes during treatment, including estrogen activation-related genes (ESR1, PGR, FOXA1, MAPT or BLVRA); and 12 downregulated genes, including proliferation-related genes (MKI67 or KIF2C) and HER2-E-related genes (ERBB2 or TMEM45B). Similar results were obtained with HR+/HER2- PDXs when analyzed separately.

Conclusions

In BC PDXs, B-L biology associates with lower response to ribociclib monotherapy than Luminal or HER2-E. Ribociclib induces a luminal phenotype with high GE of estrogen-regulated genes and low GE of proliferation genes, a biological switch that could explain the better efficacy of ribociclib in the endocrine therapy (ET)-resistant HER2-E subtype observed in clinical trials when combined with ET.

Legal entity responsible for the study

Institut d'Investigacions Biomèdiques August Pi i Sunyer.

Funding

Has not received any funding.

Disclosure

M. Oliveira: Honoraria (self): Roche, Novartis, Seattle Genetics; Advisory/Consultancy: Roche/Genentech, GlaxoSmithKline, Puma Biotechnology, AstraZeneca, Seattle Genetics; Research grant/Funding (institution): Philips Healthcare (Inst), Roche/Genentech (Inst), Novartis (Inst), AstraZeneca (Inst), Immunomedics (Inst), Seattle Genetics (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Cascadian Therapeutics (Inst), Sanofi (Inst), Celldex Therapeutics; Travel/Accommodation/Expenses: Roche, Novartis, Grünenthal Group, Pierre Fabre, GP Pharm, Eisai. N. Chic: Travel/Accommodation/Expenses: Novartis, Eisai, Pierre Fabre. R. Dienstmann: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Research grant/Funding (self): Merck; Research grant/Funding (self): Pierre Fabre. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca, Daiichi Sankyo, Merck, Sharp and Dohme España SA, Novartis, Pfizer, Puma, Synthon; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene, Clovis Oncology, Eisai, F. Hoffmann-La Roche Ltd., Genomic Health, Odonate Therapeutics, Philips Healthwork, Pierre Fabre, prIME Oncology, Sanofi Aventis, Zymeworks; Research grant/Funding (institution): Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Piqur Therapeutics, Roche, Synthon. A. Prat: Advisory/Consultancy, Research grant/Funding (self): Novartis Farma, SA; Advisory/Consultancy: Lilly Spain; Advisory/Consultancy: Pfizer, SLU; Advisory/Consultancy, Research grant/Funding (self): Roche Farma, SA; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Amgen, SA; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Oncolytics Bioteck; Research grant/Funding (self): Sysmex Europe GmbH; Research grant/Funding (self): Medica Scientia Inno, Research, SL; Research grant/Funding (self): Celgene, SLU; Research grant/Funding (self): Astellas Pharma, SA; Research grant/Funding (self): NanoString Technologies; Officer/Board of Directors, Member executive Board: Breast International Group (BIG).; Officer/Board of Directors, Member executive Board and Foundation: SOLTI; Research grant/Funding (self): Puma; Research grant/Funding (self): Incyte. V. Serra: Research grant/Funding (self): Novartis, Genentech. All other authors have declared no conflicts of interest.

Background

Obesity is associated with T-cell dysfunction and reduced antitumor immune response. In TNBC, high sTILs seem to predict pathologic complete response (pCR) and favorable prognosis only in normal weight patients (Desmedt et al. Cancer Res 2020).

Methods

TNBC patients, who received anthracycline-taxane-based chemotherapy in GeparDuo, GeparTrio, GeparQuinto, GeparSixto, GeparSepto, and GeparOcto, with available BMI and pretreatment sTILs (centrally assessed) were considered. Patients with BMI <18.5 kg/m² were excluded. Associations between BMI (normal weight, 18.5-<25 vs overweight/obese ≥25 kg/m²), sTILs (high ≥30% vs low <30) and pCR were assessed using Fisher`s exact test; between sTILs (continuous, dichtomized) and pCR (ypT0/is ypN0) according to BMI and interaction BMI*sTILs by logistic regression, between sTILs and disease-free survival (DFS) according to BMI and interaction BMI*sTILs by Cox regression.

Results

Of 1288 patients, 49.8% were normal weight, 50.2% overweight/obese; median age was 47 [21-78] vs 50 [21-76] years (p<0.001), cT3-4 12.0% vs 16.6% (p=0.021) and N+ 32.7% vs 37.0% (p=0.125). Normal weight patients had a higher pCR than overweight/obese patients (47.2% vs 39.9% p=0.009). Median sTILs was 30%, 50.4% of patients had high sTILs (normal weight 50.2% vs overweight/obese 50.6%, p=0.868). Higher level of sTILs was predictive for pCR both in normal weight (sTILs continuous OR 1.10, 95%CI 1.03-1.17, p=0.002) and in overweight/obese patients (OR 1.15, 95%CI 1.08-1.22, p<0.001). Interaction BMI*sTILs, p=0.302. Results were similar for dichotomized sTILs. Median follow-up was 54.7 months. Each 10% increase in sTILs was associated with an 11% reduction in the risk of a DFS event in normal weight (HR 0.89, 95%CI 0.82-0.95, p=0.001) and 8% in overweight/obese patients (HR 0.92, 95%CI 0.87-0.99, p=0.017). Interaction TILs*BMI, p=0.366.

Conclusions

Our results do not confirm differences in the predictive and prognostic role of sTILs according to BMI in TNBC as described previously. A joint analysis to explore the source of observed heterogeneity is planned.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Denkert: Research grant/Funding (self): European Commission H2020; Research grant/Funding (self): German Cancer Aid Translational Oncology; Honoraria (self): Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Molecular Health; Research grant/Funding (self): Myriad; Honoraria (self): Merck, Sividon diagnostics; Licensing/Royalties, patent VMScope digital pathology software with royalties paid: patent VMScope digital pathology software; Licensing/Royalties, cancer immunotherapy pending: patent WO2020109570A1; Licensing/Royalties, therapy response issued: patent WO2015114146A1 and WO2010076322A1. M. Untch: Honoraria (self), Non-remunerated activity/ies: AbbVie; Honoraria (self), Non-remunerated activity/ies: Amgen GmbH; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): BMS; Honoraria (self), Non-remunerated activity/ies: Celgene GmbH; Honoraria (self), Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (self), Non-remunerated activity/ies: Eisai GmbH; Honoraria (self): Lilly Deutschland; Honoraria (self), Non-remunerated activity/ies: Lilly Int.; Honoraria (self), Non-remunerated activity/ies: MSD Merck; Honoraria (self), Non-remunerated activity/ies: Mundipharma; Honoraria (self), Non-remunerated activity/ies: Myriad Genetics; Honoraria (self), Non-remunerated activity/ies: Odonate; Honoraria (self), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (self): PUMA Biotechnology; Honoraria (self), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (self), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (self), Non-remunerated activity/ies: Teva Pharmaceuticals Ind Ltd.; Honoraria (self), Non-remunerated activity/ies: Novartis, Clovis Oncology; Honoraria (self): Pierre Fabre, Seatlle Genetics. A. Schneeweiss: Honoraria (self), Research grant/Funding (self), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Research grant/Funding (self): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Research grant/Funding (self), Medical writing grant: Roche. V. Mueller: Speaker Bureau/Expert testimony: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, MSD, Novartis, Roche, Teva, Seagen, Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro, Nektar; Advisory/Consultancy: Genomic Health, Hexal, Roche, Pierre Fabre, Amgen, ClinSol, Novartis, MSD, Daiichi Sankyo, Eisai, Lilly, Tesaro and Nektar; Research grant/Funding (institution): Novartis, Roche, Seattle Genetics, Genentech. M. van Mackelenbergh: Honoraria (self): Amgen, AstraZeneca, Genomic Health, Mylan, Novartis, Pfizer, Pierre Fabre, Roche. P.A. Fasching: Honoraria (self): Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, Merck Sharp & Dohme, Lilly, Pierre Fabre, Seattle Genetics, Roche, Hexal; Research grant/Funding (self): Biontech, Cepheid. F. Marmé: Research grant/Funding (self): AstraZeneca; Honoraria (self): AstraZeneca, MSD, Clovis, GSK/Tesaro, Pfizer, Novartis, Lilly, Roche, Celgene, Seagen, Myriad, PharmaMar, Eisai, Janssen-Cilag. S. Loibl: Honoraria (institution), Research grant/Funding (institution), honorario for lectures and ad boards: Abbie, Celgene; Honoraria (institution), honorario for lectures: PriME/Medscape; Honoraria (self): Chugai; Honoraria (self), Honoraria (institution), Research grant/Funding (institution): Daiichi Sankyo; Honoraria (institution), honorarium for ad boards paid to: Lilly; Advisory/Consultancy, advisor honorarium paid to institute: BMS, Puma; Research grant/Funding (institution): Immunomedics; Honoraria (institution), Research grant/Funding (institution), honorarium for lectures and ad: AstraZeneca, Amgen, Novartis, Pfizer; Honoraria (institution), honorarium for lectures and ad: Pierre Fabre, Merck; Honoraria (institution), advisor honorarium paid to institute: EirGenix; Honoraria (institution), Research grant/Funding (institution), grant and honorarium paid to: Roche; Honoraria (institution): Seagen; Licensing/Royalties, pending: EP14153692.0. All other authors have declared no conflicts of interest.

Background

Breast cancer (BC) diagnosed at ages <40 years is known to present more aggressive tumor phenotypes and poorer clinical outcome. To gain a better understanding of the age-related expression of BC promoting genes, we aimed to identify transcriptional alterations supporting cancer progression in BC of young women.

Methods

We studied mRNA gene expression data from two METABRIC cohorts. Differentially expressed genes (DEGs) and gene sets (Gene Set Enrichment Analysis) differentially enriched between primary BC for patients <40/≥40 years were explored. Protein-protein interaction (PPI) networks were explored by the STRING database and visualized by Cytoscape software. Hub genes were identified by MCODE and CytoHubba plugins. Drug signatures were explored by Connectivity Map (CMAP).

Results

We identified 91 and 99 commonly up- and downregulated DEGs in women <40 in the two METABRIC cohorts. Gene sets reflecting proliferation were among the top results reported (REACTOME and gene ontology; FDR <10%). Six hub genes presenting highest PPI network connectivity were identified. High signature score (sum of hub genes expression values) was significantly associated with high tumor diameter, histologic grade, lymph node metastasis, ER negativity, basal-like and HER2 enriched subtypes (P <0.001). The signature score showed strong correlation with proliferation signatures OncotypeDx and PCNA (ρ=0.90-0.96, P <0.001), and associated with reduced cancer specific survival (P <0.001), also when adjusted for traditional clinico-pathologic variables in both cohorts (HR: 1.074-1.081, 95% CI: 1.046-1.109, P ≤0.003). The signature score associated with survival when adjusting for traditional clinico-pathologic variables in OncotypeDx-low tumors in both cohorts (HR: 1.54-1.077, 95% CI: 1.034-1.251, P <0.001). By CMAP, inhibitors of CDK, PI3K and AURKA are suggested with potential relevance for BC of the young.

Conclusions

The current study provides new insights into age-related gene expression alterations in BC. We found evidence of higher tumor cell proliferation in young BC patients, and identified a gene expression signature reflecting tumor proliferation, aggressive tumor features and reduced survival, also in subsets of low OncotypeDx score.

Legal entity responsible for the study

The authors.

Funding

The study was funded by support from Centre for Cancer Biomarkers CCBIO, University of Bergen, the Research Council of Norway, and the Western Norway Regional Health Authority (Helse Vest RHF).

Disclosure

All authors have declared no conflicts of interest.

Background

Splicing is a central RNA-based process commonly altered in human cancers; however, how spliceosomal components are co-opted during tumorigenesis remains poorly defined. Previous work on MYC-driven triple negative breast cancer (TNBC) has revealed the spliceasome as an essential vulnerability that can be targeted to achieve disease control. Therefore, an important outstanding question is the contribution of individual components of the spliceosome machinery to the tumorigenic process downstream of MYC hyperactivation.

Methods

Our data is supported by extensive mechanistic analysis of spliceosome regulatory dynamics using both in vitro and in vivo models as well as patient material (RNA seq and tissue microarray of a cohort of TNBC patients as well as publicly available datasets).

Results

We unravel that specific spliceosomal components are translationally regulated during oncogenic stress. Indeed, we found that MYC enables SF3A3 translation through an eIF3D-dependent mechanism. This ensures accurate splicing of mRNAs enriched for mitochondrial regulators. Altered SF3A3 translation leads to metabolic reprogramming and stem-like properties that fuel MYC tumorigenic potential in vivo. Furthermore, SF3A3 protein analysis reveals a dichotomous role associated with MYC activity in triple negative breast cancers. Our analysis of human TNBC patient samples provides strong evidence that SF3A3 post-transcriptional regulation is associated with unique gene expression signatures that stratify the clinical outcomes in these patients.

Conclusions

These findings unveil a post-transcriptional interplay between splicing and translation that governs critical facets of MYC-driven oncogenesis.

Legal entity responsible for the study

The authors.

Funding

Swedish Foundations’ Starting Grant StemTherapy, Swedish Research Council (Vetenskapsrådet), Swedish Cancer Society (Cancerfonden) and the Fru Berta Kamprad Foundation.

Disclosure

A. Bosch: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Novartis; Travel/Accommodation/Expenses: Roche. All other authors have declared no conflicts of interest.

Background

PIK3CA represents one of the most mutated genes, both in hormone receptor-positive BC and HER2-positive ones. Several clinical trials demonstrated that the detection of PIK3CA mutations in ctDNA could represent a predictive biomarker of PI3K-inhibitor treatment response. BELLE-2, BELLE-3, and SOLAR-1 trials prospectively showed a significant progression-free survival benefit in ctDNA PIK3CA-mutant patients, suggesting PIK3CA mutation detection in ctDNA could represent a PI3K-Is predictive biomarker. Still, it would seem that liquid biopsy could be potentially more reliable than a tissue biopsy, as emerged from the BELLE-2 study. Yet, the diagnostic accuracy of liquid biopsy in detecting mutations on PIK3CA in BC is still being evaluated.

Methods

Our purpose was to provide a comparative analysis of diagnostic accuracy between tissue and liquid biopsies. Moreover, we deeply investigated if different diagnostic molecular techniques could influence the accuracy of liquid biopsy in detecting PIK3CA mutation. Variables which could potentially affect the results (technique, tumor burden, time elapsed between tissue and blood samples collection) were considered. The pooled analysis was carried out on 25 works for a total of 1966 patients, for which matched tumor tissue and plasma specimens have been collected.

Results

The results proved a better performance of NGS-based technologies in terms of sensitivity and specificity compared to ddPCR/BEAMing and Real Time-Polymerase Chain Reaction (RT-PCR). In particular, we reported AUC values for NGS-based assays of 0,98 (ddPCR/BEAMing 0,92; PCR 0,77), resulting in absence of significant heterogeneity for the pooled specificity (I² = 0 %, Cochran’s Q test p-value = 0.52).

Conclusions

We would suggest the use of NGS rather than conventional RT-PCR to screen for the presence of a PIK3CA mutation in BC patients. Finally, given the not well-established applications of ctDNA analysis in the clinical management of BC, this meta-analysis could add intriguing insights supporting the introduction of liquid biopsy in clinical practice as a routine procedure.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Russo: Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Ambrosetti; Advisory/Consultancy: Kyowa Kirin; Speaker Bureau/Expert testimony: Roche Diagnostics. All other authors have declared no conflicts of interest.

Background

Hypoxia occurs in most solid tumors including BC and may negatively impact treatment response. We investigate the incidence of BACH1 (a key regulator of mitochondrial metabolism) and HIF1α (a hypoxia-inducible factor) expressions and their correlation with clinical outcomes in early HER2-negative BC.

Methods

We correlated tumor BACH1 and HIF1α mRNA expression from available RNA-Seq data with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS) in the GeparSepto trial (NCT01583426), which randomized pts with early-stage BC to either neoadjuvant solvent-based paclitaxel (P) or nP followed by EC. BACH1 and HIF1α values were analyzed as a continuous variable and categorized as low and high by median cut-off. Multivariate logistic (for pCR) and Cox (DFS and OS) regressions were used to adjust for age, cT, and cN.

Results

RNA-Seq expression data was available for 279 out of 810 HER2-negative BC pts, median age was 49 years (range 22-76) and median follow-up 49.8 months (range 2.3-62.4). There was a positive correlation between BACH1 and HIF1A expression levels (Pearson correlation 0.498). Overall, BACH1 and HIF1α continuous expressions were significantly associated with increased pCR (OR=4.21 [95%CI 1.44-12.30), p=0.009), OR=2.08 [95%CI 1.14-3.82], p=0.018, respectively) but did not impact survival in multivariate models. The table shows effects of BACH1 and HIF1α expression in nP vs P arm, both high BACH1 and HIF1α expressions were significant independent predictors of pCR and were associated with numerically better survival Table: 21P

Conclusions

HER2-negative BC with elevated BACH1 and HIF1α expression benefits from nP-based treatment. There was a positive correlation between increased BACH1 and HIF1α levels for predicting pCR. We suggest that high BACH1 and HIF1α expressions enhance the efficacy of nP treatment, perhaps through triggering the hypoxic tumor adaptation.

Clinical trial identification

NCT01583426.

Legal entity responsible for the study

GBG Forschungs GmbH.

Funding

Has not received any funding.

Disclosure

A. Schneeweiss: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Non-remunerated activity/ies, Medical writing grant: Roche; Research grant/Funding (institution): AbbVie; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. C. Denkert: Research grant/Funding (institution), Oncobiome project: European Commission H2020; Research grant/Funding (institution), INTEGRATE-TN project: German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Molecular Health; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options: Sividon diagnostics; Licensing/Royalties, patent royalties: VMScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. V. Mueller: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seagen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Teva; Honoraria (self): Janssen-Cilag; Advisory/Consultancy: Hexal; Advisory/Consultancy: Nektar. M. Untch: Honoraria (institution), Non-remunerated activity/ies: AbbVie; Honoraria (institution), Non-remunerated activity/ies: Amgen; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene; Honoraria (institution), Non-remunerated activity/ies: Daiichi Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai; Honoraria (institution), Non-remunerated activity/ies: Lilly Deutschland and Int.; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genetics; Honoraria (self), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer; Honoraria (self): PUMA Biotechnology; Honoraria (institution), Non-remunerated activity/ies: Roche; Honoraria (institution), Non-remunerated activity/ies: Sanofi Aventis Deutschland GmbH; Honoraria (institution), Non-remunerated activity/ies: Teva; Honoraria (institution), Non-remunerated activity/ies: Novartis; Honoraria (institution): Pierre Fabre and Seattle Genetics; Honoraria (institution), Non-remunerated activity/ies: Clovis Oncology. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): SeaGen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc.; Honoraria (institution): Prime/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. All other authors have declared no conflicts of interest.

Background

HER2-low breast cancer (BC) is defined by an immunohistochemistry (IHC) assay score 1+ or 2+ with negative in situ hybridization (ISH). Genomic characterization of this subset of BC is still limited. We aimed to compare the genomic alterations found in a subgroup of HER2-low metastatic BC versus HER2-zero tumors (IHC score 0) in order to identify potential biomarkers.

Methods

A retrospective analysis was carried out in a sample of 121 metastatic BC patients from Hospital Universitario 12 de Octubre and HM CIOCC (Madrid, Spain) collected from 2017-2020. Next-generation sequencing (NGS) was performed in formalin-fixed paraffin embedded (FFPE) samples of BC. Biopsies included both primary or metastatic tumor, whichever most recent/accesible was available. Somatic mutations and copy number variations (gains and loss) were gathered from the NGS reports. Two-sided Chi-Square test was used for comparisons of proportions between groups and p values below 0.05 were deemed statistically significant.

Results

We identified a total of 67 HER2-low and 54 HER2-zero breast carcinomas. Both groups were similar in the median age of patients, menopausal status and metastatic pattern. The most frequent phenotype was luminal B for both groups, with a significantly higher prevalence in HER2-low carcinomas (65.7% and 37.0%, p<0.01). The most frequently mutated genes were (Table) PIK3CA (31.3% vs 35.2%, p=0.34) and TP53 (34.3% vs 48.2%, p=0.12) in both HER2-low and HER2-zero categories, respectively. We observed a higher prevalence of FGFR1 amplification (defined as ≥10 copy number gain) in the HER2-low group (12% vs 1.8%, p=0.03) compared to HER2-zero carcinomas. Table: 22P

Only gene alterations with a frequency of ≥5% in any group are shown

Conclusions

In our sample, PIK3CA and TP53 were the most frequently mutated genes in both HER2-low and HER2-zero breast carcinomas. FGFR1 amplification was more prevalent in the HER2-low category compared to HER2-zero tumors. This finding needs to be further confirmed as a potential target in this subset of patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Sanchez Bayona: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer. P. Tolosa: Speaker Bureau/Expert testimony: AstraZeneca, Amgen, MSD, Roche and Pfizer. E.M. Ciruelos: Advisory/Consultancy: Pfizer, Eli Lilly, Roche, Novartis, AstraZeneca and MSD; Speaker Bureau/Expert testimony: Roche, Pfizer and Eli Lilly; Travel/Accommodation/Expenses: Roche, Pfizer. All other authors have declared no conflicts of interest.

Background

The HER2-E subtype within HR+/HER2- ABC represents 10-25% and is characterized by poor prognosis. In the MONALEESA program, ribociclib + ET was found highly active in this subtype compared to ET. Here, we explored the prognostic and predictive value of HER2-E in patients (pts) treated with a CDK4/6 inhibitor (CDK4/6i) + ET in the real-world setting.

Methods

This is a retrospective study of 144 consecutive pts with HR+/HER2- ABC treated with a CDK4/6i + ET in the first line setting from 2014-2020 in Hospital 12 de Octubre (Madrid) and Clinic of Barcelona. Research-based PAM50 was performed in FFPE tumors collected before CDK4/6i (primary tumors or metastatic biopsies). Univariate and multivariable cox model progression-free survival (PFS) analyses were performed adjusting for the presence of visceral or “de novo” disease, menopausal status and performance status.

Results

114 pts (79%) had PAM50 data (50% primary/50% metastatic), and 47%/46%/7% received palbociclib/ribociclib/abemaciclib. Subtype distribution: Luminal A (33%), Luminal B (37%), HER2-E (19%), normal-like (8%) and Basal-like (5%). Median PFS for HER2-E disease was 7.4 months (mo) (95% confidence interval [CI] 5.0-22.0) and 21.1 mo (95% CI 16.6-31.3) for non-HER2-E disease (adjusted hazard ratio [aHRatio]=2.38, p=0.010). Median OS for HER2-E disease was 30.9 months (mo) (95% confidence interval [CI] 13.2-not reached [NR]) and NR (95% CI 47.2-NR) for non-HER2-E disease (aHRatio=4.39, p=0.021). Although exploratory and statistically non-significant, the PFS HRatio estimates of ribociclib vs palbociclib/abemaciclib in Luminal A, Luminal B and HER2-E subtype were 0.88, 0.90 and 0.44, respectively. Finally, the overall response rate of ribociclib in Luminal A/B and HER2-E disease was 40.5% and 42.9% vs 36.8% and 25.0% with palbociclib/abemaciclib.

Conclusions

In a real-world setting, we confirmed the poor prognosis of the HER2-E subtype in HR+/HER2- ABC. Despite the limitations, our results support the observation from the ML program where ribociclib in combination with ET was particularly active in the HER2-E subtype.

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III (PI19/01846) (to A.P.) Instituto 299 de Salud Carlos III (PI18/01408) (to E.C.) Breast Cancer Research Foundation (to 300 A.P.) PhD4MD (to N.C.) Fundació La Marató TV3 (to A.P) RESCUER Horizon 2020 301 (to A.P.) Save the Mama (to A.P.) Pas a Pas (to A.P.) Asociación Cáncer de Mama 302 Metastásico (to A.P.) Fundación Científica Asociación Española Contra el Cáncer (to 303 F.B.M.) Fundación SEOM (SEOM 2018 Grant: Fellowship for Training in 304 Research in Reference Centers) (to T.P.).

Disclosure

O. Martínez-Sáez: Advisory/Consultancy: Roche; Travel/Accommodation/Expenses: Roche; Speaker Bureau/Expert testimony: Eisai. P. Tolosa: Honoraria (institution), Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: MSD; Speaker Bureau/Expert testimony: Eisai. T. Pascual: Advisory/Consultancy: Roche; Advisory/Consultancy: Genentech. N. Chic: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Pierre Fabre. J.C. Laguna: Speaker Bureau/Expert testimony: Kyowa Kirin. M. Vidal: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self): Daiichi Sankyo; Travel/Accommodation/Expenses: Pfizer. M. Muñoz: Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Lilly; Speaker Bureau/Expert testimony: Pierre Fabre; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Eisai. A. Prat: Honoraria (self), Research grant/Funding (institution): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Amgen; Honoraria (self), Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: Bristol-Myers Squibb; Honoraria (self): MSD Oncology; Advisory/Consultancy: NanoString Technologies; Honoraria (self): Lilly; Advisory/Consultancy: Pfizer. E.M. Ciruelos: Advisory/Consultancy: MSD; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest.

Background

Several genomic assays are available to profile early breast cancer (BC) that, according to current evidence, can provide reliable information including the risk of recurrence. However, little is known regarding their current use and the perception of utility across Europe. The PROCURE project aims to develop a consensus on the utility of breast cancer multigene signatures (BCMS) in treatment decision making for different eBC patient profiles based on the opinion of a panel of experts.

Methods

A Scientific Committee of 8 experts in BC from 8 European countries developed a Delphi questionnaire to be administered in two-waves to experienced clinicians across Europe, selected based on their experience in BC. The questionnaire includes 5 sections in order to characterize the participants and their expertise in BCMS, to understand the current clinical practice in eBC and the use of BCMS, to recall the participant’s opinion on the utility of the BCMS in eBC according to the patient profiles, to define recommendations on the use of BCMS in clinical practice and finally, to identify unmet needs and future applications of BCMS. 180 participants, including medical oncologists, surgeons, pathologists and gynaecologists, are expected to answer anonymously the online Delphi questionnaire. 70% agreement will be used to determine consensus on a topic.

Results

At the end of January 2021, 146 participants from 11 European countries (Austria, Denmark, France, Germany, Italy, Norway, Portugal, Spain, Sweden, Switzerland and the UK) registered to participate. 61 of them had already fully completed the 1^st wave Delphi questionnaire. Results from the 1^st wave will be presented to engage larger discussion with congress participants.

Conclusions

The PROCURE Project will provide useful information regarding how BCMS are currently used in clinical practice across Europe and will help to measure the utility attributed to the different BCMS by BC experts for their daily clinical practice, to establish recommendations on the use of BCMS to make treatment decision in different eBC patient profiles and to define current unmet needs and future applications of BCMS according to experts point of view.

Editorial acknowledgement

Adelphi Targis SL.

Legal entity responsible for the study

Veracyte Inc.

Funding

Veracyte Inc.

Disclosure

G. Curigliano: Advisory/Consultancy: Novartis; Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: Veracyte; Advisory/Consultancy: Genomic health; Advisory/Consultancy: Ellipsis. F. Cardoso: Honoraria (self): Amgen; Honoraria (self): Astellas/Medivation; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self): Daiichi Sankyo; Honoraria (self): GE Oncology; Honoraria (self): Genentech; Honoraria (self): GlaxoSmithKline; Honoraria (self): Macrogenics; Honoraria (self): Medscape; Honoraria (self): Merck-Sharp; Honoraria (self): Merus BV; Honoraria (self): Mylan; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): priME Oncology; Honoraria (self): Roche; Honoraria (self): Samsung Bioepis; Honoraria (self): Eisai. M.I. Gnant: Honoraria (self): Veracyte; Honoraria (self): Amgen; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Daiichi Sankyo; Honoraria (self): Tolmar; Honoraria (self): LifeBrain. A-V. Lænkholm: Honoraria (self): Veracyte. F. Penault-Llorca: Honoraria (self), Research grant/Funding (self): Veracyte; Honoraria (self), Research grant/Funding (self): Exact science former Genomic Health; Honoraria (self): Agendia; Honoraria (self), Research grant/Funding (self): Myriad. A. Prat: Honoraria (self): Veracyte; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy: Amgen; Advisory/Consultancy: BMS; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: AbbVie; Honoraria (institution): NanoString technologies; Research grant/Funding (institution): Incyte; Honoraria (self): Oncolytics; Honoraria (self), Research grant/Funding (self): Novartis; Advisory/Consultancy: Peptomyc; Honoraria (self), Advisory/Consultancy: Guardian health; Honoraria (self), Shareholder/Stockholder/Stock options: Reveal genomics; Advisory/Consultancy: AstraZeneca; Research grant/Funding (self): Incyte. All other authors have declared no conflicts of interest.

Background

Toll-like receptor 4 (TLR4) and phosphorylated signal transducer and activator of transcription protein 3 (pSTAT3) hold a key role in inflammatory response and promote tumor immune escape upon expression on tumor cells. We evaluated the incidence and clinical relevance of CTCs expressing TLR4 and/or pSTAT3 in patients with mBC.

Methods

Peripheral blood was obtained from 100 mBC patients (recurrent: n=72; de novo metastatic: n=28) prior to first-line therapy. Triple immunofluorescence staining for cytokeratins (CK), TLR4 and pSTAT3 was performed on peripheral blood mononuclear cell cytospins. CK+ CTCs were characterized for TLR4 and pSTAT3 expression using the Ariol microscopy system.

Results

CK+ CTCs (n=28) were detected in 19 out of 100 patients. TLR4+ CTCs and pSTAT3+ CTCs were detected in 13% and 14% of patients, respectively, and represented the 53.6% and 60.7% of total CK+ CTCs, respectively. TLR4+/pSTAT3+ CTCs prevailed in patients with triple-negative BC (n=12), as compared to hormone receptor-positive/HER2-negative and HER2-positive subtypes (25%, 9.5% and 0%, respectively, p=0.033). The detection of CK+ CTCs was predictive for shorter OS (median: 24.9 vs 36.5 months; p=0.042; Kaplan Meier), whereas the detection of TLR4+ CTCs was associated with shorter PFS (median: 11.4 vs 12.6 months; p=0.036). In the de novo mBC setting, lower survival rates were encountered for patients harboring TLR4+ CTCs (median PFS: 9.6 vs 20.8 months; p=0.024), or pSTAT3+ CTCs (median PFS: 3.4 vs 20.8 months; p=0.006; median OS: 19 vs 60.8 months; p=0.005), and especially those with TLR4+ and/or pSTAT3+ CTCs (median PFS: 9.6 vs 31.9 months; p=0.003; median OS: 23.1 vs 74.8; p=0.014).

Conclusions

These results provide first evidence on the expression of TLR4 and pSTAT3 at the CTC-level in breast cancer (BC) with clinical relevance, implying that TLR4/STAT3 signaling pathways may have a role in BC progression. CTC detection and phenotyping according to TLR4 and pSTAT3 expression could serve for the refinement of prognosis in mBC.

Legal entity responsible for the study

Sofia Agelaki, Associate Professor of Medical Oncology, UoC.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

De-novo metastatic breast cancer (MBC) represents a distinct entity, characterized by different genomic and prognostic features compared to relapsed MBC. Although evidence suggests that half of all breast cancers show low HER2 expressions, and that HER2 expressions may increase between the early and metastatic stage, little is known on HER2-low expressions features of de-novo MBC.

Methods

We retrospectively reviewed clinical-pathological data of breast cancer patients consecutively referred to our New Drugs Division (from Jan2014 to Dec2019) with an available pathological analysis of the tumor (on either the primary lesion or a metastatic site). We divided HER2-negative cases by ASCO/CAP 2018 guidelines into an IHC 0 subgroup and a HER2-low subgroup (1+ and 2+/ISH-negative). χ2-test was used for comparisons between categorical parameters.

Results

442 breast cancer patients were eligible for the analysis, of whom 17% (N=75) had de-novo MBC. 65% of all de-novo MBC were luminal-like, 20% were HER2-positive and 15% were triple negative. 43% (n=32) of de-novo MBC showed low HER2-expressions, more commonly among luminal-like (49% HER2-low) than triple negative tumors (32% HER2-low), although this difference was not statistically significant (p=0.17). Compared to de-novo MBC, low HER2-expressions were significantly more common in relapsed MBC (57% vs 43%, p< 0.03). By comparing HER2-expression in relapsed MBC based on the site of sampling, HER2-low expression rate did not differ if the biopsy was performed on breast/lymph nodes or in visceral sites (68% vs 58%, p=0.1). No significant difference was found in low HER2-expression between de-novo MBC and early stage breast cancers (43% vs 44%, p=0.98).

Conclusions

De-novo MBC shows a rate of low HER2-expression comparable with early breast cancer, and significantly lower compared with relapsed MBC. This difference did not appear to be related to the biopsy site. Confirmation of these observations on larger populations of patients is warranted.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

G. Curigliano: Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Seattle Genetics; Honoraria (self): Lilly; Honoraria (self): Ellipses Pharma; Honoraria (self): Foundation Medicine; Honoraria (self): Samsung. All other authors have declared no conflicts of interest.

Background

In recent years, studies have shown that GATA3 can promote the expression of ERα and inhibit tamoxifen (TAM) resistance, whereas miR-221/222 could promote epithelial-to-mesenchymal transition (EMT), which could result in TAM resistance. Moreover, GATA3 also inhibits EMT. However, the specific mechanism by which miR-221/222 interacts with GATA3 and induces TAM resistance remains unknown. Our study aims to investigate the regulatory mechanism of miR-221/222 on GATA3 expression and clarify its regulatory role in the process of TAM resistance.

Methods

After the establishment of TAM-resistant MCF7 cell lines, we detected and compared the endogenous expression levels of miR-221/222, GATA3, ERα, E-cadherin and vimentin in MCF7 and MCF-TAM^R strains, as well as in different breast cancer cell lines, by PCR and western blotting. After overexpressing miR-221/222 in MCF7 cell lines, we characterized the GATA3, ERα and E-cadherin protein levels, and evaluated the migration and invasion ability of MCF7 cells by comparing wound healing and transwell migration with or without a miR-221/222 inhibitor. In order to confirm the effect of miR221/222 and GATA 3 on TAM resistance, a Cell Counting Kit-8 (CCK8) assay was used to quantify TAM resistance in the MCF-TAM^R cell lines.

Results

In the TAM-resistant and ERα-negative breast cancer cell lines, endogenous expression of miR-221/222 and vimentin were higher, whereas the expression of GATA3, ERα and E-cadherin was relatively low. After overexpressing miR-221/222, the protein levels of GATA3, ERα and E-cadherin decreased, indicating an inverse correlation between miR-221/222 and GATA3, ERα and E-cadherin. Wound healing and transwell experiments showed that miR221/222 promoted the migration and invasion of breast cancer cells, and CCK8 assay demonstrated that miR-221/222 can promote TAM resistance and that GATA 3 can reverse it.

Conclusions

Overall, our results suggest that miR-221/222 may down-regulate GATA3 expression, thereby down-regulating ERα and promoting breast cancer EMT to ultimately promote tamoxifen resistance. This regulating network may be due to the targeting of miR-221/222 to the 3’ UTR of GATA3 mRNA.

Legal entity responsible for the study

Yuan-Ke Liang.

Funding

Interdisciplinary project of Li-Ka-Shing Foundation, (No.2020LKSFG05C); Guangdong Basic and Applied Basic Research Foundation (No. 2019A1515110953); Funded by China Postdoctoral Science Foundation(2020M672753); Supported by Department of Education of Guangdong Province (2019KQNCX035, 2019KQNCX033); \"Dengfeng Project \" for the construction of high-level hospitals in Guangdong Province–the First Affiliated Hospital of Shantou University Medical College Supporting Funding (No. 202003-5, No. 202003-27); National Natural Science Foundation of China (No.81602345).

Disclosure

All authors have declared no conflicts of interest.

Background

Overexpression of the proto-oncogene EVI1 has been implicated as a prognostic factor in breast cancer (BC), particularly triple-negative BC (TNBC). The purpose of this study was to investigate frequency and clinical relevance of EVI1 expression in newly diagnosed BC treated with neoadjuvant chemotherapy.

Methods

EVI1 expression was determined by immunohistochemistry in pretherapeutic biopsies of BC patients treated with anthracycline/taxane based neoadjuvant chemotherapy within the GeparTrio trial. EVI1 expression was analyzed as a continuous variable and dichotomized into low or high based on median expression. Logistic regression and Cox proportional hazard models were used to correlate EVI1 expression with pathological complete response (pCR) and survival outcome, respectively. Disease-free survival (DFS) and overall survival (OS) rates according to EVI1 dichotomized expression were estimated with Kaplan-Maier curves with log-rank p-values.

Results

Of the 993 tumors with evaluable EVI1, 50.8% were HR+/HER2-, 15% HR+/HER2+, 9.8% HR-/HER2+, and 24.5% TNBC. Median EVI1 H-score was 112.16 (range 0.5-291.4). High EVI1 expression was more frequently observed in HR+/HER2- (52%) and TNBC (25%) compared to 13% in HR+/HER2+ and 10% in HR-/HER2+ and was significantly associated with smaller tumor size (cT1-2, p=0.004) in HR+/HER- BC. Elevated EVI1 levels were not significantly associated with therapy response and survival in the overall cohort. However, TNBC patients with high EVI1 showed a trend towards higher pCR rates compared to low EVI1 group (37.7% vs 27.5%, p=0.072; odds ratio 1.60 (95%CI 0.90-2.85, p=0.110) and numerically better survival (DFS: HR=0.77 [95%CI 0.48-1.23], log-rank p=0.271); OS: (HR=0.76 [95% 0.44-1.31], log-rank p=0.314).

Conclusions

EVI1 did neither influence response to neoadjuvant therapy nor patient survival in the overall cohort. TNBC patients with elevated EVI1 expression showed numerically better pCR and improved survival. Further analyses are needed to verify our findings, especially in the pathological work-up of newly diagnosed TNBC patients.

Clinical trial identification

NCT00544765; NCT00544765.

Legal entity responsible for the study

GBG Forschungs GmbH.

Funding

Has not received any funding.

Disclosure

B. Ataseven: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): AstraZeneca; Honoraria (self): Clovis; Non-remunerated activity/ies: PharmaMar; Honoraria (self), Non-remunerated activity/ies: Tesaro/GSK; Honoraria (self): MSD; Honoraria (self): Celgene; Honoraria (self): Amgen. V. Mueller: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Roche; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seagen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Genentech; Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self), Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self): Teva; Honoraria (self): Janssen-Cilag; Advisory/Consultancy: Hexal; Advisory/Consultancy: Nektar. J-U. Blohmer: Honoraria (self), Research grant/Funding (institution): Sysmex; Research grant/Funding (institution): Somatex; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): SonoScape. F. Marmé: Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Clovis; Honoraria (self): GSK/Tesaro; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Seagen; Honoraria (self): Myriad; Honoraria (self): PharmaMar; Honoraria (self): Eisai; Honoraria (self): Janssen-Cilag. P.A. Fasching: Honoraria (self): Novartis; Research grant/Funding (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Research grant/Funding (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): Mylan; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Pierre Fabre; Honoraria (self): Roche. C. Denkert: Research grant/Funding (institution), Oncobiome project: European Commission H2020; Research grant/Funding (institution), INTEGRATE-TN project: German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Molecular Health; Research grant/Funding (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options, Cofounder/shareholder until 2016: Sividon diagnostics; Licensing/Royalties, patent royalties: VMScope digital pathology software; Licensing/Royalties, patent pending: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. A. Stenzinger: Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony: AGCT; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Illumina; Advisory/Consultancy, Speaker Bureau/Expert testimony: Janssen; Advisory/Consultancy, Speaker Bureau/Expert testimony: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Seattle Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Advisory/Consultancy, Speaker Bureau/Expert testimony: Thermo Fisher; Research grant/Funding (institution): Chugai. S. Loibl: Research grant/Funding (institution): AbbVie; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Pfizer; Honoraria (institution): SeaGen; Research grant/Funding (institution): Immunomedics/Gilead Sciences Inc.; Honoraria (institution): Prime/Medscape; Honoraria (institution): Eirgenix; Research grant/Funding (self), Research grant/Funding (institution): DSI; Honoraria (institution): BMS; Honoraria (institution): Merck; Honoraria (institution): Puma; Speaker Bureau/Expert testimony: Chugai; Licensing/Royalties, patent pending: EP14153692.0-Immunsignature in TNBC. All other authors have declared no conflicts of interest.

Background

ESR1 mutations have been identified as a mechanism for endocrine resistance and occur frequently after treatment with aromatase inhibitors. Here, we assessed whether the combination of bevacizumab/paclitaxel yields sufficient anti-tumor activity to justify further exploration in advanced ER+/HER2- breast cancer patients with acquired ESR1 mutations in circulating tumor DNA (ctDNA).

Methods

We assessed ESR1 mutations in baseline plasma samples from patients who started with paclitaxel/bevacizumab (AT arm) in the phase II ATX study (BOOG-2006-06) and who were previously treated with an aromatase inhibitor in the adjuvant and/or metastatic setting. Baseline plasma samples from 44 patients were analyzed for ESR1 mutations by next generation sequencing. The primary objective was to assess the progression-free survival (PFS) rate at six months. We applied a two-stage design with α=0.05, β=0.20, P0=0.4 and P1=0.75 was applied, requiring at least 8 of 14 ESR1 mutant patients to be free of progression at 6 months on paclitaxel/bevacizumab. For P0, we assumed a 6-months PFS rate of 40% on fulvestrant, which is a commonly used treatment in these patients. Secondary outcomes were objective response rate (ORR) and overall survival (OS).

Results

ESR1 mutations were detected in 20 (45%) baseline samples. The 6-month PFS rate was 83% for ESR1 wild-type patients versus 85% for ESR1 mutant patients (17/20). The median PFS was 8.6 months [95% confidence interval (CI), 8.2-9.1] for ESR1 wild-type patients versus 8.1 months [95% CI, 7.2-9.0] for ESR1 mutant patients [log rank P=0.807]. The ORR was higher in ESR1 wild-type patients than in ESR1 mutant patients [75% vs 50%] although this percentage was not significant [P=0.052]. The median OS was 24.8 months [95% confidence interval (CI), 17.4-32.2] for ESR1 wild-type patients versus 20.7 months [95% CI, 2.1-39.3] for ESR1 mutant patients [log rank P=0.443].

Conclusions

This explorative study indicates that in advanced breast cancer patients with ESR1 mutations in plasma it is worthwhile to start bevacizumab/paclitaxel as further treatment.

Legal entity responsible for the study

Erasmus MC Cancer Institute.

Funding

Dutch Cancer Society.

Disclosure

All authors have declared no conflicts of interest.

Background

In an era of immunotherapeutic approaches, immune checkpoint blockers (ICBs) have revolutionised the oncology market. Yet, most patients do not benefit. The new direction has shifted towards identifying novel predictive biomarkers in the field of precision immuno-oncology. Thus, the development of a multifactorial synergistic predictive-model has become a pressing need. Triple-negative breast cancer (TNBC) and especially at younger age (<40 years) tends to exhibit an aggressive phenotype evading immune surveillance mediated by immune cells. This occurs by overexpressing PDL1 and shedding of CD155. Our group has recently identified sONE, a tumor suppressor lncRNA that is absent in young TNBC patients. sONE functional activity was found to be directly correlated to other immunomodulatory microRNAs. However, their expression signature in young TNBC patients has never been investigated. The aim of this study was to identify an immunomodulatory-related miRNA signature for young TNBC patients.

Methods

TNBC patients (n=28) were recruited. Median age at the time of diagnosis was 39 years old (range 22-70). Lymph node metastasis was evident in 60.7%. High Ki-67 ( >15) was observed in 71%. Stage 3 diagnosis was evident in 53.6 %of patients. Almost 93% of tumors were invasive ductal carcinoma (IDC) and the rest were invasive lobular carcinoma (ILC). Tumor size >5 cm was recorded in 68%. RNA was extracted from tissues and serum, reverse transcribed and quantified using q-RT-PCR. TNBC cell lines were cultured, transfected using oligonucleotides using lipofection.

Results

An elevated expression pattern for PDL1 in young TNBC patients and a marked repression of CD155, let-7a, miR-34a and miR-486-5p compared to the older group were observed. Ectopic expression of let-7a and miR-34a resulted in a significant repression of PDL1 while miR-486-5p mimics resulted in an induction of CD155 levels. Such an immuno-modulatory miRNAs expression pattern was inversely correlated with tumor size and Ki-67 in TNBC patients. Yet, PDL1 was directly associated with lymph node metastasis and stage of disease.

Conclusions

This study identified a panel of three immunomodulatory miRNAs as a signature among young TNBC patients overexpresing PDL1 and underexpressing CD155.

Legal entity responsible for the study

German University in Cairo.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Febrile neutropenia (FN) incidence across taxane or anthracycline chemotherapy regimens (T/AC) for breast cancer (BC) is high. BC patients (BCp) with FN face higher susceptibility to sepsis and other life-threatening infections, with FN-related mortality rate in BCp at 2-6%. Cancer susceptibility genetic variants can amplify chemotherapy-induced cytotoxicity that result in FN onset. We studied the association between carriership of protein truncating variants (PTV) in 34 BC predisposition genes and FN in T/AC-treated BCp.

Methods

Targeted sequencing (Fludigm Juno 192.48, Illumina Hiseq4000) was performed for 1,596 adult BCp with invasive BC (median age=52 years) treated with adjuvant/neoadjuvant T/AC (2000-2016). Genes known or suspected to predispose BC, including genes on commercial panels for predicting BC risk, were analysed: ABRAXAS1, AKT1, ATM, BABAM2, BARD1, BRCA1, BRCA2, BRIP1, CDHT, CHEK2, EPCAM, FANCC, FANCM, GEN1, MEN1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PIK3CA, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL, RINT1, STK11, TP53 and XRCC2. 441 BCp who received granulocyte-colony stimulating factor ≤30 days before or during T/AC were excluded. PTVs (frameshift/nonsense mutations or splice sites) were identified and collapsed into a binary variable. Association between PTV carriership (PTVship) and FN was analysed with logistic regression model; single gene PTVship associations were analysed with Fisher’s exact test.

Results

In 1,155 BCp studied, 9% were carriers of at least one PTV. PTVship was found to decrease FN risk (OR=0.27, 95%CI 0.11-0.68, p=0.005, adjusted by site, ethnicity, BMI and first 4 principal components). No single gene was found to be significantly associated with FN.

Conclusions

PTVship appears to be protective against FN. Other FN risk factors need to be considered in future studies.

Legal entity responsible for the study

Agency for Science, Technology and Research (A*STAR).

Funding

National Research Foundation Singapore, National University of Singapore, National University Cancer Institute Singapore (NCIS), Breast Cancer Prevention Programme (BCPP), Asian Breast Cancer Research Fund, and National Medical Research Council (NMRC) Singapore.

Disclosure

S.G.W. Ow: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Background

PI3K/AKT/mTOR pathway is frequently altered in breast cancer. PIK3CA mutations have been described in up to 40% of luminal breast carcinomas. Mutations located in two hotspots in exons 9 and 20 (codons 545, 546 and 1074) account for more than 85% of all point mutations in this gene. PIK3CA alterations have been shown to be related with endocrine therapy resistance.

Methods

We have searched for mutations on PIK3CA exons 9 and 20 in a set of 166 luminal, treatment naive, breast cancer cases. DNA was extracted from paraffin embedded tissue from the primary tumor. We used a previously published pyrosequencing protocol by Nosho et al (Neoplasia, 2008). We reviewed current literature on early breast cancer and sistemic therapy resistance.

Results

26.5% (44 samples) of all the cases in our serie was mutant for either exons 9 or 20. Mutation distribution showed codon 1074, exon 20, as the most frequently mutated (16.87%). H1047R was the most common change seen. PIK3CA mutations have been commonly considered an adquired resistance mechanism to endocrine therapy. Its importance on early breast cancer development and treatment selection has not been deeply explored.

Conclusions

PIK3CA mutations are common in luminal breast cancer. These changes also occur among treatment naive patients. The role of such alterations in the natural history of the disease and its role on primary resistance to endocrine therapy remains to be determined.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Epigenetic alterations play an important role in the development of breast cancer and could differ between the different subtypes as well act as prognostic and/or predictive factor of response to chemotherapy. The potential reversibility of these alterations justifies the growing interest in their research as possible therapeutic targets in the context of precision medicine. Our aim is to perform a DNA methylation screening to identify potential biomarkers of prognosis and treatment response in breast cancer.

Methods

We retrospectively analyzed 138 breast cancer patients treated with neoadjuvant chemotherapy based on anthracyclines and taxanes. Patients were classified in breast cancer subtypes according to clinical and pathological characteristics. In the epigenetic analysis, a \"discovery\" cohort was selected from the BRCA cohort from TCGA. 28 cases with available methylation data were chosen, and 3 candidate genes (ID1, HOXB2 and ATOH8) were selected using bioinformatics tools. These biomarkers were validated in our \"validation cohort\" by pyrosequencing techniques. Results were correlated with clinical-pathological characteristics, response rate and survival.

Results

After pyrosequencing analyses, ID1 methylation was different (p< 0.001) among breast cancer subtypes; its hypomethylation was associated with triple negative subtype. Hypomethylation of HOXB2 was mostly detected in luminal tumors and was associated with a lower response rate (p=0.025) and worse survival. The combination of both hipermethylated ID1 and hypomethylated HOXB2, defined a subgroup of luminal patients with worse prognosis. Hypomethylation of ATOH8 was correlated with triple negative tumors (p=0.01), but it was related to a higher rate of pathological complete responses (p=0.016) and a trend to a greater disease-free survival in this subgroup.

Conclusions

Epigenetic platforms could be a useful tool to select predictive and prognostic markers in cancer. Although a validation in a larger and prospective cohort is required, ID1, HOXB2 and ATOH8 are suggested as epigenetic biomarkers for predicting response to chemotherapy and prognosis in breast cancer.

Legal entity responsible for the study

The authors.

Funding

Celgene.

Disclosure

V. Quiroga Garcia: Honoraria (self): Roche; Honoraria (self): Pfizer; Research grant/Funding (institution): Celgene; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Roche. B. Cirauqui Cirauqui: Advisory/Consultancy: BMS; Advisory/Consultancy: Roche; Advisory/Consultancy: Merck; Speaker Bureau/Expert testimony: BMS; Speaker Bureau/Expert testimony: Roche; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: BMS; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: MSD. M. Romeo Marin: Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): GSK; Research grant/Funding (institution): Clovis. All other authors have declared no conflicts of interest.

Background

In Russia, more than 50,000 women are diagnosed with breast cancer every year. Russia is a multinational country - about 200 ethnic groups live on its territory. To date, there are a limited number of reports on inherited gene mutations associated with breast cancer among Khakass (Mongoloid indigenous people in Russia). The aim of this study was to assess the prevalence of mutations of breast cancer-associated genes in 27 Khakass women with breast cancer.

Methods

Our study included 27 Khakass patients with breast cancer (range, 28 to 47 years). Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit, Hereditary Cancer Solution™ (SOPHiA GENETICS, Switzerland), covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). Next-generation sequencing (NGS) was performed using the Illumina NextSeq500 System (Illumina, USA).

Results

In our study, one pathogenic mutation was detected in ATM (rs780619951, NC_000011.10:g.108259022C>T) gene in two unrelated individuals with family history of cancer (prevalence of 7,4%, 2/27). As known, this sequence change creates a premature translational stop signal at codon 805 (p.Arg805*). It is also expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with ataxia-telangiectasia, as well as an individual with a personal or family history of breast or ovarian cancer.

Conclusions

To the best of our knowledge, this report is the first to describe the pathogenic variant in the ATM gene (rs780619951) in two Khakass breast cancer patient with family history of cancer. The reported study was funded by RFBR according to research project 18-29-09046.

Legal entity responsible for the study

The authors.

Funding

The reported study was funded by RFBR according to research project 18-29-09046.

Disclosure

All authors have declared no conflicts of interest.

Background

CD4 CTLs are a subset of CD4 T cells that infiltrate the tumor immune environment (TIME) and have cytotoxic activity against malignancies. A gene signature defining the CD4 CTLs was recently developed (Cell. 2020; 181(7):1612-1625.e13). The prognostic value of CD4 CTLs in breast cancer TIME is unknown.

Methods

We tested a gene signature that identified the CD4 CTL subset within the T cells basin in the breast cancer TIME and examined its association with breast cancer patients’ outcomes. We extracted the transcriptomic and clinical outcomes of patients with primary breast cancer from the cancer genomic atlas TCGA database (TCGA-BRCA). Z-scores of the five genes defining active CD4 CTL (ABCB1, APBA2, SLAMF7, GPR18, and PEG10) were used to calculate the signature score using principal component analysis. The CD4 CTL signature score was dichotomized into high vs. low scores using the median (0.02). The abundance of other T-cells populations was estimated using CIBERSORT.

Results

Transcriptomic and clinical data of 1083 breast cancer patients were retrieved from TCGA-BRCA. The median score of the CD4 CTL-defining gene signature was 0.02 (range -4.45-4.79). High signature scores were significantly more frequent in younger patients (< 55 years) (57% vs. 42%, P = 0.001), luminal subtype (62% vs. 37%, P = 0.001) and invasive duct carcinoma (IDC) (76% vs. 24%, P = 0.008). In multivariate analysis, adjusting for age, TNM stage and subtype, high CD4 CTL signature score was significantly associated with better disease-free and overall survival (OS) (hazard ratio (HR): 0.62, 95% Confidence Interval (CI): 0.42-0.96, P = 0.03 and HR: 0.66, 95%CI: 0.43-.0.99, P = 0.001) respectively. In a stratified Log-rank survival test, higher score was associated with better OS among advanced T stage (T3-T4) (P = 0.014) and node-positive cohorts (P = 0.016). Correlating CD4 CTL with different immune infiltrate fractions showed a significant positive correlation with CD8 T cells (rho = 0.44, P = 0.001).

Conclusions

Cytotoxic CD4 T cell is an emerging prognostic biomarker within the breast cancer immune environment. Further dissection of CD4 CTL activity could carry a predictive signal for immunotherapy in patients with breast cancer.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Breast cancer is the most frequent cancer in women; over 1,000,000 new cases are diagnosed per year worldwide. Breast cancer is a complex polygenic disease in which genetic factors play a very important role in disease etiology and pathologic process. The TNRC9 / LOC643714 locus on chromosome 16q12 was one among the first breast cancer regions known through genome-wide association study.

Methods

This study included seventy-five subjects (fifty breast cancer patients and twenty-five healthy controls). The studied participants were subjected to full history taking, clinical examination, and laboratory investigations include tumor markers (CEA and CA15-3) and genotyping of TNRC9 (rs3803662) and LOC643714 (rs12922061) single nucleotide polymorphisms by using real time-PCR, for patients; pathological, clinical and survival data were analyzed.

Results

Significant higher frequencies of the LOC643714 rs12922061 CT genotype and T allele were observed in breast cancer patients (p=0.016, OR (95%CI); 4.114 (1.30-13.0 and p= 0.044, OR (95%CI); 1.02-5.39 respectively). This significant difference was also observed under a dominant model (CC vs CT+TT OR 3.551; 95%CI 1.26 – 10.02; p= 0.017) and Over-dominant model (CT vs CC+TT OR 3.692; 95%CI :1.19–11.39; p= 0.023). Regards rs12922061 genotype distribution, there was significant difference regards menopausal state under the dominant model (p=0.044) and there was significant difference regards nodal stage under both the dominant model (p=0.049) and over dominant model (p=0.028). No significant association was found between the rs3803662 polymorphism and breast cancer patients. Regarding survival after 2 years of follow up of breast cancer patients both LOC643714 (rs12922061) and TNRC9 (rs3803662) were not associated with significant survival difference C/C versus C/T +T/T and G/G versus A/A+ A/G respectively.

Conclusions

While there was no significant association regarding the TNRC9 rs3803662, our study found that rs12922061 of LOC643714 was related to breast cancer risk. Moreover, the rs12922061 is related to menopausal state and nodal stage.

Legal entity responsible for the study

Menoufia University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Increasing data demonstrate that various genetic alterations are involved in the process of breast cancer invasion; however, their contribution to the individual mode of breast cancer invasion, which is associated with distant metastasis, remains unclear.

Methods

Samples of a tumor and normal breast tissue obtained during surgery from patients with breast cancer (n=10) were used. Type of the invasive component (collective or individual) was determined using morphological analysis of hematoxylin and eosin-stained sections of tumor tissue. DNA isolated from samples was used to prepare exome libraries (SureSelect XT HS, Agilent, USA). Sequencing was performed on the NextSeq500 platform in the PE75 mode (Illumina, USA). Data processing was carried out using the GATK pipeline. Selection of genetic variants found only in cases with an individual mode of breast cancer invasion (compared to the collective mode of invasion) and potentially associated with cell migration and invasion on the basis of literature data was carried out. A stable cell line MCF10A with KLK5 knockout (MCF10A KLK5 KO) was established using CRISPR/Cas9 genetic editing system. Stable cell lines MDA-MB-231 with KLK5 variants (MDA-MB-231 KLK5 WT, MDA-MB-231 KLK5 H142P) were established using a site-directed mutagenesis and plasmid transfection. Cell migration analysis was performed using videomicroscopy. Statistical analysis was carried out using the DiPer program.

Results

Based on the results of whole-exome sequencing and subsequent selection of genetic variants, PIK3CA H1047R, KLK5 H142P and other genetic alterations potentially associated with individual mode of breast cancer invasion were found. Genetic variant KLK5 H142P was selected for in vitro analysis. Analysis of the migration of MCF10A KLK5 KO cells demonstrated that they migrate faster than MCF10A KLK5 WT cells (p<0.01). Analysis of migration of MDA-MB-231 cells with KLK5 variants showed that MDA-MB-231 KLK5 WT cells migrate slower than MDA-MB-231 WT cells and MDA-MB-231 KLK5 H142P (p<0.01).

Conclusions

Genetic variant KLK5 H142P is associated with individual mode of breast cancer invasion and affects the migratory behavior of tumor cells.

Legal entity responsible for the study

The authors.

Funding

Russian Foundation for Basic Research, French National Centre for Scientific Research.

Disclosure

All authors have declared no conflicts of interest.

Background

Glucocorticoid receptor (GR) is shown to have variable frequency of expression in invasive tumors of the breast. Investigation of additional nuclear receptors like GR in receptor negative tumors like triple negative breast cancer (TNBC) may have prognostic and therapeutic significance.

Methods

Expression of GR was evaluated by immunohistochemistry in 175 tumors of invasive breast cancer with long term follow up. GR Expression was separately evaluated in invasive tumor cells, stromal cells and tumor infiltrating lymphocytes (TIL’s). Staining pattern was categorised as positive when more than 1% of the cells stained in each subpopulation of cells. Disease free survival was analysed between GR positive and negative status by Kaplan Meier analysis.

Results

Of the 175 tumors, 121 (70%) were ER positive, 53 (30%) were ER negative and 29% (51) were triple negative. 74% (130/175) tumors showed expression of GR in invasive tumor cells while (84%) 147/175 had expression in TIL’s. No significant difference in distribution of GR was noted between ER positive and ER negative tumors (78% vs 66%, p-0.1). Of the TNBC’s 54% (28/51) and 70% (36/51) showed expression of GR in invasive tumor and TIL’s respectively. Overall, GR positive tumors had significant better survival than GR negative tumors (mean survival time of 85 vs 59 months respectively, p-0.04) Contrary to the reports that GR expression in TIL’s are associated with immunosuppressive activity in model systems, TNBC’s with increased expression of GR in immune cells were associated with better survival (Mean survival time 74 vs 41 months, log rank test- p-0.03). TNBC tumors which were GR negative had higher lymph node metastases (p-0.04) and none of the other clinical features like age, menopausal state, tumor size and grade were different between GR positive and negative tumors within TNBC.

Conclusions

Glucocorticoids (GC) are often used to alleviate the adverse symptoms during chemotherapy. Determining the GR status is of importance due to the pro cell survival effect of the glucocorticoids mediated through GR during chemotherapy. Though GC mediated effects on chemotherapy are controversial, our results indicate favourable effects in TNBC.

Legal entity responsible for the study

The authors.

Funding

Department of Biotechnology Wellcome Trust India Alliance.

Disclosure

All authors have declared no conflicts of interest.

Background

In Mexico, breast cancer (BC) is the leading cause of cancer death in women over 25 years old. Access to genomic platforms for biological intrinsic subgroups identification is not covered by the public health system. Within early BC (EBC) RH+/HER2- the non-luminal subgroup is associated with poor oncologic outcomes.

Methods

A retrospective review of 580 consecutive records of a BC prospective cohort attendeding INCMNSZ during the period Jan-2011 to Jun-2019. A combined score based on ER, PR and Ki67 levels was calculated. NOLUS formula was derived: −0.45^∗ER −0.28^∗PR +0.27^∗Ki67 + 73.02. High-NOLUS cutoff point ≥ 51.38 identified non-luminal population and low NOLUS < 51.38. The model was tested in EBC to identify the frequency of the non-luminal subtype.

Results

Luminal subtype 65.9%, triple negative 17.7%, HER2+ 16.4%. St Gallen classification: luminal A 58.3%, luminal B 33.8%, luminal B HER2+ 7.9%, Within the RH+/HER2- subgroup (n 175) low-NOLUS was 90.3%, and high-NOLUS 9.7%. Tumor grade was G1 37.7%, G2 49.7%, G3 12.6%. 63.9% of the patients with low-NOLUS had luminal A and 36.1% were luminal B. 5.9% of patients with high-NOLUS had luminal A vs 94.1% luminal B (p=<0.001). 82.3% received surgical treatment as initial strategy, neoadjuvant (n 31) 17.7%, (22 chemotherapy, 9 endocrine therapy). None of the patients presented pathologic complete response. Chemotherapy was received in 54.9%, endocrine therapy 95.4%. Median follow-up was 35.5 months, disease-free survival (DFS) of the entire cohort was 95.4% and cancer-specific survival (CSS) 97.1%. Relapse occurred in 4.6% (8/175). Distant recurrence (DR) in 7, all in the high-NOLUS group. DFS for low-NOLUS was 98.1% vs 70.6% high-NOLUS (p=<0.005). CSS for low-NOLUS was 98.1% vs high-NOLUS 88.2% (p=<0.044).

Conclusions

The frequency of the non-luminal subgroup in Mexican patients with EBC RH+/HER2- represented by high-NOLUS is similar to that reported in the literature. Patients with high-NOLUS have worse outcomes in DR and CSS. The NOLUS model is useful to identify non-luminal subgroups in RH+/HER2- EBC in the absence of genetic platforms.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

PgR expression is a biomarker of ER functionality, cellular progression to malignancy, and response to endocrine therapy (ET) in HR+ BC. ONA, a type I antiprogestin showed activity in patients with metastatic BC, but early trials with its immediate release formulation showed liver toxicity and further studies were halted. The development of a new extended-release formulation (Context Therapeutics, PA, USA), which is associated with a lower liver toxicity (Cottu PH, PLOS ONE, 2018) has strongly supported the relaunching of ONA clinical development. ONA blocks Ser294 phosphorylation of PgR, a posttranslational event associated with elevated PgR transcriptional activity coupled to rapid PgR turnover and also, downregulates PgR gene targets both in tumor cells expressing a sumo-deficient/phospho-mimic activated (KR) and non-activated (WT) PgR phenotype, independent to the presence of progesterone. Considering BC heterogeneity and that PgR analysis by standard immunohistochemistry (IHC) does not perfectly correlate with PgR target gene expression, the identification of biomarkers allowing the selection of patients with PgR-driven tumors that may benefit from antiprogestins treatment is currently an unmet need.

Trial design

ONAWA is an open-label, single arm, multicenter window of opportunity clinical trial of ONA (50 mg extended-release tablets BID for 21 days) for postmenopausal women with EBC amenable to receive a short course of ET before surgery. Ten patients with ER+/PgR+/HER2- and ki67 ≥ 15% BC will be enrolled at 4 sites of the SOLTI network. The primary objective is to evaluate the biological activity of ONA by the rate of Complete Cell Cycle Arrest determined by Ki67 (≤2.7%). Secondary endpoints include safety and correlating biological activity with IHC of tumor expression (ER, PgR, Ser294-PgR, CD24, CD44, ALDH1, Ki67), estradiol, and progesterone blood levels, and gene expression profile (NanoString nCounter® Breast 360^TM panel). The study was approved in July 2020 and recruitment started in November 2020. Seven patients have been enrolled at the time of this submission.

Clinical trial identification

NCT04142892; EudraCT Number: 2019-001433-13.

Legal entity responsible for the study

SOLTI Breast Cancer Research Group.

Funding

Context Therapeutics.

Disclosure

X. González-Farré: Honoraria (self), Non-remunerated activity/ies: Roche; Honoraria (self): Eisai; Honoraria (self): SOLTI. P. Villagrasa: Speaker Bureau/Expert testimony: NanoString. A. Prat: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (self): NanoString; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: Amgen; Advisory/Consultancy: Puma. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Hoffman-La Roche; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Genomic Health; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sharp and Dhome España SA; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Philips Healthwork; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pierre Fabre; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: prIME Oncology; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Puma; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Synthon; Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi Aventis. All other authors have declared no conflicts of interest.

Background

Neratinib (Nerlynx®) is an irreversible pan-HER inhibitor that significantly improves invasive disease-free survival (iDFS) vs placebo as extended adjuvant therapy in HER2-positive (HER2+) early-stage breast cancer (eBC) after trastuzumab-based therapy. The phase III ExteNET trial (NCT00878709) showed an absolute iDFS benefit of 2.5% and distant disease-free survival benefit of 1.7% with neratinib after 5 years’ follow-up. The brain is a common first site of metastasis after HER2-directed adjuvant therapy for eBC. To date, no HER2-directed therapies have prevented central nervous system (CNS) metastases in this setting.

Methods

Women with HER2+ eBC who had completed adjuvant therapy (± neoadjuvant therapy) with trastuzumab + chemotherapy were randomized to oral neratinib 240 mg/d or placebo for 1y. OS was analyzed after 248 events (powered for the ITT population). CNS outcomes: cumulative incidence of CNS recurrences (time from randomization to CNS recurrence as first distant recurrence); CNS disease-free survival (CNS-DFS, time from randomization to any CNS recurrence or death from any cause). Cut-off dates: 5y (Mar 2017); OS (Jul 2019).

Results

2840 patients were randomized (1420 per group). After a median follow-up of 8.1y, 8y OS rates were 90.1% (95% CI 88.3‒91.6) for neratinib and 90.2% (95% CI 88.4‒91.7) for placebo (absolute difference –0.1%; stratified HR=0.95; 95% CI 0.75‒1.21; p=0.6914). At 5y, cumulative incidence of CNS recurrences was 1.3% (95% CI 0.8–2.1) with neratinib and 1.8% (95% CI 1.2–2.7) with placebo, and CNS-DFS rates were 97.5% (95% CI 96.4–98.3) and 96.4% (95% CI 95.2–97.4), respectively (HR=0.73; 95% CI 0.45–1.17). No new safety signals were reported.

Conclusions

There were fewer deaths with neratinib than placebo in ExteNET, but the results did not reach statistical significance. Long-term CNS outcomes at 5y were also improved with neratinib. Neratinib is the first HER2-directed agent to show a trend towards improved CNS outcomes in HER2+ eBC, providing further support for current NCCN guidelines that recommend neratinib-based therapy for brain metastases from HER2-positive breast cancer.

Clinical trial identification

NCT00878709.

Editorial acknowledgement

Lee Miller, Miller Medical Communications Ltd.

Legal entity responsible for the study

Puma Biotechnology Inc.

Funding

Puma Biotechnology Inc.

Disclosure

B. Moy, I. Gore: Research grant/Funding (institution): Puma Biotechnology Inc. R.P. Bryce, F. Xu, A. Wong: Shareholder/Stockholder/Stock options, Full/Part-time employment: Puma Biotechnology Inc. F.A. Holmes: Travel/Accommodation/Expenses: Puma Biotechnology Inc. All other authors have declared no conflicts of interest.

Background

In the primary analysis of the neoadjuvant phase of the FeDeriCa study (NCT03493854; Tan AR, et al. Lancet Oncol 2021), PH FDC SC cycle 7 P + H serum trough concentrations were non-inferior to intravenous (IV) P + H, with comparable total pathological complete response rates and safety profiles. We present updated descriptive safety data that span the adjuvant phase of the study, with an additional 12 months beyond the primary analysis.

Methods

Patients (pts) with HER2-positive operable, locally advanced or inflammatory stage II–IIIC BC and left ventricular ejection fraction (LVEF) ≥55% were randomised 1:1 to eight neoadjuvant chemotherapy cycles (investigator’s choice between two standard regimens) + P IV (loading dose 840 mg, maintenance 420 mg) + H IV (8 mg/kg → 6 mg/kg) or chemotherapy + PH FDC SC (1200 mg P/600 mg H → 600 mg each as FDC SC) every 3 weeks during cycles 5–8. After surgery, pts continued adjuvant HER2-targeted treatment only, as randomised, to complete 18 cycles. Safety was assessed by NCI-CTCAE v4.

Results

Clinical cut-off was 10 July 2020. Adverse events (AEs) are shown in the table; the most common were diarrhoea, radiation skin injury and arthralgia. Infusion-/administration-related reactions within 24 hours were higher with PH FDC SC (17%) than with P + H IV (5%), all grade 1/2 and mostly due to local injection site reactions. No grade ≥3 anaphylaxis/hypersensitivity was reported in either arm. Table: 46P

Conclusions

Overall safety and tolerability, including cardiac safety, of PH FDC SC in the adjuvant phase of FeDeriCa remained comparable to P + H IV, with the exception of AEs associated with the different routes of administration. Results are in line with the expectation that most AEs with PH FDC SC or P + H IV are observed during concomitant chemotherapy.

Clinical trial identification

NCT03493854 (WO40324), 2 Feb 2018.

Editorial acknowledgement

Support for third-party writing assistance for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Funding

F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Disclosure

S-A. Im: Advisory/Consultancy: AstraZeneca, Amgen, Eisai, Hanmi, GSK, Lilly, MSD, Novartis, Roche, Pfizer; Research grant/Funding (institution), Investigator-initiated clinical trial research grant through institution: AstraZeneca, Eisai, Daewoong Pharm, Roche, Pfizer; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. A.R. Tan: Honoraria (self): Genentech, Novartis, Immunomedics, Celgene, AbbVie, Athenex, G1 Therapeutics, Eisai, Merck; Research grant/Funding (institution), Institutional clinical trial support: Roche/Genentech, Pfizer, Merck, Tesaro; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. A. Mattar: Advisory/Consultancy, Advisory board consultant: Roche, Novartis, Pierre Fabre, AstraZeneca, Exact sciences; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. R. Colomer: Honoraria (self): Roche, Eli Lilly, MSD, AstraZeneca; Research grant/Funding (institution): Roche, Lilly, MSD, BMS, AstraZeneca, Pfizer, Novartis; Non-remunerated activity/ies: Roche, MSD; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. D. Stroyakovskii: Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. Z. Nowecki: Travel/Accommodation/Expenses: Roche; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. M. De Laurentiis: Honoraria (self), Speaker’s honoraria and advisory board honoraria: Pfizer, Novartis, Roche, Celgene, AstraZeneca, Eisai, Lilly, Amgen, MSD, Pierre Fabre, Genomic Health, Daiichi Sankyo; Advisory/Consultancy: Pfizer, Novartis, Roche, Celgene, AstraZeneca, Eisai, Lilly, Amgen, MSD, Pierre Fabre, Genomic Health, Daiichi Sankyo; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. J-Y. Pierga: Honoraria (self): Roche, AstraZeneca, Pfizer, Amgen, Novartis, Exact Sciences, Seagen, Lilly, Pierre Fabre, MSD; Honoraria (institution): BMS, Roche, MSD, Eisai, Novartis, Sanofi; Speaker Bureau/Expert testimony: Daiichi Sankyo; Research grant/Funding (institution): Servier, Roche, Menarini Silicon Biosystems; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. K.H. Jung: Honoraria (self), Advisory board honoraria: Roche, Novartis, AstraZeneca, Takeda, Celgene; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. C. Schem: Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. C. Aguila: Full/Part-time employment, Full-time: Roche; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. T. Badovinac Crnjevic: Shareholder/Stockholder/Stock options: Roche; Licensing/Royalties, Issued patent (fixed-dose combination of pertuzumab and trastuzumab): Roche; Full/Part-time employment, Full-time: Roche; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. S. Heeson: Shareholder/Stockholder/Stock options: Roche; Licensing/Royalties, Issued patent (fixed-dose combination of pertuzumab and trastuzumab): Roche; Full/Part-time employment, Full-time: Roche Products Limited; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. M. Shivhare: Shareholder/Stockholder/Stock options: Roche Products Limited; Full/Part-time employment, Full-time: Roche Products Limited; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. A. Alexandrou: Full/Part-time employment, Full-time: Roche Products Limited; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. E. Restuccia: Shareholder/Stockholder/Stock options: Roche; Full/Part-time employment, Full-time: Roche; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche. C. Jackisch: Honoraria (self): AstraZeneca, Roche, Lilly, Novartis, Exact Sciences, Pierre Fabre; Advisory/Consultancy: AstraZeneca, Roche, Lilly, Novartis, Exact Sciences, Pierre Fabre; Research grant/Funding (institution): Roche, Exact Sciences; Travel/Accommodation/Expenses: AstraZeneca, Roche, Lilly, Novartis, Exact Sciences, Pierre Fabre; Non-remunerated activity/ies, Support for third-party writing assistance, furnished by Daniel Clyde, PhD, of Health Interactions: Roche.

Background

Endocrine therapy (ET) and chemotherapy (CHI) are among the adjuvant treatments for breast cancer (BC) that reduce the risk of recurrence and death. They are also known to impact quality-of-life (QoL) during treatment but little is known on their long-term consequences. The main objective is to analyze the impact of these treatments on reported sequelae and QoL 5 years after a diagnosis of BC.

Methods

Data from the French national VICAN5 survey on living conditions of people with cancer 5 years after diagnosis were used. This survey makes available three databases: a patient questionnaire conducted 5 years after diagnosis, a medical questionnaire, and the medical-administrative databases of the French health insurance (SNIIRAM databases). The analyzes were restricted to early BC women. We first modeled ET adherence profiles over the 5 years of ET treatment using the SNIIRAM databases, by applying Group-Based Trajectory Modeling (GBTM) based on the monthly proportion of days covered by ET. Then, we analyze the impact of ET and CHI on QoL and other reported sequelae 5 years after diagnosis, by introducing the ET adherence profiles.

Results

852 women were included in our study, of which 76.4% initiate ET and 53.7% received CHI. A 5-trajectory model of ET adherence profiles was selected, in which: 3 groups described non-persistent profiles, in which they stopped ET long before the recommended duration of treatment, and were therefore merged into a single group (11.3%), 1 group showed a declining adherence (13.2%) and 1 group had an optimal adherence (51.9%). The combination of CHI (yes/no) and ET profiles (no initiation, non-persistence, decline and optimal adherence) resulted in 8 groups of women. These groups presented differences in QoL scores 5 years after diagnosis. Regarding mental QoL, women treated with CHI and belonging to the declining ET group had significantly lower scores of mental QoL compared to the other groups of women.

Conclusions

To date, ET must be taken daily for 5 years, a number of studies have shown its effectiveness but also the benefit of continuing it for another 5 years. The impact of the different treatments on the QoL at a distance from the diagnosis seems to be important.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

monarchE demonstrated that adjuvant abemaciclib (oral CDK4 & 6 inhibitor)+endocrine therapy (ET) significantly improves invasive disease-free survival (IDFS) in HR+, HER2- high-risk early breast cancer (EBC) compared to ET alone. Here, we report the primary outcome (PO) efficacy and safety data in patients (pts) located in Asia (mainland China, Hong Kong, Japan, Korea, Singapore, and Taiwan), comprising 1,155 (20.5%) of the 5,637 pts of the intent-to-treat (ITT) population.

Methods

Pts with HR+, HER2-, high risk EBC were randomized 1:1 to abemaciclib+ET or ET alone and stratified by prior treatment (txt), menopausal status, and region (North America/Europe; Asia; Other). Exploratory analyses were conducted among pts enrolled from Asia, (median follow-up: ∼19 months in both arms).

Results

In total, 75 IDFS events were observed in pts from Asia (33 in abemaciclib+ET; 42 in ET alone). Abemaciclib+ET demonstrated numerical benefit in IDFS, reflecting a 22.3% reduction in the risk of developing invasive disease [HR (95% CI) = 0.777 (0.493, 1.227)]. Two-year IDFS rates were 93.2% in abemaciclib+ET and 90.1% in ET alone. There was also a numerical improvement in distant relapse free survival (DRFS) [HR (95% CI) = 0.758 (0.455, 1.264)], with 2-year DRFS rates of 94.4% vs 91.7%. The median txt duration of abemaciclib was 17.7 months. In the abemaciclib arm, the most frequent adverse event (AE) was diarrhea (89.5%), most were G1/2 (55.8%/28.7%). More G≥3 AEs and serious AEs were observed with abemaciclib+ET vs ET (53.5% vs 10.5% and 12.1% vs 6.3%), with neutropenia (31.5%) being the most frequent G≥3 AE. Interstitial lung disease occurred in 6.6% pts, G≥3 in 0.3% pts. G≥3 ALT and AST increases occurred in 4.2% and 3.1% pts, respectively.14.5% of abemaciclib-treated pts discontinued abemaciclib or all txt due to AEs.

Conclusions

In pts from Asia with HR+, HER2-, high-risk EBC, abemaciclib plus standard adjuvant ET led to a clinically meaningful improvement in IDFS and DRFS, consistent with benefits demonstrated in the ITT population. Safety was consistent with the known safety profile of abemaciclib. Abemaciclib is the first CDK4 & 6 inhibitor to demonstrate effective and tolerable txt in pts with high-risk EBC, including pts from Asia.

Clinical trial identification

NCT03155997.

Editorial acknowledgement

Eglantine Julle-Daniere.

Legal entity responsible for the study

Eli Lilly.

Funding

Eli Lilly.

Disclosure

Y-S. Yap: Advisory/Consultancy, Personal fees/non-financial support: Eli Lilly; Advisory/Consultancy, Personal fees/non-financial support: Novartis; Advisory/Consultancy, Personal fees/non-financial support: Pfizer; Advisory/Consultancy, Personal fees/non-financial support: AstraZeneca; Advisory/Consultancy, Personal fees/non-financial support: Eisai; Advisory/Consultancy, Personal fees/non-financial support: Roche; Advisory/Consultancy, Personal fees/non-financial support: MSD; Advisory/Consultancy, Personal fees: Inivata. S-B. Kim: Research grant/Funding (self): Novartis; Research grant/Funding (self): Sanofi-Aventis; Research grant/Funding (self): DongKook Pharm Co. Y. Sagara: Honoraria (self), Personal fees: Eli Lilly; Honoraria (self), Personal fees: Pfizer; Honoraria (self), Personal fees: AstraZeneca. S. Sherwood: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly. R.E. McNaughton: Full/Part-time employment: Eli Lilly. R.J. Wei: Shareholder/Stockholder/Stock options, Full/Part-time employment: Eli Lilly. M. Toi: Honoraria (self), Research grant/Funding (self): Chugai, Takeda, Pfizer, Taiho, Eisai, AstraZeneca, Eli Lilly, Shimadzu, Yakult; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Kyowa-Kirin; Research grant/Funding (self): JBCRG association; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Daiichi Sankyo; Honoraria (self): MSD; Honoraria (self): Exact Science; Honoraria (self): Novartis; Honoraria (self), Advisory/Consultancy, Honoraria for an advisory meeting: Konica Minolta; Research grant/Funding (self): Astellas; Honoraria (self), Advisory/Consultancy, Honoraria for an advisory meeting: BMS; Honoraria (self), Research grant/Funding (self), Research Fund and Honoraria for lecture: Nippon Kayaku; Research grant/Funding (self): AFI technologies; Advisory/Consultancy: Athenex Oncology, Bertis, Terumo, Kansai Medical Net; Advisory/Consultancy, Research grant/Funding (self): Luxonus; Research grant/Funding (self): Shionogi; Research grant/Funding (self): GL Science; Officer/Board of Directors, Board of directors: JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast Cancer Research Network. All other authors have declared no conflicts of interest.

Background

Data on the influence of socioeconomic status (SES) on the effectiveness of cancer-directed treatment in premenopausal breast cancer patients is scarce.

Methods

From the Danish Breast Cancer Group (DBCG) clinical database, we assembled a cohort of all premenopausal women who were diagnosed with non-metastatic breast cancer and prescribed docetaxel-based chemotherapy during 2007–2011. The DBCG provided information on ER and HER-2 status, tumor size and lymph node status (to derive stage), histological grade, cancer-directed treatment, and recurrence. Danish population-based registries provided data on comorbidities, death, and SES at diagnosis (marital status, education, income, and employment). Follow-up began 6 months after diagnosis (to approximate the end of chemotherapy) and continued to 10 years, recurrence, death, or 31 December 2016, whichever occurred first. We computed incidence rates (IRs) per 1,000 person-years (PYs) and cumulative incidence proportions of recurrence and death. We used Poisson regression to calculate incidence rate ratios (IRRs) and 95% confidence intervals of recurrence and death according to SES, adjusting for patient, tumor, and treatment characteristics.

Results

Our cohort included 2,616 women; 286 developed recurrent breast cancer (13%, IR:18/1,000 PYs, median follow-up: 6.7 years) and 223 died (11%, IR:13/1,000 PYs, median follow-up: 7.2 years). As expected, women with ER‒ or triple negative tumors, higher stage and grade had elevated risk of recurrence and death. We observed increased risk of recurrence and death in unmarried women, mainly those with ER+ tumors prescribed tamoxifen. Women with ER+ tumors and health-related work absenteeism before diagnosis had increased mortality compared with their employed counterparts. Increased mortality in women with low SES, captured as low income or elementary school education, was explained by tumor characteristics.

Conclusions

Established prognostic characteristics were associated with recurrence and mortality in premenopausal women treated with docetaxel. Yet, we found unfavorable prognosis among unmarried women and women with health-related absenteeism from work; this may be partly related to tamoxifen adherence.

Legal entity responsible for the study

The study was approved by the Danish Data Protection Agency (AU 2016-051-000001, #808), the Regional Ethics Committee (Record no. 1-10-72-4-18) and the DBCG, the Danish Breast Cancer Group (DBCG-2019-08-20).

Funding

The Danish Cancer Society (R167-A11045-17-S2).

Disclosure

All authors have declared no conflicts of interest.

Background

There is a scarcity of data exploring prognostic factors in young patients with breast cancer (BC), and the independent negative impact of age by itself is still debated. We aimed to assess shared and intrinsic prognostic factors in a large cohort of patients aged 35 years or younger, compared to a control group aged from 36 to 50.

Methods

Patients ≤50 years old were retrospectively identified from a large cohort of 23 134 early BC patients who underwent primary surgery in 18 academic centers between 1990 and 2014. Multivariate Cox analysis aiming to identify factors associated with disease-free and overall survival (DFS and OS) were built for the total cohort, and then for the ≤35 years cohort only. To further assess the independent impact of age on DFS and OS, 1 to 3 case control analysis was performed by matching ≤35 and 36 to 50 according to histology, grade, tumor size, lymphovascular invasion (LVI), nodal status, endocrine receptors (ER), endocrine therapy (ET) and chemotherapy (CT).

Results

On 6 481 patients included, 556 were aged ≤35 years, and 5 925 from 36 to 50. Compared to the 36-50 group, age ≤35 was significantly associated with larger tumors, higher grade, ER negativity, macroscopic lymph node involvement, LVI, and higher rates of mastectomy and chemotherapy use. In multivariate analysis, age ≤35 was associated with worse DFS (HR 1.59, 95% CI 1.35-1.88; p<0.001), and OS (HR 1.32, 95% CI 1.06-1.64; p=0.014), as were high grade, large tumor size, LVI, macroscopic lymph node involvement, ER negativity, and absence of ET or CT. Adverse prognostic impact of age ≤35 was maintained in the case control-matched analysis for DFS (HR 1.56, 95%CI 1.28-1.91, p<0.001), and OS (HR 1.33, 95%CI 1.02-1.73, p=0.032). When considering patients ≤35 for multivariate analysis, only ER, tumor size, lymph node involvement and LVI remained statistically significantly associated with OS and DFS.

Conclusions

An age ≤35 years is associated with less favorable features at BC diagnosis, and more aggressive treatment strategies. Our results support the poor prognosis value of young age, which independently persisted when adjusting for other prognostic factors and treatments, as well as in the control-matched analysis.

Legal entity responsible for the study

Institut Paoli-Calmettes.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Multigene signatures (MGS) select women with oestrogen receptor positive human epidermal growth factor receptor 2 negative (ER+/HER2-) breast cancer for whom adjuvant chemotherapy can be avoided. As MGS are expensive and require additional test material and time, models based on clinical-pathological features have been developed, mainly for OncotypeDX® but none exist for MammaPrint® (MP). We evaluated these models and the possibility of creating a new model for MP high/low genomic risk result.

Methods

This retrospective study, approved by the Ethics Committee of University Hospitals Leuven (S63323), included patients diagnosed at University Hospitals Leuven between 2013 and 2020 with primary operable ER+/HER2- lymph node negative or positive breast cancer. Tumour tissue of 143 patients was analysed by MP. Seven statistical models were computed: Magee equations (1, 2, 3 and average), Memorial Sloan Kettering simplified score, Breast Cancer Recurrence Score Estimator, OncotypeDXCalculator, MyMammaPrint.com, new Adjuvant! Online and PREDICT v2.1. The outcome of these models (N=10), clinical-pathological features (N=38) and the combination of both were tested as input for a new model. Patients were split (75/32/36) in train, test and validation sets. Feature selection was performed through an automated algorithm. Random forests (RF), support vector machines (SVM) and linear discriminant analysis (LDA) models were tested.

Results

The number of selected features and the accuracies of the machine learning models are shown in the table. The best performance was obtained with the combined feature set resulting in accuracies up to 75% with a sensitivity of 78% (14/18 true low risk) and a specificity of 72% (13/18 true high risk). These models had better MP risk prediction accuracies (75%) compared to the existing statistical models (<67%). Table: 51P

Number of selected features and accuracy of the models

Conclusions

Our predictive model, based on clinical-pathological features, can be used for patient selection for MP and therefore reduce cost, tumour tissue and time.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Slembrouck: Honoraria (self): Agendia. All other authors have declared no conflicts of interest.

Background

Approximately 50% of HER2-positive breast cancer lesions express hormone receptors. These tumors present a unique therapeutic challenge, and the optimal endocrine therapeutic approach remains controversial. We aimed to study the optimal adjuvant endocrine therapy in this setting in order to better establish the bases for clinical recommendations in HER2-positive disease.

Methods

We conducted a literature search up to May 2020 in which we identified randomized controlled trials (RCTs) that investigated the efficacy of various adjuvant hormonal therapies among premenopausal and postmenopausal patients with hormone receptor (HR)-positive HER2-positive early breast cancer. Disease-free survival (DFS) was calculated with the random effect model and hazard ratios (HRs) with 95% confidence intervals (CI).

Results

Six RCTs (n=5,390 patients) were included in the final analysis. There was no significant difference in DFS between adjuvant treatment with aromatase inhibitors and tamoxifen (HR 0.99, 95% CI 0.68-1.44, P=0.96). After omitting the ALTTO trial because it did not randomize patients to hormonal therapy, no significant difference was observed between the two protocols (HR 1.06, 95% CI 0.65-1.73, P=0.81).

Conclusions

Our study demonstrates similar DFS with tamoxifen and aromatase inhibitors as adjuvant endocrine treatment in HER2-positive HR-positive early breast cancer patients. Future larger prospective studies focusing on the various contemporary endocrine regimens are warranted to validate our findings.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Pegfilgrastim, a long-acting G-CSF, reduces the risk of chemotherapy-induced FN. Results from the previously reported multicenter, prospective, observational study demonstrated the utility of pegfilgrastim (Neulasta OBI®) in decreasing FN risk and improving adherence and compliance to G-CSF support in cancer patients treated with myelosuppressive chemotherapy. Results of a subgroup analysis in breast cancer patients are reported here.

Methods

Adult patients with breast cancer were stratified into curative or palliative intent groups and further categorized based on the first chemotherapy cycle into subgroups receiving Neulasta OBI® vs other physician choice options. Eligibility criteria for the main analysis included patients with breast, lung, NHL, or prostate cancer with a life expectancy of >6 months, at least 4 planned chemotherapy cycles administered once every 3 or 4 weeks with high (>20%) or intermediate (10%-20%) FN risk and ≥1 risk factor, and no radiation <2 weeks before enrollment. Primary endpoint is the incidence of FN and other endpoints include adherence, compliance and chemotherapy delivery. The subgroup analysis focused on these endpoints in the breast cancer patients exclusively.

Results

A total of 1,776 patients with breast cancer were eligible (OBI, 1,196; Other, 580). Baseline characteristics were generally well balanced across both groups. Across all cycles, incidence of FN was lower in OBI group (4.4%) than in Other group (7.4%). Adherence and compliance to pegfilgrastim was higher in the OBI group (93.8% CI: [92.45%–95.18%] / 90.5% CI: [88.80%–92.13%]) vs Other group (69.8% CI: [66.09%–73.56%] / 53.2% CI: [48.70%–57.80%]).

Conclusions

Breast cancer patients who received Neulasta OBI® showed a lower rate of FN compared with other physician choice options. These results could be achieved due to increased adherence and compliance to G-CSF support in the OBI group compared with other physician choice options.

Editorial acknowledgement

The authors received medical writing and editing support from Advait Joshi, PhD, of Cactus Life Sciences (part of Cactus Communications), which was supported by Amgen Inc.

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

R. Mahtani: Advisory/Consultancy: Amgen, Agendia, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Genentech, Eli Lilly, Novartis, and Puma; Research grant/Funding (self), contracted research: Genentech. G.H. Lyman: Advisory/Consultancy: Agendia, Amgen, Bristol-Myers Squibb, G1 Therapeutics, Genomic Health, Halozyme, Helsinn, Hexal, Partners HealthCare, and Pfizer; Research grant/Funding (self), contracted research: Amgen. R. Rifkin: Advisory/Consultancy: Amgen, Coherus, Mylan, and Pfizer; Research grant/Funding (self), contracted research: Amgen. D. Dale: Advisory/Consultancy: Amgen; Research grant/Funding (self), contracted research: Amgen. A. Brookhart: Advisory/Consultancy: Amgen, Merck, FibroGen, and RxAnte; Research grant/Funding (self), contracted research: Amgen and AbbVie; Shareholder/Stockholder/Stock options, ownership interest: NoviSci. S. Lewis, L. Decosta, T. Lawrence, R. Belani: Shareholder/Stockholder/Stock options, Full/Part-time employment: Amgen. J. Crawford: Advisory/Consultancy: Amgen, AstraZeneca, Coherus, Enzychem, Merck, and Pfizer; Research grant/Funding (self), contracted research: AstraZeneca, Genentech, and Helsinn; Officer/Board of Directors, Chair/DSMB member: BeyondSpring.

Background

The purpose is to conduct a systematic review and meta-analysis evaluating the impact of overweight on prognosis in triple-negative breast cancer (TNBC) patients.

Methods

Systematic searches were conducted in PubMed and Embase using variations of the search terms triple-negative breast neoplasms (population), overweight and/or obesity (exposure), and prognosis (outcome). Data were extracted from longitudinal observational studies, which used survival statistics with hazard ratios (HRs) to examine disease-free survival and/or overall survival according to body mass index measured at the time of diagnosis of TNBC. Overweight was defined using the World Health Organization guidelines. Guided by the Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist, study data were extracted and study quality assessed with the Newcastle-Ottawa Scale independently by two authors. The effect sizes (HRs) were combined with random-effects models, and the results were evaluated and adjusted for possible publication bias.

Results

The study selection process identified 11 eligible studies of 5,556 TNBC patients. The pooled estimates indicated that, relative to non-overweight, overweight was associated with both shorter disease-free survival (HR=1.33; 95%CI: 1.13–1.58) and shorter overall survival (HR=1.39; 95%CI: 1.15-1.69). Supplementary Bayesian meta-analyses showed strong evidence for non-zero effects, with the alternative hypothesis being 12.7 and 13.5 times more likely than the null-hypothesis for disease-free survival and overall survival, respectively.

Conclusions

Relative to non-overweight, overweight was associated with a shorter disease-free and overall survival among TNBC patients.

Legal entity responsible for the study

Aarhus University.

Funding

Slagtermester Max Wørzner og Hustru Wørzners Memorial Foundation, Health Research Foundation of Central Denmark Region, Aarhus University.

Disclosure

R. Zachariae: Honoraria (self), Shareholder/Stockholder/Stock options, None of this had any role in the design, data collection, analysis, or preparation of the manuscript: Novo Nordisk. S. Borgquist: Honoraria (self), Travel/Accommodation/Expenses, None of this had any role in the design, data collection, analysis, or preparation of the manuscript: Pfizer; Honoraria (self), Travel/Accommodation/Expenses, None of this had any role in the design, data collection, analysis, or preparation of the manuscript: Roche. All other authors have declared no conflicts of interest.

Background

Breast cancer ranks first in females, concerning cancer incidence and mortality. Breast cancer in premenopausal patients (vs. postmenopausal patients) has unique gene expression patterns, rendering molecular drivers of tumor progression in premenopausal women of particular clinical interest. Our research focused on premenopausal patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), early breast cancer (EBC), and the molecular drivers of distant metastases after standard adjuvant treatment.

Methods

We performed a retrospective, single-center, case-control study in premenopausal HR+/HER2- EBC patients treated at the LMU (Ludwig Maximilian University) breast center. We selected 48 patients who developed metastases before 2018 (the median distant metastasis-free survival was 54 months, range: 7-184 months) and 49 patients who did not (the median follow-up was 149 months, range: 121-191 months). All patients received surgery and endocrine therapy, 85.6% received radiotherapy, and 72.2% received chemotherapy. Total RNA of primary tumor FFPE specimens was extracted using the miRNeasy FFPE kit (Qiagen, Germany). Gene expression profiling was done using the NanoString nCounter® system (NanoString technology, USA) with Breast Cancer 360 panel (BC360®) which includes 776 genes across 48 biological signatures, and analyzed following the panel-specific processing protocol (BC360 data analysis).

Results

The bone was the most common site of distant metastases. Tumor size, histological grade, and stage influenced DMFS (distant metastasis-free survival). Claudin-low, mammary stemness, PGR (Progesterone Receptor) signatures were significantly downregulated in patients who developed metastases, and as expected, ROR (Risk of recurrence) was increased. These four signatures were also correlated to patients' DMFS. Besides, ten differentially expressed genes were identified.

Conclusions

Among the tested biological signatures, claudin-low, mammary stemness, PGR, and ROR impact on DMFS in premenopausal patients. Detailed analyses will be presented at the meeting.

Legal entity responsible for the study

The authors.

Funding

The first author receives scholarship from the China Scholarship Council.

Disclosure

H. Ni: Research grant/Funding (self), Scholarship: China Scholarship Council. J. Kumbrink: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: QUIP; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche Pharma. R. Wuerstlein: Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Agendia, Onkowissen; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Amgen, Paxman; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Aristo, Palleos; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Aristo Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Carl Zeiss, Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Celgene, Puma Biotechnology; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Clinsol, Riemser; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Daiichi Sankyo, Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eisai, Sandoz/Hexal; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Genomic Health; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Glaxo Smith Kline; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Hexal, Seattle Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Lilly, Tesaro Bio; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Medstrom Medical, Teva; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Mundipharma; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: NanoString; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Odonate. N. Harbeck: Honoraria (self), Advisory/Consultancy: Agendia; Honoraria (self), Advisory/Consultancy: Genomic Health. T.K. Eggersmann: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Aristo Pharma. All other authors have declared no conflicts of interest.

Background

Symptomatic breast cancers share aggressive clinico-pathological characteristics compared to screen-detected breast cancers. The decision to administer adjuvant chemotherapy for early hormone receptor positive (HR+) HER-2 negative (HER2-) breast cancer patients, is guided by both the genomic and the clinical risk of disease recurrence. We assessed the association between the method of cancer detection and genomic and clinical risk, and its effect on adjuvant chemotherapy recommendation.

Methods

Patients with early HR+ HER2- breast cancer, and known OncotypeDX Breast Recurrence Score (RS) test were included. A natural language processing (NLP) algorithm was used to identify the method of cancer detection. The clinical and genomic risks of symptomatic and screen-detected tumors were compared.

Results

The NLP algorithm identified the method of detection of 401 patients, with 216 (54%) diagnosed by routine screening, and the remainder secondary to symptoms. The distribution of OncotypeDX RS varied between the groups. In the symptomatic group there were lower proportions of low RS (13 vs 23%) and higher proportions of high RS (24 vs. 13%) compared to the screen-detected group (p=.03). Symptomatic tumors were significantly more likely to have a high clinical risk (59 vs 40%; p<.0001). Based on genomic and clinical risk and current guidelines, we found that women aged 50 and under, with symptomatic cancer, had an increased probability of receiving adjuvant chemotherapy recommendation compared to women with screen-detected cancers (57 vs. 35%; p=.03).

Conclusions

We demonstrated an association between the method of cancer detection and both genomic and clinical risk. Symptomatic breast cancer, especially in young women, remains a poor prognostic factor that should be taken into account when evaluating patient prognosis and determining adjuvant treatment plans.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

I. Wolf: Speaker Bureau/Expert testimony, Research grant/Funding (self): BMS; Speaker Bureau/Expert testimony, Research grant/Funding (self): MSD; Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Speaker Bureau/Expert testimony, Research grant/Funding (self): Novartis. A. Sonnenblick: Advisory/Consultancy: Eli lilly; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Teva; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Medison; Speaker Bureau/Expert testimony: Roche; Research grant/Funding (self): Novartis; Research grant/Funding (self): Roche. All other authors have declared no conflicts of interest.

Background

Oncotype DX (ODX) assay identifies specific subset of patients with hormone-receptor (HR)-positive breast cancer (BC) who would benefit the most from adjuvant chemotherapy (CT). This study aimed to examine inter-agreement among several medical oncologists, as well as each oncologist intra-agreement on adjuvant CT decisions before and after Oncotype DX.

Methods

The data of 145 patients with HR-positive, HER2 negative BC were reviewed in retrospect. Traditional histopathological information with and without ODX RS was sent to 16 oncologists. The inter and intra-observer agreement among oncologists on prescribing adjuvant CT before and after ODX RS result were assessed. The result of ODX RS was interpreted as continuous variable and as per-risk level; low (0-17), intermediate (18-30) and high risk (≥ 31) groups. A P-value of < 0.05 was considered significant.

Results

The mean age at diagnosis ± SD was 51.9 ± 9.4 years. 76 patients (52.4%) were postmenopausal. The mean ODX RS was 17.8 ± 8.6 where 54.5% was low, 37.9% was intermediate and only 7.6% was high, respectively. Grade 2 (53.1%) and T(1) (49%) BC accounted for the majority. Positive (1-3) lymph nodes reported in one-third. The agreement among oncologists improved with the addition of ODX result from fair to moderate (kappa = 0.52; p <0.001). The addition of ODx RS result avoided CT in 20.4% and identified 9.1% as candidates for adjuvant CT (Kappa = 0.38; p <0.001). On average, an oncologist’s decision of prescribing adjuvant CT pre and post ODx had an agreement in 70.6% of the cases. The table shows agreement and disagreement between pre & post-ODX decision. Table: 57P

Agreement and disagreement between pre & post-Oncotype decision when RS is sub-categorized

Conclusions

We conclude that Oncotype DX RS boosted the level of agreement among oncologists and led to a decrease in the use of adjuvant chemotherapy compared to the pre-Oncotype DX recommendations.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Patients with residual invasive HER2-positive early breast cancer after completion of neoadjuvant therapy have a high risk of recurrence or death despite of receiving standard treatment of Trastuzumab. Trastuzumab emtansine (T-DM1), which act as a breakthrough therapy, has been proved to reduce 50% incidence of recurrence or death compared with Trastuzumab alone. This study was aimed to estimate cost-effectiveness of T-DM1 vs. trastuzumab as the adjuvant treatment in China.

Methods

A validated 6-state Markov model with monthly cycle was constructed to estimate the lifetime incremental cost-effectiveness ratio (ICER). Main clinical input was the time spent in invasive disease-free survival state, estimated by parametric extrapolations to survival data observed in the clinical trial Katherine. Utilities were calculated from EQ-5D of patients in Katherine and the published literatures. The costs obtained both from real world data and local published resources including drugs, administration, adverse events management, follow-up and therapeutic costs. Furthermore, indirect costs were included when analyzed from the society perspective. Costs and outcomes were both discounted at 5%. Sensitivity analysis were conducted to verify the robustness of the results.

Results

T-DM1 provided 1.49 more QALYs with additional costs than trastuzumab. From healthcare system perspective, the ICER was CNY 112,004/QALY. Further 39% lower indirect costs in T-DM1 group resulting an ICER of CNY 98,757/QALY from the society perspective. Both ICERs were between 1∼2 times GDP per capita, far below the local threshold of 3 times GDP per capita in 2019 (CNY 212,676). Acquisition cost of T-DM1 is partially offset by the prevention of disease recurrences over the time. Cost for managing recurrences in T-DM1 group was 44% lower than that in trastuzumab group. Probabilistic sensitivity analysis showed that T-DM1 was more cost-effective in more than 95% simulations at local threshold regardless of the perspective.

Conclusions

Compared to trastuzumab, T-DM1 is more cost-effective as the adjuvant treatment for patients with residual invasive HER2-positive early breast cancer in China.

Legal entity responsible for the study

The authors.

Funding

Shanghai Roche Pharmaceuticals Ltd.

Disclosure

C. Liu, Q. Yang: Full/Part-time employment: Shanghai Roche Pharmaceuticals Ltd. All other authors have declared no conflicts of interest.

Background

Adjuvant trastuzumab (TZM) improves outcomes of women with ≥T1c or node-positive HER2+ early-stage BC yet phase III trials are lacking in women with T1a/bN0 disease. Our study aims to assess outcomes of women with HER2+ T1a/bN0 BC who received adjuvant TZM in a Canadian province.

Methods

Women with HER2+ T1a/bN0 BC diagnosed during 2008-2017 in Saskatchewan were evaluated. Cox proportion multivariate analysis was performed to determine factors correlated with survival.

Results

91 eligible women with median age of 61 yrs (30-89) were identified. 47% had lumpectomy, 57% received adjuvant radiation and 58% received adjuvant endocrine therapy. 39 (43%) women received adjuvant TZM and 57% were in the control group. Women in the TZM group were significantly younger (57 vs. 65 yrs, p=0.02) and had a higher rate of T1b disease (92 vs. 40%, p<0.0001). All women in TZM group received chemotherapy vs. 1 woman in the control. 8% women developed recurrent breast cancer (3% in TZM vs. 12% in control, p=0.23). Median disease-free survival (DFS) was not reached. 5-year DFS was 94.8% in TZM group vs. 82.7 % in the control, p=0.22. 5-year invasive breast cancer-freesurvival was 97.4% in TZM vs. 94.2% in control, p=0.29. Median OS of control was 10.6 yrs and was not reached in the TZM group. 5-year survival was 100% in TZM group vs. 90.4% in the control (p=0.038). On multivariate analysis grade III tumor was significantly correlated with DFS (Hazard ratio [HR], 5.5, 95%CI: 0.92-9.5, p=0.004). Lack of adjuvant TZM (HR, 3.0, 95%CI: 0.92-9.5) did not correlate with DFS.

Conclusions

Overall outcomes of women with HER2+ T1a/bN0 BC is good. Women who received adjuvant TZM had numerically better DFS and a significantly better overall survival. High-grade tumor was correlated with inferior disease-free survival.

Legal entity responsible for the study

Shahid Ahmed.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Oncotype DX® is a 21-gene assay to guide adjuvant treatment decisions in HR+, HER2- early stage breast cancer. The aim of the study was to evaluate the impact of Recurrence Score® (RS) on decision-making (% change in treatment recommendation), to assess real-life utilization of Oncotype DX test in node-negative, micrometastases, and 1-3 positive lymph nodes patients.

Methods

Data from 630 patients (N0=401, N1=229) from 9 Institutions in the autonomous community of Galicia between May 2013 and Oct 2018 were collected and retrospectively analyzed in accordance with the study objectives. The majority of these data were collected prior to the publication of TAILORx and/or RxPONDER.

Results

Median age: 56 y; 77% of patients were > 50 years; 31% of patients were premenopausal, 50% postmenopausal, and 19% perimenopausal. Tumor size : pT1a-b 21%, pT1c 59%, pT2 19%, pT3 1%; Grade: G1 23%, G2 68%, G3 9%; Ki 67 <10% 20,7%, 10%-20% 39,2%, >20% 40,1%; Luminal subtype (based on Ki 67 and PR status): luminal A 75% and luminal B 25%. Nodal status: N1: 35.7% and N0: 64.3% Recurrence Score results distribution in N+ population was: RS <17: 63%, RS 17-31: 34.5%, and RS >31: 2.5%), and in N0 population: RS ≤ 25: 82.5% and RS >25: 17.4%. Changes in treatment decision are reported in the table. Table: 60P

Conclusions

Based on RS results, a major change in therapeutic decision occurs in patients diagnosed with breast cancer, and chemotherapy recommendations changed in a substantial proportion of patients. In N0 patients, following the outcome of RS results, the indication of chemotherapy was decreased by 25%. In N1 patients, the chemotherapy indication is dramatically reduced by 63%. Our results confirmed in real clinical life the utility of the Oncotype DX assay to guide chemotherapy treatment decisions, and provided additional support for its use both in N0 and N1 patients based on TAILORx and RxPONDER studies.

Legal entity responsible for the study

The authors.

Funding

Genomic Health International.

Disclosure

I. Fernandez-Perez: Speaker Bureau/Expert testimony: Genomic Health; Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: AstraZeneka; Advisory/Consultancy: GSK. L. De Paz Arias: Advisory/Consultancy, Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Novartis. L. Vazquez Tuñas: Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Clovis; Speaker Bureau/Expert testimony: PharmaMar; Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy: GSK; Advisory/Consultancy: Leo Pharma. S. Varela Ferreiro: Advisory/Consultancy, Speaker Bureau/Expert testimony: GSK; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: PharmaMar; Speaker Bureau/Expert testimony: Pfizer. A.Q. Gonzalez Quintas: Speaker Bureau/Expert testimony: Pfizer. J.F. Cueva Banuelos: Advisory/Consultancy: Clovis; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: PharmaMar; Speaker Bureau/Expert testimony: Palex; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self): Roche; Speaker Bureau/Expert testimony: GSK; Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Lilly; Speaker Bureau/Expert testimony: Eisai; Speaker Bureau/Expert testimony: Celgene; Speaker Bureau/Expert testimony: Pierre Fabre. C. Hagen: Full/Part-time employment, Officer/Board of Directors: Genomic Health. L. Inglada-Pérez: Full/Part-time employment: Genomic Health. L. Iglesias Rey: Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Merck; Advisory/Consultancy: Leo Pharma; Speaker Bureau/Expert testimony: Rovi. All other authors have declared no conflicts of interest.

Background

Multigene assays (MGAs) can reduce over and under-treatment with adjuvant chemotherapy in oestrogen receptor positive (ER+), human epidermal growth factor 2 negative (HER2-) early breast cancer. The cost of treatment of early breast cancer and distant recurrence of breast cancer are important parameters in the economic evaluation of MGAs. The recent approval of new treatments in the UK, such as CDK4/6 inhibitors, is likely to increase the cost of management of breast cancer. This study aimed to estimate the cost of adjuvant chemotherapy in early breast cancer and the cost of treating distant recurrence in the UK using expert opinion and published sources.

Methods

A survey of breast cancer specialists in the UK was conducted to identify the distribution of adjuvant drug treatments used in early breast cancer and distant recurrence of breast cancer. The weighted average of clinician questionnaire responses was combined with estimates of length of treatment and drug unit costs from published studies to estimate the weighted mean cost by type of treatment and setting. The analysis was conducted from a UK healthcare cost perspective and included drug list prices, cost of administration and supportive treatments.

Results

The weighted average 6-monthly cost of treatment in early breast cancer and distant recurrence (in 2020 Pound Sterling) is reported in the table. Table: 61P

Summary of cost estimates by treatment

Conclusions

Adjuvant chemotherapy represents a substantial use of scarce healthcare resources in the UK and differs by nodal status. The cost of distant recurrence may be considerably higher than estimates reported in previous studies, which was partly driven by the use of effective, but costly new treatments. The use of the Oncotype DX® Breast Recurrence Score test to guide chemotherapy is likely to result in cost savings by avoiding over-treatment with chemotherapy and avoiding distant recurrence through targeted treatment of patients with a high genomic risk score.

Legal entity responsible for the study

The authors.

Funding

Exact Sciences.

Disclosure

V. Berdunov, J. Griffin: Research grant/Funding (institution): Exact Sciences. S. Millen, A. Paramore, S. Reynia, N. Fryer, N. Georges: Full/Part-time employment: Exact Sciences.

Background

One of the greatest challenges in the treatment of breast cancer (BC) is the correct detection of those patients with early-stage (ES) Luminal BC who do not require treatment with adjuvant chemotherapy (CT). The use of genomic platforms shows a prognostic / predictive value, and information on the intrinsic subtype of BC. This is a fundamental tool for the identification of these patients. The objective of this study is to assess the influence that the use of the Prosigna^â/PAM50 genomic platform has on therapeutic decisions in patients with ES Luminal BC.

Methods

A prospective study of 143 patients diagnosed with ES BC was carried out at the University Hospital of Salamanca between 2015 and 2020. All tumour samples were analysed with PAM50 / Prosigna^â (NanoString Technologies, Seattle, WA, USA). Statistical analysis was performed using EZR (Easy R) v1.5 software.

Results

The median age was 54 years [32–74]. Using immunohistochemistry (IHC), 64 tumours (44.8%) were classified as Luminal A-like and 79 (55.2%) as Luminal B-like. After reclassifying the tumours using PAM50, a total of 91 (63.6%) tumours were reclassified as Luminal A, and 52 (36.7%) were deemed Luminal B. A resulting change in post-test therapeutic decisions occurred in 41 patients (29%). Of the 97 patients with a pre-test decision of only adjuvant hormonal therapy (HT), 27 of them (28%) decided to add CT. Of the 46 patients with a pre-test decision of CT + HT, 14 (30%) received only HT after the test results. In 28% of the patients, the decision change was from HT to CT + HT. The change from CT + HT to HT alone occurred in 39% of the cases. With a median follow-up of 32 months, there have been no relapses to date, after making the decision using PAM50.

Conclusions

Despite the small sample size of our series, we have confirmed the great importance of the performance of a gene expression profile in clinical practice, as it directly impacts decisions concerning the adjuvant treatment of Luminal BC. PAM50 also made it possible to reclassify the intrinsic subtype in a significant proportion of patients. As no relapse has occurred in the included patients, this tool should be used in the selection of the most appropriate treatment for these patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Mammographic density (MD) has been strongly associated with increased risk of breast cancer (BC). In view of this, we aimed to investigate the predictive value of MD in a large consecutive cohort of BC patients (pts) treated with neoadjuvant chemotherapy (NAC).

Methods

Data on NAC treated pts prospectively collected in the registry of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (May 2009-Aprill 2020) were identified. Diagnostic mammograms were used to evaluate MD, which was categorized by the Breast Imaging-Reporting and Data System (BI-RADS). BI-RADS identify 4 categories of MD in keeping with the masking effect of fibroglandular tissue, as following: A (almost entirely fat), B (scattered areas of fibroglandular density), C (heterogeneously dense), and D (extremely dense). Multivariable logistic regression was used to assess the odds ratios (OR) for pathological complete response (pCR), ie absence of invasive tumor in breast and node surgical specimens, comparing BI-RADS categories with adjustment for patient age, BMI, and tumor characteristics.

Results

A total of 442 pts were analyzed, of which 120 (27.1%) attained a pCR. BI-RADS categories A, B, C, and D accounted for 10.0%, 37.8%, 37.1% and 15.2% of cases, respectively, with corresponding pCR rates of 20.5%, 26.9%, 30.5%, 23.9%. At multivariable analysis cases classified as BI-RADS C showed an increased likelihood of pCR as compared to A (odds ratio [OR]=2.79), B (OR=1.70), and D (OR=1.47) independently of age, BMI (OR underweight vs normal=3.76), clinical N and T (OR T1/Tx vs T4=3.87), molecular subtype (HER2 vs luminal=10.74; triple negative vs luminal=8.19). In subgroup analyses, the strongest association of MD with pCR was observed in triple negative (ORs of B, C and D versus A: 1.85, 2.49 and 1.55, respectively) and HER2 positive cases (ORs 2.70, 3.23, and 1.16). Notably, no significant differential effect of MD with respect to pCR was observed in luminal BC (ORs of B, C and D versus A: 0.88, 2.01 and 1.58).

Conclusions

Patients with dense breast are more likely to attain a pCR after NAC at net of other current clinical and pathological predictive factors. The potential of MD to assist decisions on BC management and as a stratification factor in neoadjuvant clinical trials should be considered.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Sentinel lymph node biopsy has gained attention due to its potential for less invasive management of the axilla and the increasing number of early-stage breast cancer patients treated with neoadjuvant systemic therapy prior to surgery. One-Step Nucleic Acid Amplification (OSNA) assay is an accurate and reliable option for intraoperative molecular analysis of SLN status. NEOVATTL study demonstrates its predictive and prognostic value for non-SLN involvement and disease recurrence in breast cancer patients who had received NST. Therefore, the aim of the study was to show the follow-up of those patients that were recruited in NEOVATTL study and to corroborate the favorable prognosis of the patients with low axillary tumour load.

Methods

This is a multicentric and retrospective study in which the patients underwent intraoperative SLN biopsy after NST. The data was obtained from a Spanish Sentinel Lymph Node database. TTL was defined as the total sum of CK19 mRNA copies in all positive SLNs.

Results

A total of 314 patients were included; 75.0% were cN0 prior to NST. 91.7% received chemotherapy with or without biologic therapy, and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement at a cut-off of 15,000 copies/μL had a negative predictive value of 90.5%. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/μL.

Conclusions

TTL >15,000 mRNA copies/μL was predictive of non-SLN involvement and TTL >25,000 mRNA copies/μL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST. Follow up between five to ten years have demonstrated a favourable prognosis of patients with low TTL (<15,000mRNA).

Legal entity responsible for the study

Sociedad Española de Senología y Patología Mamaria (SESPM).

Funding

Sysmex España S.L.

Disclosure

All authors have declared no conflicts of interest.

Background

Several trials confirmed a survival benefit from temporary menopause during or after chemotherapy (CT) for patients with estrogen receptor-negative early BC. We investigated the impact of menopause on TNBC outcome after neoadjuvant CT (NACT).

Methods

GeparSixto evaluated the addition of carboplatin to anthracycline-taxane-based NACT. We aimed to determine the impact of menopausal status on continuous Ki-67 and TILs from baseline biopsies in all patients, and according to germline (g)BRCA1 status. TILs and gBRCA status were centrally assessed. Secondary objectives were the impact of age (≤40 vs >40 years) on baseline Ki-67 and TILs in all patients and according to gBRCA1 status, baseline menopausal status and age on pathological complete response (pCR, ypT0 ypN0), disease-free survival (DFS) and distant disease-free survival (DDFS) according to pCR.

Results

43/315 included patients had a gBRCA1 mutation (14.8%); mean Ki-67 was higher in ≤40 compared to >40 years (63.9 vs 57.9%, p=0.045) and in pre- compared to postmenopausal patients (63.1 vs 53.9%, t-test p=0.001). Mean TILs did not differ according to age (38.4 vs 33.5%, p=0.126) or menopausal status (35.9 vs 33.0%, p=0.311). There was no difference in Ki-67 or TILs according to age and menopausal status in gBRCA1 carriers. pCR rate was higher in women ≤40 years (55.4 vs 44.4%) and premenopausal (50.5 vs 36.6%). For multivariate analysis for DFS refer to the below table. Neither young age nor premenopausal status at baseline predicted for DFS. In non-pCR patients, premenopausal status at baseline but not age ≤40 years was associated with a higher relapse risk (Table). Similar results were obtained for DDFS. Table: 66P

Conclusions

In patients with early TNBC, premenopausal compared to postmenopausal status is associated with a higher cancer cell proliferation at baseline and a higher risk of relapse in case of no pCR.

Legal entity responsible for the study

GBG.

Funding

Has not received any funding.

Disclosure

S.I. Labidi-Galy: Honoraria (self): AstraZeneca; Honoraria (institution): Novimmune. A. Schneeweiss: Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses, Research Grant, Travel expenses, Medical writing grant: Celgene; Honoraria (self), Honoraria (institution), Travel/Accommodation/Expenses, Expert testimony, Research Grant, Travel expenses: Roche; Honoraria (institution), Research Grant: AbbVie; Honoraria (self), Expert testimony, Honoraria: AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses, Honoraria, Travel expenses: Pfizer; Honoraria (self), Honoraria: Novartis; Honoraria (self), Honoraria: MSD; Honoraria (self), Honoraria: Tesaro; Honoraria (self), Honoraria: Lilly. J-U. Blohmer: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Honoraria (institution): Sysmex; Honoraria (self): Roche; Honoraria (self): Pierre Fabre. J. Huober: Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Celgene; Honoraria (self): Roche; Travel/Accommodation/Expenses: Daiichi; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer; Honoraria (institution): Novartis; Honoraria (institution): Hexal. T. Link: Honoraria (self): Teva; Honoraria (self): Tesaro; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Amgen; Honoraria (self): Clovis; Honoraria (self): Celgene; Honoraria (self): Lilly; Honoraria (self): Myriad. C. Hanusch: Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Lilly. C. Jackisch: Honoraria (self): Celgene. P.A. Fasching: Honoraria (self): Novartis; Honoraria (institution): Biontech; Honoraria (self): Pfizer; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Eisai; Honoraria (self): Merck Sharp & Dohme; Honoraria (institution): Cepheid; Honoraria (self): Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Seattle Genetics; Honoraria (self): Roche; Honoraria (self): Hexal. K.E. Rhiem: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): MSD. C. Denkert: Honoraria (institution), Oncobiome project: European Commission H2020; Honoraria (institution), INTEGRATE-TN project: German Cancer Aid Translational Oncology; Honoraria (self): Novartis; Honoraria (self): Roche; Honoraria (self): MSD Oncology; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): Molecular Health; Honoraria (institution): Myriad; Honoraria (self): Merck; Shareholder/Stockholder/Stock options, Cofounder/shareholder until 2016: Sividon diagnostics; Licensing/Royalties: VMScope digital pathology software; Licensing/Royalties: WO2020109570A1 - cancer immunotherapy; Licensing/Royalties: WO2015114146A1 and WO2010076322A1- therapy response. M. Untch: Honoraria (institution), All fees to the institution/employer: AbbVie; Honoraria (institution), All fees to the institution/employer: Amgen GmbH; Honoraria (institution), All fees to the institution/employer: AstraZeneca; Honoraria (institution), All fees to the institution/employer: BMS; Honoraria (institution), All fees to the institution/employer: Celgene GmbH; Honoraria (institution), All fees to the institution/employer: Daiichi Sankyo; Honoraria (institution), All fees to the institution/employer: Eisai GmbH; Honoraria (institution), All fees to the institution/employer: Lilly Deutschland; Honoraria (institution), All fees to the institution/employer: Lilly Int.; Honoraria (institution), All fees to the institution/employer: MSD Merck; Honoraria (institution), All fees to the institution/employer: Mundipharma; Honoraria (institution), All fees to the institution/employer: Myriad Genetics; Honoraria (institution): Odonate; Honoraria (institution), All fees to the institution/employer: Pfizer GmbH; Honoraria (institution): PUMA Biotechnology; Honoraria (institution), All fees to the institution/employer: Roche Pharma AG; Honoraria (institution), All fees to the institution/employer: Sanofi Aventis Deutschland GmbH; Honoraria (institution), All fees to the institution/employer: TEVA Pharmaceuticals Ind Ltd.; Honoraria (institution), All fees to the institution/employer: Novartis; Honoraria (institution), All fees to the institution/employer: Pierre Fabre, Clovis Oncology, Seatlle Genetics. S. Loibl: Honoraria (institution), honorario for lectures and ad boards paid to institute: AbbVie; Honoraria (institution), honorario for lectures and ad boards paid to institute: Celgene; Honoraria (institution), honorarium for lectures paid to institute: PriME/Medscape; Honoraria (self), lecture: Chugai; Honoraria (self), Honoraria (institution), honorario paid to institute: Daiichi Sankyo; Honoraria (institution), honorarium for ad boards paid to institute: Lilly; Honoraria (institution), advisor honorarium paid to institute: BMS; Honoraria (institution), advisor honorarium paid to institute: Puma; Honoraria (institution), paid to institute: Immunomedics; Honoraria (institution), honorarium for lectures and ad boards paid to institute: AstraZeneca; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Pierre Fabre; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Merck; Honoraria (institution), advisor honorarium paid to institute: EirGenix; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Amgen; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Novartis; Honoraria (institution), honorarium for lectures and ad boards paid to institute: Pfizer; Honoraria (institution), grant and honorarium paid to institute: Roche; Honoraria (institution), paid to institute: Seagen; Licensing/Royalties, Immunsignature in TNBC: EP14153692.0. All other authors have declared no conflicts of interest.

Background

It is controversial to perform sentinel lymph node biopsy (SNB) after neoadjuvant chemotherapy (NAC) in breast cancer (BC) due to the high false negativity rates (FNR). ¹⁸F-fluorodeoxyglucose positron emission tomography/computerized tomography (FDG-PET/CT) has been previously studied in the evaluation of response after NAC. In our study, we evaluated the diagnostic value of FDG-PET/CT for predicting ypT0 and ypN0 separately. Thus, we aimed to evaluate whether it is possible to omit SNB with prediction of pathological response by FDG-PET/CT in BC.

Methods

We evaluated 85 consecutive patients with operated BC after NAC. The maximum standardized uptake value (SUVmax) on FDG-PET/CT after NAC at both primary tumor (postSUVmax-T) and axillary lymph nodes (postSUVmax-N) were assessed to predict the ypT0 and the ypN0, respectively.

Results

We detected clinically meaningful correlation between postSUVmax-N with ypN0 in patients with human epidermal receptor-positive (Her2+) and triple-negative (TN) BC (in Her2+ BC: r=0.596, p < 0.001, in TN BC: r=0.782, p = 0.001). The postSUVmax-N predicted ypN0 with 90.5% positive predictive value (PPV) and 85.7% negative predictive value (NPV) in patients with Her2+ and TN BC. The postSUVmax-T predicted ypT0 with 87.5% positive predictive value (PPV) and 100% NPV in patients with TN BC (AUC: 0.938, P <0.01).

Conclusions

According to our study's findings, FDG-PET/CT may be an alternative to SNB to protect patients from axillary lymph node dissection when the expected FNR of the SNB is high in patients with Her+ and TN BC.

Legal entity responsible for the study

Eda Tanrikulu Simsek.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities in multiple malignances. However, the efficacy of ICIs against breast cancer remains unclear. This meta-analysis was conducted to evaluate the efficacy and safety profile of adding ICIs to neoadjuvant chemotherapy against triple-negative breast cancer (TNBC).

Methods

Eligible studies were retrieved from the PubMed, Embase, and Web of Science databases. Randomized controlled trials (RCTs) that investigated ICI-containing versus ICI-free neoadjuvant therapy were included in this study. Meta-analyses were performed using Review Manager Version 5.2 software with a random-effects model.

Results

This study included four RCTs containing 1795 patients with early TNBC. Compared with ICI-free neoadjuvant therapy, ICI-containing neoadjuvant therapy significantly increased the pathological complete response (pCR) rate in TNBC (odds ratio [OR] = 2.14, 95% confidence interval [CI]: 1.37–3.35, P < 0.001). In subgroup analysis, the addition of ICI to neoadjuvant chemotherapy was significantly associated with increased pCR rate in both PD-L1-positive TNBC (OR = 1.79, 95% CI: 1.33–2.41, P < 0.001) and PD-L1-negative TNBC (OR = 1.84, 95% CI: 1.14–2.99, P = 0.01). Patients with TNBC receiving ICI-containing neoadjuvant therapy had a better event-free survival (hazard ratio = 0.66, 95% CI: 0.48–0.89, P = 0.007) than those who receiving ICI-free neoadjuvant therapy. A significantly higher risk of adverse events including adrenal insufficiency, aspartate aminotransferase increased, dry skin, hepatitis, hyperthyroidism, hypothyroidism, infusion related reaction, pyrexia, and stomatitis was observed with ICI-containing neoadjuvant therapy.

Conclusions

ICI-containing neoadjuvant therapy significantly increased the pCR rate in TNBC patients, independently of PD-L1 status. The addition of ICI to neoadjuvant chemotherapy may be considered an option for TNBC patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

One of the key potential benefits of NAC is to sterilise the axilla of patients who present with axillary stage positive disease. In certain patients, this allows axillary conservation as opposed to an axillary clearance (ANC). This unit’s standard practice was to offer TAD to patients with node positive disease with favourable biology following NAC if a radiological response had been seen. This prospective study considers the impact of this approach to the management of these patients in a real-world setting.

Methods

Prospective data collection from a large breast screening institution of all patients undergoing NAC with axillary node positive disease (1-2 nodes or 3+ nodes) from May 2014 to January 2021. Axillary pCR is defined as no tumour cells seen in nodes.

Results

A total 99 patients, with node positive disease, were treated with NAC in this time-period. The overall axillary pCR rate in the population was 49.5%. In patients with 1-2 nodes, the pCR rate was 56.3% compared with 43.1% in a higher axillary burden; breakdown of these figures as stratified by hormone receptor status is illustrated in the table. TAD was performed successfully in 70.4% patients with 1-2 nodes without the need for an ANC. Of the 22 patients who had 3+ nodes at presentation with a pCR, 72.7% (16) underwent an ANC who may have avoided this if they had been considered for a TAD. Table: 69P

pCR rate stratified by axillary burden and hormone receptor status

Conclusions

Pathological response rates in this study are relatively consistent with those published in recent major trials. Evolution of the practice in this unit now includes offering patients presenting with 3+ nodes, favourable biology and a radiological response, a TAD rather than a potentially unnecessary ANC following appropriate counselling.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Verrill: Honoraria (self), Research grant/Funding (self): Roche; Honoraria (self), Research grant/Funding (self): Pfizer; Honoraria (self), Research grant/Funding (self): Novartis; Research grant/Funding (self): Amgen; Honoraria (self): Lilly; Honoraria (self): Exact Science. N. Cresti: Advisory/Consultancy, Research grant/Funding (institution): Roche. H. Cain: Advisory/Consultancy: Roche; Advisory/Consultancy: AZ; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Exact Science. All other authors have declared no conflicts of interest.

Background

A considerable shift from adjuvant chemotherapy (ACT) to neoadjuvant chemotherapy (NACT) has been observed in the last 2 decades. Once equivalence in survival was confirmed, NACT became a standard treatment option for operable and locally advanced disease. The aim of our study was to demonstrate that prognosis of patients treated with NACT has progressively improved in a single institution over the last twenty years.

Methods

Data were extracted from the prospectively collected Oncology Unit Database. We reviewed patients with biopsy-proven, stage I to III breast cancer, who were diagnosed between February 1997 and June 2019 and treated with neoadjuvant chemotherapy at the University General Hospital of Alicante, Spain. Four period cohorts were assigned: cohort 1 (C1) 1997-2004, cohort 2 (C2) 2005-2009, cohort 3 (C3) 2010-2014 and cohort 4 (C4) 2015-2019. The Kaplan-Meier actuarial method was employed for survival estimations, and the log-rank test for comparison among curves. Values of P <0.05 were considered statistically significant.

Results

We identified 563 eligible patients. Median follow-up time for the entire cohort was 5.51 years. Median follow-up times for each cohort were 10.03, 10.70, 6.27 and 3.36 years in C1, C2, C3 and C4, respectively. Significant differences in survival between cohorts were observed, for Invasive disease-free survival (IDFS) (χ²=27.539; p≤0.001) and distant disease-free survival (DDFS) (χ²=19.028; p≤0.001). Cox regression analysis showed lower HR events for IDFS and DDFS in C4 than C3, C2 and C1 respectively. Table: 70P

Conclusions

We demonstrate that prognosis of patients treated with NACT in our institution has improved over the last two decades. This is not only due to new therapies, but also to the learning curve in the selection of patients who can benefit the most from NACT. This improvement is the result of adequate patient management by the multidisciplinary breast cancer committee.

Legal entity responsible for the study

University General Hospital of Alicante.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

High BMI is generally considered a poor prognostic factor in BC. However, its association with pCR and survival after NAC is still controversial. The aim of this study was to evaluate the prognostic impact of BMI on clinical outcomes in BC patients undergoing NAC.

Methods

Retrospective review of 314 patients with BC who received NAC from 2010 to 2018 at the Department of Medical Oncology, Hospital Universitario de Gran Canaria Dr Negrin (Spain). Patients were categorized as underweight/normal weight (UW/NW) (BMI<25) or overweight/obese (OW/OB) (BMI>=25). Logistic regression analysis was used to evaluate the associations between BMI, classic clinical-pathological prognostic factors and pCR (defined as ypT0/Tis ypN0). Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and associations with prognostic factors were obtained using the Cox proportional hazards regression analysis.

Results

Median BMI was 26.0 kg/cm2. In total, 122 patients were UW/NW and 192 were OW/OB. A pCR was obtained in 23.4% of patients. The pCR did not differ between groups (20% for patients with BMI<25 and 25% for those with BMI>=25, p=0.271). Multivariate analysis revealed that only hormonal receptors negative, HER2 positive, and cT1-2 were found to be independent predictor factors for pCR. Non-significant differences in EFS or OS were observed between the two baseline BMI categories. Multivariate analysis confirmed tumor grade G3 and absence of pCR as independent prognostic factors associated with a worse EFS. Factors associated with a worse OS in the multivariate analysis were cT3-4, hormone receptors negative, and no-pCR after NAC.

Conclusions

In our experience, BMI was not associated with clinical outcomes (pCR, EFS and OS) in BC patients receiving NAC. Classic pathological features of the tumor are the main prognostic factors related with pCR and survival. Achieving pCR after NAC is the most consistent factor associated with EFS and OS. Prospective studies are needed to determine the exact role of BMI in this setting.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Invasive lobular breast cancer (ILBC) is the most common histologic subtype after invasive ductal BC. It is characterized by a distinct clinical course including presentation, sites of metastatic relapse and response rates to conventional therapies. In ILBC, loss of E-cadherin (CDH1) expression is the most frequent oncogenic event (90% of cases). In vivo studies investigating synthetic lethality approaches, have shown profound antitumor effects of ROS1 inhibitors in models of E-cadherin–defective BC, providing the preclinical rationale for assessing their activity in this disease. Entrectinib is a potent small-molecule tyrosine kinase inhibitor that targets TRK, ROS1 and ALK tyrosine kinases. We aim to evaluate the combination of neoadjuvant entrectinib and ET in women with estrogen receptor positive (ER+), HER2-negative (HER2-) early ILBC.

Trial design

Single arm, multi-center, phase II trial testing entrectinib plus ET in pre/post-menopausal patients (pts) with ER+/HER2-, stage II-III (T>20mm, N0/1) ILBC. Pts will receive four 28-day cycles of letrozole (2.5 mg daily) + entrectinib (600 mg daily) +/- goserelin (3.6 mg every 28 days, only in premenopausal pts). Surgery will take place after at least 16 weeks of treatment, during weeks 17−18. Surgery and post-operative therapy will follow local practice. Primary endpoint will be residual cancer burden (RCB) 0/1 rate by local evaluation. Secondary endpoints will include pCR in breast and axilla (ypT0/Tis ypN0), tumor objective response by locally-assessed breast MRI via modified RECIST, and safety. Exploratory analyses on pre- and post-treatment tumor tissue, whole blood and plasma samples will be performed to identify differences between responders and non responders. With a two-step, optimal, Simon design with a one-sided alpha=beta=10%, we defined RCB 0/1 rate of 3% (P0) as minimal required level of activity (target RCB 0/1=15% [P1]). A futility analysis is planned on the first 17 pts. If RCB 0/1 in ≥ 1/17 pts, the study will continue until 39 evaluable subjects are enrolled. If RCB 0/1 in ≥ 3/39 pts, the combination will be considered worthy for further investigation.

Clinical trial identification

NCT04551495.

Legal entity responsible for the study

Institut Jules Bordet, Belgium.

Funding

Roche.

Disclosure

L. Buisseret: Research grant/Funding (institution): AstraZeneca; Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: iTEOS therapeutics; Speaker Bureau/Expert testimony: BMS. D. Taylor: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: Novartis; Advisory/Consultancy: Lilly; Advisory/Consultancy: Daiichi Sankyo; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: AstraZeneca. F.P. Duhoux: Research grant/Funding (self), postdoctoral clinical mandate (2017-034) from a not-for-profit organisation: Foundation Against Cancer; Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Pierre Fabre; Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Teva; Speaker Bureau/Expert testimony: Mundi Pharma. H. Denys: Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Novartis; Advisory/Consultancy: Amgen; Advisory/Consultancy: Tesaro; Advisory/Consultancy: GSK; Travel/Accommodation/Expenses: PharmaMar; Travel/Accommodation/Expenses: Teva. F. Coussy: Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Lilly; Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis. B. Pistilli: Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Puma Biotechnology; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Novartis; Advisory/Consultancy: Myriad Genetics; Advisory/Consultancy: Pierre Fabre; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD Oncology; Honoraria (self), Research grant/Funding (self), Research grant/Funding (institution): Pfizer; Research grant/Funding (self), Research grant/Funding (institution): Daiichi; Research grant/Funding (self), Research grant/Funding (institution): Merus. M. Piccart: Advisory/Consultancy, Board Member (Scientific Board): Oncolytics; Research grant/Funding (institution), Board Member (Scientific Board): Radius; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Camel-IDS; Advisory/Consultancy: Crescendo Biologics; Advisory/Consultancy: DebioPharm; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Genentech; Advisory/Consultancy: Huya; Advisory/Consultancy: Immunomedics; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy: Menarini; Advisory/Consultancy, Research grant/Funding (institution): MSD; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Odonate; Advisory/Consultancy: Periphagen; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy: Seattle genetics; Research grant/Funding (institution): Servier. M. Ignatiadis: Advisory/Consultancy: Celgene; Advisory/Consultancy: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Tesaro; Research grant/Funding (institution): Roche; Research grant/Funding (institution): Menarini; Research grant/Funding (institution): Silicon Biosystems; Research grant/Funding (institution): Janssen Diagnostics; Travel/Accommodation/Expenses: Amgen. P.G. Aftimos: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Macrogenics; Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy: Novartis; Advisory/Consultancy: Amcure; Advisory/Consultancy: Servier; Advisory/Consultancy: G1 Therapeutics; Advisory/Consultancy: Radius; Advisory/Consultancy: Deloitte; Honoraria (self): Synthon; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Honoraria (self): Gilead; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche. All other authors have declared no conflicts of interest.

Background

The combination of cyclin-dependent kinase inhibitors (CDK4/6i) with first or second-line endocrine therapy are the standard of care for HR+/HER2-negative metastatic breast cancer (BC); its role in the early-setting is being evaluated in several studies with discordant results. In HR+/HER2-negative BC, pathologic complete response (pCR) rates after NAC are around 15%. Additional therapeutic strategies to eradicate these residual tumor cells are needed. To characterize the biological effect of CDK4/6i in residual disease (RD) after NAC, could help to better understand their role in early BC.

Trial design

SOLTI-1710 PROMETEO II is an open-label, multicenter window of opportunity trial of Palbociclib and letrozole tested in patients with HR+/HER-negative RD after completing anthracycline/taxane-based NAC. PROMETEO II will include 22 patients. Invasive RD must be confirmed by core-biopsy and have a diameter ≥ 10mm measured by ultrasound. Adequate organ function and ECOG PS 0-1 are required. A short course of Palbociclib is administered at a dose of 125 mg/day for 21 days and letrozole 2.5 mg/day continuously until surgery. BC surgery is carried out 1 week after the last dose of palbociclib. The primary objective of the trial is to evaluate the antitumor activity by the Complete Cell Cycle Arrest (CCCA) rate determined by Ki67 ≤2.7%, centrally assessed at surgery. Secondary endpoints include pCR rate, RCB and safety. To date, 12 patients have been included at 8 sites in Spain.

Clinical trial identification

NCT04130152.

Legal entity responsible for the study

SOLTI.

Funding

Pfizer.

Disclosure

E. Ciruelos: Advisory/Consultancy, Non-remunerated activity/ies: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Lilly; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Novartis; Advisory/Consultancy: MSD. X. González-Farré: Advisory/Consultancy: SOLTI Breast Cancer Group; Advisory/Consultancy, Non-remunerated activity/ies: Roche; Advisory/Consultancy: Eisai. P. Villagrasa: Honoraria (self): NanoString. A. Prat: Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Novartis; Honoraria (self), Advisory/Consultancy: MSD Oncology; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Research grant/Funding (self): NanoString Technologies; Advisory/Consultancy: Oncolytics Biotech; Advisory/Consultancy: Amgen; Advisory/Consultancy: PUMA. S. Pernas Simon: Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Daiichi Sankyo; Advisory/Consultancy: Polyphor; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Roche. All other authors have declared no conflicts of interest.

Background

Mammography screening reduces breast cancer mortality by 20-40%, but a large proportion of breast cancers are detected at later stages or as interval cancers. The KARMA model was developed that identifies women who are likely to be diagnosed with breast cancer before or at the next mammography screen.

Methods

The study was based on the prospective screening cohort KARMA including 70,877 participants. The study included 974 incident cancers and 9,376 healthy individuals from the cohort. We developed an image-based risk score based on mammographic features (density, masses, microcalcifications), their left-right asymmetries, and age. A lifestyle extended score also included menopausal status, family history of breast cancer, body-mass-index, hormone replacement therapy, and use of tobacco and alcohol. A genetic extended score was also developed including a polygenic risk score including 313 single nucleotide polymorphisms in addition to the image and lifestyle factors. Relative risks were estimated using logistic regression. Tumor sub-type specific risks were also estimated. Absolute risks were estimated based on relative risks, national incidence rates, and competing mortality risk.

Results

The image-based model area under the curve (AUC) was 0.73 (95% CI 0.71,0.74). The lifestyle and genetic extended model AUCs were 0.74 (95% CI 0.72,0,75) and 0.77 (95% CI 0.75,0.79) respectively. There was a relative 8-fold difference in risk between the women at high and general risk. High risk women were more likely diagnosed with large tumors. The image-based model was validated in two external cohorts.

Conclusions

Three mammographic features and their left-right asymmetries generated the basis of the model. The model could optionally be extended with lifestyle factors, family history, and a polygenic risk score. The models identified women at high likelihood of being diagnosed with breast cancer within two years of a negative screen who possibly are in need of supplemental screening or preventive intervention.

Legal entity responsible for the study

Karolinska Institutet.

Funding

Hans and Märit Rausing.

Disclosure

All authors have declared no conflicts of interest.

Background

High mammographic density decreases the sensitivity of mammography. Tamoxifen reduces mammographic density and could therefore increase the sensitivity of a mammogram. We tested if low-dose tamoxifen could be used to increase the sensitivity of mammography in premenopausal women.

Methods

The study was based on the KARMA prospective screening cohort including 28,282 premenopausal women and 517 incident breast cancers. Mammographic density was measured as percent density and as a computerized BI-RADS score using the STRATUS tool. Mammographic density-dependent screening sensitivities and tumor sizes were estimated in each of the four BI-RADS categories (A, B, C, D). The 2.5 mg tamoxifen arm of the KARISMA tamoxifen six-month trial was used to define the change of mammographic density that we would observe in KARMA, if the women were exposed to low-dose tamoxifen for 6 months. Screening sensitivities and tumor sizes were predicted in the KARMA cohort assuming all women were exposed to 2.5 mg of tamoxifen. Reduction in interval and advanced cancers were estimated in women with relative mammographic density decreases from 10% to 50%.

Results

During the 8-year follow-up, 287 (56%) screening-detected and 230 (44%) interval cancers were diagnosed in the KARMA cohort. The screening sensitivities before exposure to tamoxifen were 77%, 69%, 53%, 46% for the BI-RADS categories A, B, C and D. The mean density decrease after exposure to 2.5 mg of tamoxifen was 15.4% and the BI-RADS category-dependent change in sensitivity was 0% (p=0.95), 2% (p=0.01), 4% (p<0.001), and 5% (p<0.001), respectively. A density decrease of ≥20% reduced the number of interval cancers by 24% (p<0.01) and the probability of identifying >20 mm tumors by 4% (p<0.01).

Conclusions

Low-dose tamoxifen has the potential to increase the sensitivity of a screening mammogram and therefore reduce the proportion of interval and advanced cancers in mammography screening.

Legal entity responsible for the study

Hans and Märit Raussing, Kamprad Foundation.

Funding

Hans and Märit Raussing, Kamprad Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

The prognostic value of postmastectomy radiotherapy (PMRT) in T1-2N1 breast cancer patients remains controversial. The aim of this study was to evaluate the benefit of PMRT in overall survival (OS) of T1-2N1 breast cancer patients based on the combination of lymph node numbers and tumor size.

Methods

We used data extracted from the Surveillance, Epidemiology, and End Results program. Women diagnosed as T1-2N1M0 breast cancet betweent 2004 and 2015 was abstracted. The primary outcome was overall survival. Multivariate Cox proportional hazard models were used to estimate the independent prognostic factors and to assess hazard ratios (HR) and their 95% confidence intervals (CI) with OS. Subgroup analysis of patients with different node positive number and tumor size were enrolled in our study.

Results

A total of 29366 patients included the final analysis, 20167 (68.7%) patients in no-PMRT group and 9199 (31.3%) patients in PMRT group. Multivariable Cox model analysis showed that radiotherapy could improve the overall survival (Hazard ratio [HR]0.89;95%CI 0.83-0.96, P=0.001) for T1-2N1 breast cancer patients. Subgroup analysis based on different tumor burden types showed that there was not all survival benefit to every subgroup. Analysis shows the benefits of PMRT are associated with exaltation in breast cancer overall survive rate among the patients with tumor size 4-5 cm and two or three positive lymph nodes respectively (HR 0.69; 95%CI 0.51-0.94; P=0.017or HR0.65; 95%CI 0.44-0.95; P= 0.027,separately). PMRT also has a beneficial effect for the patients with tumor size 2-3 cm and three positive lymph nodes (HR 0.61; 95%CI 0.48-0.78; P<0.001), but not in the others.

Conclusions

The integration of tumor size and the number of positive lymph nodes status seems to be a reliable predictor of overall survival from radiotherapy, which may enable physician to make clinical decision more precisely and effectually about PMRT, especially in the low -risk breast cancer subgroup.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

In this study we will, compare VAE with surgical excision for the treatment of benign and high risk lesions, regarding cosmetic outcome and direct health care costs.

Methods

This was a retrospective cohort study, data was collected from electronic patient files in the period between January 2016 and December 2019. VAE was introduced in our hospital (a large teaching hospital) as a treatment for benign and high-risk lesions in July 2017. Cosmetic outcome was measured with the BCTOS cosmetic subscale and presented as an unweighted mean score. Health care costs were presented as mean (SD) and the difference between the two groups (VAE or SE).

Results

Between January 2016 and December 2018, 280 patients were treated for 329 benign or high-risk lesions in our hospital. The initial procedure was a VAE in 104 patients. Mean cosmetic outcome score was not significantly different for VAE (mean 1.54, SD 0.45) compared to SE (mean 1.51, SD 0.45) (p = 0.544). If patients were initially treated with VAE, the total costs of treatment were lower than when patients were initially treated with SE (mean difference € 2527,81). The biggest differences in costs were seen in the procedural and procedure related costs. Even after correcting for tumor size, the number of resected tumors per patient, the number of procedures per patient, the presence of complications, BI-RADS category and the follow-up time, the difference between VAE and SE remained significant (β = -0.65, p < 0.001). All but one of the patients that underwent both VAE and SE preferred VAE over SE, due to the less invasive character of the treatment.

Conclusions

This is the first study in which the cosmetic outcome and direct health care costs of VAE and surgical excision are compared. Health care related costs are significantly lower for patients initially treated with VAE without compromising cosmetic outcome. The health care costs of patients undergoing surgical resection were more than double the costs of patients undergoing a VAE. Implicating that if VAE would be used in more high-risk lesions possibly resulting in more surgical re-excisions due to upgrading of the lesions, VAE might still be cost-effective.

Legal entity responsible for the study

Franciscus Gasthuis & Vlietland.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Adjuvant radiotherapy (RT) in breast cancer is an essential part of the local treatment of the breast and regional lymph nodes. Whether the internal mammary lymph nodes (IMNs) should be included in the RT field is controversial due to limited data. The low incidence of IMNs recurrence may be due to the incidental dose received. The aim of this study is to estimate the incidental irradiation dose recieved by IMNs during 3DCRT and whether this dose correlates with IMNs recurrence.

Methods

This retrospective dosimetric study included 137 cases treated at our institution during the year 2016-2017. Inclusion criteria: patients who underwent either MRM or BCS and were candidate to receive adjuvant locoregional radiotherapy (without intended inclusion of IMLNS in the radiotherapy field). For this study, the IMNs was contoured through the topography of the internal thoracic vessels starting cranially at the superior border of the first rib, caudally at the cranial end of the fourth rib. IMNs mean dose (IMDmean), maximum dose (IMN max) and minimum dose (IMN min) were obtained. In addition, the ipsilateral lung volume that received ≥20 Gy (V20), heart mean dose (for patients with left side tumors only), parasternal soft tissue thickness and the distance between the medial tangent field border and the mid-line were measured (both measured at level of the third rib).

Results

In all cases, PTV IM was covered by less than 95% of the prescribed dose. The IMLs mean dose was 28.50% (SD 20.71%) of the prescribed dose. There was no significant difference between the right and left side regarding IMND mean, lung v20 or heart mean dose. Six patients (4.37%) had IMNs recurrences, the IMLs mean dose in all of them was less than 28% of the prescribed dose. IMLs mean dose less than 28% significantly predicted IMLs recurrences (P value=0.05). IMN mean dose significantly correlated with the mean distance between mid line and medial tangent field border (0.8 cm) with P value< 0.0001.

Conclusions

IMN receives considerable incidental dose of radiation. The required dose to prevent against IMN recurrence may be lower than the prescribed dose for other nodal areas. Prospective trials are needed to determine the optimum dose and indication to irradiate IMN.

Legal entity responsible for the study

Alexandria University, Egypt.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Targeted Intraoperative Radiotherapy (TARGIT) involves the precise delivery of a large dose of ionizing radiation to the tumor during surgery. TARGIT has emerged as an alternative to Breast External Radiotherapy (EBRT) for women with early breast cancer. However, its efficacy compared to EBRT remain unclear. This systematic review and meta-analysis aimed to evaluate the effectiveness of TARGIT compared to EBRT.

Methods

We searched PubMed, PMC, Science Direct, Google Scholar, and Europe PMC, on January 31st, 2021 using a combination of keywords associated with TARGIT, EBRT, and Breast Cancer concerning their survival rate based on Overall Survival (OS), Mastectomy Free Survival (MFS), Distant Disease-Free Survival (DDFS), and Local Recurrence Free Survival (LRFS). Publications included are limited to English manuscripts with observational design study that were published in the past 10 years. Patients with an incomplete personal or medical information were excluded from this review. All included studies were reviewed by all 6 authors. The quality of each included study was assessed using either the Newcastle-Ottawa Scale (NOS) or Jadad Score and GRADE.

Results

We included a total of 7 studies consisting of 110.532 breast cancer patients. Based on NOS, 3 studies showed good quality. Based on Jadad, 3 studies were good in quality while 1 study was fair. Based on GRADE, these studies were moderate in quality as there was a largely consistent and precise outcome with minimal publication bias. The association of TARGIT and EBRT were found in all included studies. Six studies showed that there is no significant difference between the two groups. However, one study showed that TARGIT was an effective alternative to EBRT. Pooled analysis showed that statistically TARGIT is associated with better OS (HR = 0.96; 95% CI, 0.95 - 0.97; p < 0.00001), MFS (HR = 0.93; 95% CI, 0.77-1.12; p = 0.44), DDFS (HR = 0.92; 95% CI, 0.76-1.12; p = 0.41), and LRFS (HR = 0.99; 95% CI, 0.83-1.17; p = 0,89) when compared with EBRT.

Conclusions

There is no significant difference in survival rate between TARGIT and EBRT. Further reliable research is needed.

Legal entity responsible for the study

Audrey Hadisurya.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Inherited genes, hormonal imbalance, environmental factors, and mutation in genes are responsible for the development of breast cancer in females. Nowadays, passive immunotherapy is used to combat cancer. Trastuzumab is a humanized monoclonal antibody (mAb) and has a pronounced effect when used as adjuvant therapy, but high doses (4-8 mg/kg) and greater molecular weight (MW) increases liver retention. To fill this hiatus, antibody fragments (Fab) are generated and showed similar target specificity. The radiolabelling of Fab may provide the theranostic application in breast cancer patients.

Methods

The Fab was generated from mAb trastuzumab and characterized by MALDI-TOF. The purified Fab was standardized for conjugation with bifunctional chelating agent DTPA. The purified conjugated Fab-DTPA product was considered for radiolabelling with Ga-68, Lu-177. The radionuclide and radiochemical purity of the product was determined. HER2 binding efficacy was checked on SKBR3 cells along with the bio-layer interferometry (BLI) technique. After quality control checks: sterility, pyrogenicity, human serum, and PBS stability; radiolabelled Fab-DTPA was subjected to molecular imaging. PET and SPECT imaging were correlated with LABC and histopathologically HER2 proven cases.

Results

The generated Fab (45 kDa) and Fab-DTPA (47 kDa) was confirmed by MALDI-TOF. Radiochemical purity of ⁶⁸Ga/¹⁷⁷Lu-Fab-DTPA was > 99 %. The high specificity of ¹⁷⁷Lu-Fab-DTPA towards HER2 receptor was confirmed. The binding kinetic analysis (K_d)was 2 nM for Fab and 20 nM for Fab-DTPA. The products were stable and free from bacterial, fungal contamination up to 21 days, and endotoxin concentration (5-7 EU/mL) was found within the limit (175 EU/injection). The IC50 value calculated from the MTT assay of Lu-177 DTPA Fab was 71.1 nM (IC50 of trastuzumab 121.06 nM). PET/CT imaging of the patient was performed, MIP of ⁶⁸Ga-Fab DTPA showed SUVmax-6 in the left breast which was concordant to ¹⁸F-FDG with SUVmax-11. SPECT/CT imaging with ¹⁷⁷Lu- Fab-DTPA showed significant uptake in IHC proven HER2 breast cancer, while ¹⁸F-FDG showed SUVmax-17.

Conclusions

Radiolabelled Fab-DTPA can be used as a theranostic molecule for HER2 positive breast cancers.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Post-lumpectomy imaging (PLI) studies can contribute to the detection of residual tumor before radiotherapy (RT) is started. However, there is no solid evidence it confers any significant clinical benefit, which explains why some centers don’t integrate it. In our institution, most patients undergoing breast-conserving surgery (BCS) do mammogram + breast/axillary US. US allows to study regional nodal breast areas and detect nodal residual disease. However, the lack of studies that include US as an integral exam of PLI leads to the paucity of data regarding its value. This study intends to evaluate the value of PLI before adjuvant RT regarding the nodal regional investigation in women after BCS.

Methods

Retrospective study. Included patients after BCS, with negative margins, referred to our RT department between 01/2018 and 12/2019. Routine digital mammogram and breast and axillary US performed between surgery and RT in all patients. Imaging findings divided into suspect and not suspect. Clinicopathological and demographic information was collected and analyzed using IMB® SPSS® v26.

Results

1262 breasts (1252 woman) were included, with a mean age of 57.2 (±11.0) years. Most tumors were infiltrating ductal carcinoma associated with ductal carcinoma in situ (54.8%), grade II or III (88.3%), pT1 (60.1%), and hormone receptors positive (86.4%). The median time interval between surgery and PLI was 128.3 (±68.2) days. Among the 1262 breasts analyzed, 30 (2.4%) had suspicious findings for nodal residual disease and 24 were evaluated with cytology. Only 1/24 (4.1%) was positive for malignancy, 0.1% cases overall. No further statistical analysis was possible. Our results show the vast majority corresponds to benign lymph nodes. Only 0.1% of the overall cases proved to be malignant. The low positive predictive value of 4.1% may result from the major limitation radiologists face distinguishing malignant and reactional changes. Further nodal investigation won’t be necessary for almost every patient after BCS.

Conclusions

In most cases with suspicious findings for nodal disease, no findings for malignancy were found. Most patients had post-surgery reactional changes, and histologic confirmation may be mitigated.

Legal entity responsible for the study

André Pires.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Eight to 56% patients undergoing a mastectomy with preoperative diagnosis of ductal carcinoma in situ (DCIS) upgrade to invasive disease on final histopathological evaluation. Sentinel node biopsy in this cohort of patients cannot be safely excluded due to the high probability of finding invasive disease on final histopathological evaluation. We were keen to identify factors predictive of invasiveness and therefore probable nodal involvement.

Methods

We performed a retrospective audit of patients undergoing a mastectomy as primary treatment following a diagnosis of DCIS between Jan 2016 and Sept 2020 (n=99). We included patients diagnosed with DCIS that had normal conventional imaging following a microdochectomy for pathological nipple discharge, as well. We interrogated our data to identify predictors of invasiveness.

Results

29 of 99 patients were found to have invasive disease on final histopathological evaluation. Median pathological size of the DCIS was 60 mm (range of 10 to 180 mm). Nine patients (9.09%) were found to have involved lymph node involvement (5 micrometastases + 4 Macrometastases). Of the patients with invasive disease, 2 (6.8%) had low grade DCIS and 4 (13.7%) had intermediate grade DCIS. A higher proportion (53.8%) of those with distortion on 3D mammogram were found to have invasive disease as compared to those with micro-calcifications (25.5%; p=0.035). A smaller proportion of ER-negative DCIS were found to have invasive disease as compared to ER-positive (17.8% for ER-negative Vs 33.8% ER-positive), the difference was not statistically significant.

Conclusions

This study shows that over 71% of patients who underwent mastectomy for a preoperative diagnosis of DCIS with sentinel node biopsy that could have been avoided. Further research is needed to identify a cohort of patients with a pre-operative diagnosis of DCIS, where routine surgical staging of the axilla can be avoided to reduce additional surgical morbidity.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Axillary lymph node dissection (ALND) in patients with breast cancer has the potential to induce side effects, including upper-limb lymphedema. Axillary reverse mapping (ARM) is a technique that enables discrimination of the lymphatic drainage of the breast from that of the upper limb in the axillary lymph node (LN) basin. We aimed to determine ARM node identification rate by near-infrared (NIR) fluorescence imaging during total mastectomy with ALND and then to analyze potential predictive factors of ARM node involvement.

Methods

The study enrolls 119 patients diagnosed with invasive breast cancer with an indication for ALND. NIR imaging using indocyanine green dye was finally performed in 109 patients during standard ALND to identify ARM nodes and their corresponding lymphatic’s ducts, both in case of direct surgery than neoajduvant chemotherapy.

Results

94.5% of patients had ARM nodes identified. No difference was found between the 2 groups, with or without neoajuvant chemotherapy.The ARM nodes were localized in D zone in 64.4% of cases. The rate of metastatic axillary lymph nodes was 55.3 % in the all cohort, 19.4 % also in ARM nodes with 7.7% of metastatic ARM lymph nodes in D zone. Two patients had metastatic ARM lymph nodes and not in the remaining axillary lymph nodes. Beside number of mitosis (p 0.04), no predictive factor of ARM nodes involvement was found Table: 83P

Conclusions

Axillary reverse mapping by NIR fluorescence imaging appears as a reliable technique to identify in realtime arm node when ALND. Performing pre-operative chemotherapy, a known factor of lymphatics modification, did not significantly influence the detection rate. Our study shows that ARM node is a potential drainage route of cancer cells, finding metastasis in 19.4% of cases, raising the question on its impact on the prognosis. The collected clinical data compared with arm node histological diagnosis showed only the number of mitosis in diagnostic biopsy as a potential predictive factor of arm node involvement.

Legal entity responsible for the study

PHRC of French National Institute for Cancer.

Funding

French INCa agency (French National Institute for Cancer), grant PHRC K15-222.

Disclosure

All authors have declared no conflicts of interest.

Background

Radiation therapy (RT) is an integral component of breast cancer management. For mitigating the normal tissue toxicity, many radiotherapy techniques have been explored and utilized. In the present study, we compare post modified radical mastectomy (PMRM) radiotherapy plans utilizing 3DCRT and VMAT techniques.

Methods

This prospective, single-institutional study, includes 40 PMRM patients. For all the patient, both the plans were generated and dosimetric comparison was done. 20 patients were treated with the 3DCRT and the other half were with the VMAT. All the patients received 40Gy in 15 fractions over 3 weeks. Acute reactions were compared at end of RT, 6 weeks and 3 months.

Results

The planning target volume (PTV) receiving V95%, Homogeneity Index and Conformity Index were significantly better in VMAT than 3DCRT (p<0.001). V20, V30 and Dmean values of the ipsilateral lung (p<0.001) were significantly less in VMAT. In left-sided PMRM patients, V25 of the heart was significantly (p<0.001) lower in VMAT while in right-sided mastectomy there was a non-significant difference (p=0.13). In both left and right mastectomy patients, V5 of heart and both the lungs was significantly higher in VMAT (P<0.001). Mean dose of the oesophagus and contralateral breast were higher in VMAT (p<0.001). Both techniques were equivalent in terms of acute toxicity. Dosimetric parameters are shown in the below table. Table: 84P

Conclusions

VMAT provided better PTV coverage, reduced high dose volume to heart and I/L lung, more homogenous, and conformal plans, as compared to 3DCRT plans. VMAT will be helpful, where 3DCRT is not giving proper dose distribution due to variation in chest wall shape or is giving high heart or I/L lung doses. Consequences of higher low-dose volumes to normal tissues with VMAT need to be weighed against the benefits of reducing high-dose volumes on an individual patient basis.

Legal entity responsible for the study

Maharishi Markandeshwar Institute of Medical Sciences and Research.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

We aimed to assess correlation between radiation fractionation schedule, body mass index (BMI) and acute skin toxicity in post-operative hypofractionated radiotherapy for breast cancer.

Methods

We retrospectively evaluated 102 breast cancer patients treated with 3-dimensional conformal radiotherapy after breast conserving surgery between August 2017 and December 2019. The prescribed dose was 40.05 Gy in 15 fractions to the whole breast followed by 13.35 Gy in 5 fractions to tumor bed. BMI was categorized as underweight –normal (BMI ≤ 27) and overweight-obese (BMI > 27). Breast volume was measured manually by contouring of the breast target volume on the planning CT scan. All patients were monitored for acute skin toxicity during radiotherapy according to CTCAE v4.0 (common toxicity criteria for adverse events) scale. The correlation between the incidence of skin toxicity and its grading with BMI and breast volume was performed with the χ2 test.

Results

The median BMI was 30 kg/m² (19-45) and the median breast volume was 693.80 cc (100-2777cc). Acute G2-3 skin toxicity was significantly higher for patients with BMI > 27 than those with BMI ≤ 27 (37% vs 15% p=0.04). The mean CTV volume of patients experiencing G2-3 erythema was significantly higher than that of patients with G0-1 erythema (1005.3cc vs 731.3cc respectively [P=0.000]). Among those with a breast volume >800 cc, G2-3 skin toxicity occurred in 42% compared with 17.4% in patients with breast volume ≤800cc. Combination of a high BMI (>27) and a breast volume>800cc was associated with an increased risk of G2-3 skin toxicity (60.7% vs 39.3% in case of BMI> 27 or breast volume > 800cc [p=0.003]).

Conclusions

BMI and breast volume were correlated with higher risk of acute skin toxicity after postoperative breast hypofractionated radiotherapy but no G4 toxicity was observed. Hypofractionated schedule was not associated with severe toxicity and could be considered for this population.

Legal entity responsible for the study

Pr Lotfi Kochbati.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The use of VAE for high-risk lesions remains controversial and guidelines are ambiguous. In this study we evaluate and demonstrate how the introduction of VAE impacts the management and clinical outcomes of benign and high-risk lesions in our hospital.

Methods

A retrospective database cohort study was conducted to compare the available operation room time, and excision, re-excision, recurrence, complications and upgrading rates before and after the introduction of VAE. All patients treated for a benign or high-risk lesion in the period from January 2016 up to 2019 were included in the study. To demonstrate the difference in treatment the results for VAE and surgical excision (SE) in the after group were presented separately.

Results

A total of 319 lesions were excised in our hospital during the study period, of which 118 were excised through VAE. The proportion of excised lesions was comparable in the before and after group, but the proportion of SE decreased since the introduction of VAE. High-risk lesions were significantly more often treated with SE than VAE due to the high rate of surgically excised papillary lesions. Recurrence, re-excision and complication rates were comparable in the before and after group. Nearly all malignancies found after excision through VAE or SE were good differentiated in situ carcinoma, and no malignancies were detected during the follow-up of benign and high-risk lesions.

Conclusions

The introduction of VAE reduced OR time for benign and high-risk lesions, implicating that more OR time was available for malignant lesions. Re-excision, recurrence and upgrade rates remained low and could possibly be further reduced by better informing the patient prior to the procedure. This study contributes to the accumulating evidence for the wider deployment of VAE as a treatment option for all high-risk lesions.

Legal entity responsible for the study

Franciscus Gasthuis en Vlietland.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

HER-2+ breast cancer (BC) remains challenging as the use of Trastuzumab is ineffective in some cases. Let-7a is considered as a well-known tumor suppressor microRNA. It is epigenetically regulated by hypermethylation and suppressed by lncRNA, lin28 in many cancer such as BC. Here, we aim at restoring the expression of Let-7a through epigenetic modulation to study the impact of Let-7a on PD-1, PD-L1 and CLDN1 expression levels in CD8+ cells of HER2+ BC patients.

Methods

65 biopsies/blood samples were withdrawn from BC patients, CD8+ cells isolated from PBMCS (MojoSort™). Cells were transfected with siRNAs of NEAT1/Lin28 (HiPerFect®) then with/without Decitabine (DAC) treatment. LDH and MTT assays were performed after co-culturing transfected/treated CD8+ cells with MDA-MB-231 and MCF-7 cells ratio (5:1). One-way ANOVA and Dunnett’s test were used in statistical analysis for multiple groups.

Results

Let-7a was found to be downregulated (p=0.0001) while NEAT1 and CLDN1 were overexpressed (p=0.0052, 0.0051, respectively) compared to controls. We reported before overexpression of PD-1 and PD-L1. Let-7a levels was restored upon silencing of lin28, NEAT1 and DAC treatment (p=0.0326,0.0326,0.0014 respectively) and upon different conditions of cotransfections and DAC treatment of CD8+ cells using siLin28/silNEAT1, siLin28/DAC, siNEAT1/DAC and silin28/NEAT1/DAC (p= 0.0447, 0.0245, 0.1628,0.0011 respectively). Let-7a potential downstream targets, PD-1, PD-L1 and CLDN1 were assessed upon restoration of let-7a using the conditions of transfections mentioned above. PD-1 was downregulated (p=<0.0001, in all conditions) as well as PD-L1 (p= 0.0017, 0.0010, 0.0013, 0.0009, 0.0052, 0.0020, 0.0015, respectively) and CLDN1 was upregulated (p=0.0077, 0.0650, 0.0037, 0.0486, 0.0011, 0.0316, 0.0427, respectively) compared to mock. Tumor cytotoxicity was found to be elevated in high-Let-7a-CD8+ cells where MDA-MB-231 cells (p=<0.0001 in all conditions, but p= 0.0018 in siNEAT1) and MCF-7 cells (p=0.0006, 0.0006, 0.0015, 0.0012, 0.0005, 0.0004 and 0.0080) compared to mock.

Conclusions

These data shed the light on the pivotal role of Let-7a in HER2+ BC in an attempt to develop combined therapy with immunotherapeutic agents.

Legal entity responsible for the study

German University in Cairo - GUC.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Immunologic checkpoint blockade (ICB) is a novel approach to reverse cancer immunosuppression. Various studies observed the role of CXCR2 in tumour aggressiveness, resistance and immune-suppression. CXCR2 signaling is known to recruit myeloid derived suppressor cells (MDSCs) to tumor microenvironment where MDSCs oppose the cytotoxic T-cell-mediated antitumor effect and suppress ICB efficacy. CXCR2 inhibition was found to augment programed cell death-1 (PD-1) inhibition in pancreatic cancer. CXCR2 inhibition has been proposed as an attractive anti-tumor treatment not only to enhance immunotherapy, but also to intensify the cytotoxicity of chemotherapeutic drugs. We have previously reported the enhaced chemosensitivty of TNBC mammospheres to Doxorubicin by AZD5069 \"a selective small-molecule antagonist of human CXCR2”. Here, we investigate the potential use of AZD5069 in combination with atezolizumab (anti-PD-L1) in an ex-vivo TNBC model.

Methods

CXCR2 mRNA expression was analyzed using RealTime PCR in 65 BC biopsies and controls. MDA-MB231 cells was co-cultured with PBMCs isolated from TNBC patients’ blood (Ficoll protocol). Lactate dehrdrogenase-LDH cytotoxicity assay was performed on the ex-vivo model treated with 200 nm anti-PD-L1 and/or (10, 30, 100nm) AZD5069 for 72 hours.

Results

The relative expression of CXCR2 was found to be markedly increased in BC patients. TNBC and HER2 +ve patients showed a dramatic elevation in CXCR2 expression (p=0.0039,p=0.0286, respectively), hormonal subtypes (ER, PR +/- and HER2–ve) showed mild overexpression of CXCR2 (p=0.0179) compared to controls. While CXCR2 expression was significantly higher in TNBC patients compared to other subtypes (p=0.0199). In LDH assay, combination of 30 nm AZD5069(inhibitory dose for PBMCs according to dose-response curve) and 200 nm anti-PD-L1 induced a significant additive effect in cytotoxicity than anti-PD-L1 alone (p=0.0065). While the non-effective doses of AZD5069(10,100 nm) in combination with anti-PD-L1 showed no significant effect (P=0.073, P=0.182, respectively).

Conclusions

These data highlight the role of CXCR2 inhibition as a cutting edge approach to boost immunotherapy and combat chemo-resistance in TNBC.

Legal entity responsible for the study

German University in Cairo - GUC.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Despite the successful use of checkpoint inhibitors in cancer immunotherapy, benefits in breast cancer have largely been confined to triple-negative cancers in the metastatic setting. ER-positive breast tumors which form the major subgroup of breast cancer are considered immunologically silent with few effector tumor-infiltrating lymphocytes (TILs). We have previously demonstrated high expression of miR-18a is associated with poor prognosis and its activation of Wnt signaling in ER-positive breast cancer. In this study, we have explored the modulation of the immune signature by miR-18a within ER-positive tumors.

Methods

miR-18a was overexpressed in MCF-7 cells using a synthetic mimic and a global gene expression pattern was arrived at by microarray experiments. Functional enrichment of differentially expressed genes (DEGs) was performed to identify the deregulated pathways. Further validation of the identified pathways was done in the TCGA cohort of ER-positive tumors with high expression of miR18a, by comparison between the tumors segregated based on upper and lower quartile of its expression. Immune cell identification was done using CIBERSORT analysis in these tumors.

Results

Functional enrichment of genes in MCF-7 cells with overexpression of miR-18a demonstrated dysregulation and suppression of immune-related pathways associated with TAP binding, HLA regulated genes with antigen binding, and interferon-gamma related signaling. Cytokine mediated signaling and response to cytokine-mediated signaling was also observed to be suppressed in these cells. Stratification of the ER+ tumor samples by miR-18a levels in the TCGA cohort revealed a higher proportion of resting macrophages (p<0.0001), T-regulatory cells (p=0.001), and resting Natural Killer Cells (p=0.041) in tumors expressing high levels of miR-18a. We also observed a lower proportion of monocytes (p=0.021) and a higher CD4/CD8 ratio (p=0.001) in these tumors.

Conclusions

Our results support the existence of an epigenetic mediated repression of the immune-related gene signature within ER-positive tumors. Immunomodulation brought about by the overexpression of miR-18a may contribute to immune suppression by evading the adaptive immune response in these tumors.

Legal entity responsible for the study

St. John's Research Institute.

Funding

Department of Health Research, Ministry of Health & Family Welfare, India Nadathur Estates.

Disclosure

All authors have declared no conflicts of interest.

Background

Targeting the human epidermal growth factor receptor-2 (HER2) is the cornerstone of the treatment of HER2+ breast cancer patients. The mechanism of action of trastuzumab is partly based on lysis of tumor cells via antibody dependent cellular cytotoxicity (ADCC), which among others involves NK cells. However, NK cell and CD8+ T-cell activity is inhibited by binding of the inhibitory receptor NKG2A to HLA-E. HLA-E expression is upregulated upon tumor cells and preserved throughout disease progression. Monalizumab is an antibody targeting the NKG2A receptor, thereby blocking NKG2A-HLA-E interaction. Monalizumab has shown clinical activity in head and neck cancer when combined with cetuximab (anti-EGFR). We hypothesize that monalizumab improves trastuzumab-mediated ADCC and thereby helps to overcome trastuzumab-resistance and can promote anti-tumor immunity by unleashing NK cells and CD8+ T cells in HER2+ breast cancer.

Trial design

The MIMOSA-trial (NCT04307329) is an explorative phase II trial in which patients will be treated biweekly with trastuzumab and monalizumab. Clinical efficacy will be assessed separately in patients with high stromal tumor-infiltrating lymphocytes (sTILs) (≥ 5%) and in patients with low sTILs (< 5%) using a Simon’s-two stage design. In stage I, eleven patients will be accrued per cohort. If two or more responders are observed, another eight patients will be accrued. Inclusion criteria comprise histologically confirmed HER2+ breast cancer on a metastatic lesion, progression during previous trastuzumab or TDM-1 therapy, administration of at least one and maximum of three lines of palliative chemotherapy, a metastatic lesion accessible for biopsy and LDH <500 U/l. Primary endpoint is the objective response rate according to RECIST1.1. Secondary endpoints include to evaluate clinical benefit and progression-free survival according to RECIST1.1, overall survival and safety. Before and on-treatment blood and biopsies will be used for translational research to explore treatment-induced intra-tumoral and systemic changes with a focus on NK-cells and CD8+ T-cells. The MIMOSA-trial is currently open for enrollment at the Netherlands Cancer Institute.

Clinical trial identification

NCT04307329.

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

AstraZeneca.

Disclosure

J.B.A.G. Haanen: Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Roche; Advisory/Consultancy, Research grant/Funding (institution): Neon Therapeutics; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Ipsen; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Aimm; Advisory/Consultancy: Achilles Therapeutics; Advisory/Consultancy: Amgen; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: Celsius Therapeutics; Advisory/Consultancy: GSK; Advisory/Consultancy: Immunocore; Advisory/Consultancy: MSD; Advisory/Consultancy: Neogene Therapeutics; Advisory/Consultancy: Sanofi; Advisory/Consultancy: Seattle Genetics. G.S. Sonke: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Roche. M. Kok: Advisory/Consultancy, Research grant/Funding (institution): BMS; Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy: Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

CDK4-6 inhibitors are now considered the standard of care for advanced ER-positive HER2-negative advanced breast cancer (ABC) in combination with endocrine therapy (ET). During the first wave of the COVID-19 pandemic, clinicians were uncertain what impact CDK4-6 inhibitor-induced immunosuppression may have on the risk of contracting COVID-19 or the severity of infection. Some clinicians pre-emptively reduced doses, altered schedules, or even withheld treatment, continuing ET alone. There is currently no evidence that CDK4-6 inhibitors increase the risk or severity of COVID-19 infection, although there have reports of protracted illness. We describe our experience of 203 patients receiving CDK4-6 inhibitors during the first wave and demonstrate the safety of continuing treatment during this period.

Methods

Epidemiological and clinical data were collected prospectively for patients at the Royal Marsden Hospital (RMH) and one network hospital with a ER-positive HER2-negative ABC that were receiving a CDK4-6 inhibitor between April 1st and June 30th 2020.

Results

200 patients received a CDK4-6 inhibitor in combination with ET, of which of 65/200 fulfilled local criteria to be screened with COVID-19 PCR testing and 6/65 were swab-positive. Two patients required hospital admission but there were no ICU admissions or COVID-19-associated deaths. Only 12 patients (6%) had treatment adjustments in the form of dose reduction (3/12), regime adjustment (2/12), or temporary interruption (7/12). In 9/12 cases this was a prophylactic measure due to additional risk factors; age (n=1), co-morbidities(n=3), patient choice (n=1) or overall concerns (n=4) to reduce the risk of contracting COVID-19. Results on dispensing >2 cycles at a time, telephone clinics, deferred CT scans and complications relating due to remote monitoring will also be reported.

Conclusions

Based on this snapshot during the first wave of the COVID-19 pandemic, we conclude that continuation of CDK4-6 inhibitors appears safe. This project is helping to drive a UK-wide review of CDK4-6 inhibitor treatment continuation, adjustment during the pandemic, assessing the risk of acquiring clinically severe COVID-19 infection, and subsequent cancer-related outcomes for these patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S.R.D. Johnston: Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Speaker Bureau/Expert testimony: Eisai; Research grant/Funding (institution), Clinical Trials: Roche/Genentech; Research grant/Funding (institution), Clinical Trials: Eli Lilly; Research grant/Funding (institution), Clinical Trials: Pfizer; Research grant/Funding (institution), Clinical Trials: AstraZeneca; Research grant/Funding (institution), Clinical Trials: Novartis; Research grant/Funding (institution), Laboratory studies: Pfizer; Research grant/Funding (institution), Laboratory studies: Puma Biotechnology. A. Okines: Research grant/Funding (self): Pfizer; Honoraria (self): Leo Pharma; Speaker Bureau/Expert testimony: Seagen; Advisory/Consultancy: Roche; Research grant/Funding (self): Roche; Honoraria (self): AstraZeneca; Advisory/Consultancy: Seagen. S. McGrath: Speaker Bureau/Expert testimony: Pfizer. All other authors have declared no conflicts of interest.

Background

In Europe, BEV is approved in combination with paclitaxel (PAC) or capecitabine (CAP) as 1st-line therapy for HER2-negative aBC. AVANTI (ML22452) assessed safety, effectiveness and pt-reported outcomes (EORTC QLQ-C30) with these regimens in German routine oncology practice.

Methods

Eligible pts had HER2-negative aBC, no BEV contraindications and had received no prior CT for aBC. CT schedule, diagnostics and follow-up visits were at the physician’s discretion. Data were collected for 1 y after starting BEV, then every 6 mo for 1.5 y (max follow-up: 2.5 y). Treatment satisfaction was rated by pts and physicians. Subgroup analysis was prespecified in clinically relevant subgroups, including triple-negative breast cancer (TNBC).

Results

Between 1 Nov 2009 and 30 Apr 2016, 2065 eligible pts at 346 centres received ≥1 dose of BEV with PAC (n=1821) or CAP (n=295); 51 switched CT and were analysed in both subgroups. Data cut-off for the final analysis was 3 Feb 2020. Median age was 60 y, 21% had TNBC, 56% prior (neo)adjuvant CT and 29% de novo metastatic disease. Pts receiving BEV + CAP were less likely to have de novo disease and more likely to have TNBC, age ≥60 y and prior CT and endocrine therapy (ET). The median treatment duration was 6.0 mo (95% CI 5.6–6.3) for BEV and 4.2 mo (4.0–4.2) for CT. Overall (complete or partial) response rate was 49% (95% CI 46–51%). Median PFS was 12.6 (95% CI 11.9–13.2) mo (12.8 with BEV + PAC, 10.5 with BEV + CAP); median OS was 23.9 (22.2–25.1) mo. PFS and OS were worse in pts with TNBC, prior CT or prior ET (Table). Grade 3/4 AEs were reported in 27% of pts and led to treatment discontinuation in 15%. Treatment satisfaction was rated as good or better by 304/394 (77%) responding pts at week 54 and in 1393/2065 pts (67%) by physicians across the study. Table: 98P

Conclusions

Final results from AVANTI show median PFS of 12.6 mo and a safety profile consistent with phase III experience.

Clinical trial identification

ML22452, 13th May 2015.

Editorial acknowledgement

Medical writing assistance: Jennifer Kelly (Medi-Kelsey Ltd.).

Legal entity responsible for the study

Roche Pharma AG.

Funding

Roche Pharma AG.

Disclosure

V. Mueller: Honoraria (self), Advisory/Consultancy: Amgen; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy: Teva; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Seattle Genetics; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: Hexal; Honoraria (self), Advisory/Consultancy: Pierre Fabre; Honoraria (self), Advisory/Consultancy: ClinSol; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Tesaro; Honoraria (self), Advisory/Consultancy: Nektar; Research grant/Funding (institution): Genentech. O. Hoffmann: Honoraria (self), Advisory/Consultancy: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self), Travel/Accommodation/Expenses: Eisai; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Honoraria (self): Riemser Pharma; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Hexal. A-K. Sommer: Full/Part-time employment: Roche Pharma AG; Shareholder/Stockholder/Stock options: Roche. A. Schneeweiss: Honoraria (self), Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Speaker Bureau/Expert testimony: AstraZeneca; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Travel/Accommodation/Expenses: Pfizer; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly; Research grant/Funding (institution): AbbVie. All other authors have declared no conflicts of interest.

Background

CDK 4/6 inhibitors (CDK4/6i) in combination with an ER targeted agent are the standard of care in in the treatment of metastatic ER+ breast cancer (MBC). Despite the significant increase in progression free survival seen with this combination, all patients eventually progress and therefore, there is a need for additional therapeutic options. The AR is expressed in up to 90% of ER+ breast cancer where it acts as a tumor suppressor. Enobosarm is a selective AR activating agent that does not cause virilization, and has positive clinical attributes such as promotion of bone strength and improvement of physical function. We report the clinical activity of enobosarm post CDK4/6i in women with AR+/ER MBC.

Methods

In study G200802, women with heavily pretreated AR+/ER+ MBC were randomized to receive either 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. The safety and clear clinical activity of enobosarm in this study has previously been reported (Palmieri et al., 2020). In this analysis, the antitumor activity of targeting AR in women previously treated with and progressing on a CDK 4/6i in study G200802 was examined.

Results

There were 10 evaluable patients with measurable metastatic AR+/ER+ MBC who had progressed following treatment with a CDK 4/6i (palbociclib). Enobosarm, dosed at either 9mg or 18 mg oral daily, resulted in a clinical benefit rate of 60%, and the best objective tumor response was 33% including 2 CRs and 1 PR. The overall mean radiographic PFS in the 9 mg cohort was 10.6 months and the median was 5.2 months. Enobosarm was well tolerated.

Conclusions

We report clinical activity of enobosarm in patients with AR+/ER+ MBC with prior disease progression on ER directed therapy plus palbociclib. At the 9 mg dose, which has been selected for the phase III study, the mean rPFS was 10.6 months. These data provide support for exploring the potential clinical benefit of targeting AR with enobosarm in MBC that has progressed on a CDK4/6 inhibitor. The phase III, ARTEST trial will commence in the Q2 2021 in patients with AR+/ER+/HER2- metastatic breast cancer that has progressed on a non-steroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor.

Clinical trial identification

NCT02463032.

Legal entity responsible for the study

GTx performed the study and Veru Inc performed the data analysis.

Funding

GTx funded the clinical trial and Veru Inc supported the data analysis.

Disclosure

C. Vogel, J. O'Shaughnessy, A.M. Brufsky: Advisory/Consultancy: Veru Inc. R.H. Getzenberg: Shareholder/Stockholder/Stock options, Full/Part-time employment: Veru Inc. K.G. Barnette, M. Steiner: Shareholder/Stockholder/Stock options, Full/Part-time employment, Officer/Board of Directors: Veru Inc. All other authors have declared no conflicts of interest.

Background

Tumor metastasis is the main cause of death for patients with triple-negative breast cancer (TNBC), and identification of metastasis drivers in TNBC is an urgent therapeutic need.

Methods

Expression of target molecules in primary tumors and metastases was quantified using immunohistochemistry analysis. Cancer cell spheroids, wound healing, and cell aggregation assays were used to explore cell–cell adhesion. Pre-clinical models of metastatic diffusion and whole-transcriptome analysis were used to assess epithelial–mesenchymal transition (EMT) determinants and epithelial differentiation biomarkers. Patient survival and metastatic relapse were analyzed using Cox models and Kaplan-Meier plots.

Results

Trop-2 was similarly overexpressed across diverse experimental cancer metastasis models. Trop-2 binding to E-cadherin inactivated cell–cell adhesion through detachment of E-cadherin from the cytoskeleton. Release of β-catenin then led to anti-apoptotic signaling, increased cell migration, and enhanced cancer cell survival. We did not detect induction of EMT transcription factors or down-regulation of epithelial differentiation markers. This E-cadherin–inactivation pro-metastasis program was also seen in cancer patients (n=13,042 primary tumours). All TNBC patients with overexpression of Trop-2, E-cadherin inactivation and activation of β-catenin showed relapse within 8 years. No disease recurrence was observed in any of the control cases, devoid of activation of the Trop-2/E-cadherin/β-catenin module, over more than 12 years of follow-up.

Conclusions

We have identified functional inactivation of E-cadherin by Trop-2 as a pivotal driver of EMT-less metastatic diffusion in TNBC. The sacituzumab govitecan-hziy anti–Trop-2 antibody has been shown to be effective in metastatic TNBC. Our findings provide support for a driving role and key therapeutic relevance of Trop-2 in TNBC.

Legal entity responsible for the study

The authors.

Funding

University of Chieti.

Disclosure

All authors have declared no conflicts of interest.

Background

Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high rates of morbidity/mortality. Large cohorts are scarce. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models.

Methods

ESME MBC database (NCT03275311) includes all consecutive patients having started treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan-Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots.

Results

Of 22,266 female patients included in the ESME database covering 2008-2016, 312 were IT-treated with methotrexate, cytarabine or thiotepa and included in our analysis (15 patients have been excluded because of lack of data on the treatment line). Compared with non-IT treated ones, these were younger at MBC relapse (median age 52 years vs 61 years) and had more often lobular histology (23.4% vs 12.7%) or triple-negative subtype (24.7% vs 13.3%) (all p<0.001). Median OS was 4.5 months (95% CI 3.8-5.6) and 1-year survival rate was 25.6%. In case of IT therapy, significant prognostic factors associated with worse outcome by multivariable analysis were triple-negative subtype (HR=1.81 [95%CI 1.32-2.47]), treatment line ≥ 3 (HR=1.88 [95% CI 1.30-2.73]), ≥ 3 other metastatic sites (HR=1.33 [95%CI 1.01-1.74]), and IT cytarabine or thiotepa vs methotrexate (HR=1.68 [95%CI 1.28-2.22]), while concomitant systemic therapy was associated with better OS (HR=0.47 [95%CI 0.35-0.62]) (all p<0.001). We validated two previously published prognostic scores, the Curie score and the breast graded prognostic assessment, both with C-index of 0.57.

Conclusions

MBC patients with LM treated with IT therapy have a poor prognosis. However, in this large series, we could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used.

Clinical trial identification

NCT03275311.

Legal entity responsible for the study

UNICANCER.

Funding

UNICANCER. The ESME MBC database receives financial support from an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai and Daiichi Sankyo). Data collection, analysis and publication are managed entirely by R&D UNICANCER independently of the industrial consortium.

Disclosure

M. Campone: Honoraria (self): Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: GT1. All other authors have declared no conflicts of interest.

Background

In phase II LEO study, everolimus (EVE) plus letrozole (LET) with ovarian suppression resulted in longer progression-free survival (PFS) in tamoxifen-exposed premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer with visceral metastases. Here, we report an updated survival for the LEO study, along with the results of exploratory analyses on bone turnover marker changes and bone-specific progressive disease.

Methods

Patients who were exposed to or progressed on tamoxifen as adjuvant or palliative treatment were randomly assigned (2:1) to the EVE (leuprorelin+LET+EVE) or LET arm (leuprorelin+LET).

Results

With a median follow-up of 51 months, Median PFS was 17.5 months in EVE arm and 13.8 months in LET arm (p=0.245). PFS favored EVE arm in patients with baseline visceral metastases (median PFS, 16.4 vs 9.5 months, p=0.040), and patients with bone metastases (median PFS, 17.1 vs 10.9, p=0.003). No differences in the OS were observed (median OS, 48.3 vs. 50.8 months, p=0.948). One-year cumulative incidence of bone-specific disease progression was 6.0% in EVE arm, and 23.4% in LET arm (Hazard ratio 0.26, p<0.001). Bone markers at 6 and 12 weeks after treatment decreased in EVE arm, whereas they were increased or stationary in LET arm. Skeletal-related events occurred 6.5% and 11.1% of the patients in the EVE and LET arm, respectively.

Conclusions

EVE plus LET with ovarian-suppression prolonged PFS in patients with baseline visceral or bone metastases and offered bone-protective effect in the overall study population. However, these clinical benefits were not translated into an OS benefit.

Clinical trial identification

NCT02344550 Original release date: 31 December 2020.

Legal entity responsible for the study

The authors.

Funding

Novartis and Dongkook Pharma Co, Ltd.

Disclosure

K.H. Jung: Honoraria (self): Roche; Honoraria (self): AstraZeneca; Honoraria (self): Celgene; Honoraria (self): Novartis; Honoraria (self): Takeda. J.H. Sohn: Research grant/Funding (self): MSD; Research grant/Funding (self): Roche; Research grant/Funding (self): Novartis; Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Lilly; Research grant/Funding (self): Pfizer; Research grant/Funding (self): Bayer; Research grant/Funding (self): GSK; Research grant/Funding (self): CONTESSA; Research grant/Funding (self): Daiichi Sankyo. K.S. Lee: Honoraria (self): Roche; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): MSD; Non-remunerated activity/ies, drug supply: Dong-A ST. S-B. Kim: Research grant/Funding (self): Novartis; Research grant/Funding (self): Sanofi-Aventis; Research grant/Funding (institution): DongKook Pharm Co.; Advisory/Consultancy: Novartis; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Lilly; Advisory/Consultancy: Enzychem; Advisory/Consultancy: Dae Hwa Pharmaceutical Co. Ltd; Advisory/Consultancy: ISU Abxis; Advisory/Consultancy: Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

Abemaciclib is an oral cyclin-dependent kinase 4 & 6 inhibitor, dosed on a continuous schedule, approved for the treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) combined with ET. In this pt population, CR is rarely seen with ET alone. Pt/disease characteristics may correlate with response to a specific treatment. In this post-hoc exploratory analysis, we report characteristics of pts with CR to abemaciclib+ET in M2 and M3.

Methods

M2 (NCT02107703) and M3 (NCT02246621) were double-blind, phase III studies in which women with HR+, HER2- ABC were randomised to receive abemaciclib/placebo+ET (M2: fulvestrant; M3: aromatase inhibitor). M2 included pts with progression during or ≤1 year of (neo)adjuvant ET or on first ET for ABC. M3 included pts who had not received prior systemic therapy for ABC. Disease characteristics were described in pts who achieved CR (RECIST v1.1) across the two studies, focusing on parameters reported to be associated with poor prognosis. Data are from the final progression-free survival analyses.

Results

Of 774 pts randomised to receive abemaciclib in M2 and M3, a total of 23 achieved CR: 14/446 in M2 and 9/328 in M3 (corresponding data in M2 and M3 pts receiving placebo+ET: 1/223 and 1/165 pts, respectively). A total of 3/14 M2 and 6/9 M3 abemaciclib pts had Eastern Cooperative Oncology Group (ECOG) status 1 (remainder: ECOG 0); 2/14 M2 and 0/9 M3 pts were progesterone receptor negative; 4/14 M2 and 3/9 M3 pts had a high-grade tumour; 10/14 M2 and 9/9 M3 pts had no bone-only disease, and 2/14 M2 and 0/9 M3 pts had liver metastases at baseline. Treatment-free interval was <3 years for 3/4 M3 pts with recurrent metastatic disease who had received adjuvant ET. 10/14 M2 pts and 5/9 M3 pts achieved CR <3 months after starting treatment; 7/14 M2 and 6/9 M3 pts had duration of response >15 months.

Conclusions

A small proportion of pts with recurrent ABC treated with abemaciclib in M2 and M3 achieved CR, including some pts with disease characteristics reported to be associated with poor prognosis. Those responses had a short time to onset and were relatively durable.

Editorial acknowledgement

Medical writing assistance was provided by Gill Gummer and Caroline Spencer (Rx Communications, Mold, UK).

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Funded by Eli Lilly and Company.

Disclosure

J. Huober: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Celgene; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (self): Hexal; Honoraria (self), Advisory/Consultancy: Eli Lilly and Company; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Daiichi; Honoraria (self), Advisory/Consultancy: AstraZeneca; Honoraria (self), Advisory/Consultancy: MSD; Honoraria (self): Eisai; Honoraria (self), Advisory/Consultancy: AbbVie. N. Chouaki, C. Stoffregen, A. Korfel: Full/Part-time employment: Eli Lilly and Company. F. Lerebours: Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eisai; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly and Company; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre Fabre; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest.

Background

Incidence of TNBC is much higher in developing countries like Pakistan. Although, new drugs like PARP inhibitors, Atezolizumab plus nab Paclitaxel, ipatisertib and Sacituzumab Govitecan are approved in metastatic TNBC, these are expensive and not readily available rendering chemotherapy remains main stay of treatment. BRCA mutations are often present in TNBC and Platinum drugs have shown their efficacy in BRCA mutated breast cancer. This study is aimed to look for response of platinum containing doublet in metastatic TNBC with unknown BRCA status as it’s cheaper and easily available.

Methods

A total of 290 patients (145 in each arm) of symptomatic metastatic TNBC were randomized in 2 groups.Group A received Adriamycin (60mg/m²) plus Cisplatin (75mg/m²) while Group B received Adriamycin (60mg/m²) plus Cyclophosphamide (600mg/m²) on day 1 of 21 days cycle for a total of 4 cycles. Response was assessed using RECIST criteria v.1.01. National Cancer Institute Common Toxicity Criteria version 4.03 (CTCAE) was used to document toxicities.Health related quality of life was determined using EORTC QLQ- C30 with a minimum decrease of ≥ 10 points considered significant. Data was analyzed using spss version 23. The quantitative variables were presented as mean ±SD while qualitative variables like tumor response as percentage and frequency. Independent sample t test with confidence interval of 95% was used for comparison between groups and p value of < 0.05 taken as significant.

Results

In group A, 33(22.8%) and 67(46.2%) showed complete and partial response respectively while stable and progressive disease was noted in 25(17.2%) and 20(13.8%). In group B, 23(15.9%) had complete response while 66(45.5%), 41(28.3%) and 15(10.3%), showed partial response, stable and progressive disease respectively (p=0.094) ORR between groups was 69.0% vs.61.4%.More grade ¾ neuropathy (p=0.004) and nephropathy (p=0.00007) was seen in group A. Quality of life was comparable in both groups(p=0.540).

Conclusions

No statistically significant difference in ORR seen in both groups. However, more Complete response was achieved in group A but at expense of more grade ¾ neuropathy and nephropathy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The prevalence of male breast cancer is <1% of all breast cancer cases, limiting the ability to conduct randomized clinical studies in this population. PAL plus an aromatase inhibitor or fulvestrant (FUL) is approved for the Tx of HR+/HER2– ABC in men. This analysis describes real-world pt characteristics and PAL use in male pts enrolled in the POLARIS study.

Methods

POLARIS is an ongoing, prospective, real-world, noninterventional study in pts with HR+/HER2‒ ABC receiving PAL with a targeted enrollment of 1500 pts from ∼110 sites in the United States and Canada. Baseline demographics, clinical characteristics, and Tx patterns were descriptively analyzed in men with HR+/HER2– ABC using pt data collected from medical charts and physician surveys.

Results

A total of 15 men were enrolled at the data cutoff of December 17, 2020; median age was 66 years, 60.0% of pts had recurrent disease, 40.0% had de novo metastatic disease, and 46.7% had visceral disease (Table). PAL plus endocrine therapy (ET) was received as first-line (1L) therapy by 9 pts (60.0%), second-line (2L) therapy by 4 pts (26.7%), and 2L+ therapy by 2 pts (13.3%). Among all pts, 4 initiated PAL with letrozole, 3 with anastrozole, and 7 with FUL; 1 pt did not receive ET during cycle 1 but initiated FUL during cycle 2. PAL was initiated at 125 mg in 13 pts (86.7%) and 100 mg in 2 pts (13.3%). One pt had a dose modification (interruption due to pt decision). Table: 106P