Background

Although current guidelines recommend deciding on postmastectomy radiation therapy (PMRT) or regional nodal irradiation (RNI) after breast conserving surgery (BCS) depending on initial clinical stages before neoadjuvant chemotherapy (NAC), it is controversial whether adjuvant radiation therapy (RT) can be omitted for patients with excellent response. This retrospective study evaluates if PMRT or RNI after BCS significantly reduces locoregional recurrence rate in patients with clinically positive, pathologic negative lymph nodes (LNs) after NAC.

Methods

From 1999 to 2016, 1831 women with breast cancer underwent NAC and surgery. Of them, 427 patients with clinically node-positive and pN0 disease were analyzed.

Results

Median follow-up was 65.4 months. The 5-year locoregional relapse (LRRFS) and disease-free survival (DFS) rates were 96.9% and 88.3%, respectively. In patients with an initial nodal stage of cN2-3, RT significantly reduced LRR, with a hazard ratio (HR) of 0.132 (p = 0.009). However, RT was not shown to be effective in the cN1 group (HR = 0.893, p = 0.9). RT did not improve DFS, regardless of cN stage. PMRT/RNI was defined as the combined set of patients who received PMRT or received RT, including regional nodal irradiation (RNI) after BCS; the effects of PMRT/RNI were analyzed. PMRT/RNI significantly reduced LRR in the cN2-3 patient group (HR = 0.175, p = 0.03), but there was no significant effect for cN1 disease. Among 173 patients who underwent mastectomy, there were 108 and 65 patients, respectively, who received RT or no RT. Among all patients, PMRT had no effect on LRR (p = 0.7). However, among cN2-3 patients, PMRT significantly lowered LRR (HR = 0.10, p = 0.02), while there was no significant effect in cN1 patients.

Conclusions

In analysis of all patients and of mastectomy patients, RT consistently improved local control rate in the cN2 and higher patient group. Similar results were obtained in the combined analysis of PMRT and RNI after BCS. Therefore, in ypN0 patients graded cN2 or higher, RT including RNI is predicted to be absolutely necessary. No conclusion could be reached for cN1 disease.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Incorporating HER2-blockade into neoadjuvant drug regimens have led to a higher pathologic response in HER-positive breast cancer. In a view point of surgeon, a higher response to neoadjuvant treatment may offer a chance for de-escalating axillary surgery in patients with node-positive breast cancer at initial presentation. We investigated the rates of axillary lymph node dissection (ALND) and pathologic nodal response according to the types of neoadjuvant treatments including single or dual HER2 blockade in patients with clinically node-positive, HER2-postive breast cancer.

Methods

We retrospectively reviewed medical records from two institutions. From 2007 to 2018, patients with clinically node-positive, HER2-positive breast cancer treated with neoadjuvant chemotherapy were included. Primary outcome was the ALND rates after SLNB according to regimens. Secondary outcome was incidence of nodal pathologic complete response after axillary surgery.

Results

In a total, 512 patients were included for analysis. Two hundred and eighty-five patients (55.7%) were treated with chemotherapy alone, 135 (26.4%) with chemotherapy and trastuzumab, and 92 (18.0%) with chemotherapy, trastuzumab and pertuzumab. Nodal pCR rates were 45.6%, 77.8%, and 78.4% in each group (p-value < 0.0001). However, there was no difference in nodal pCR rates according to single or dual HER2-blockade (p-value = 0.778). In patients undergoing SLNB first, the ALND rates were 93.4%, 72.4%, and 71.6% in each group (p-value < 0.0001). The ALND rates were not different between two groups with single or dual HER2-blockade (p-value = 0.919). In 132 patients with more than three sentinel lymph nodes retrieved, the incidences of nodal pCR indicating the candidates for omission ALND were 44.3%, 86.2%, and 87.9% in each group (p-value < 0.0001).

Conclusions

For patients with node-positive, HER2-positive breast cancer, incorporating trastuzumab into neoadjuvant treatment had led to higher nodal pCR and reduced ALND. However, dual HER2-blockade with pertuzumab did not lead to increase nodal pCR and might not offer a chance of de-escalating axillary surgery compared to single HER2-blockade.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

We performed a pooled analysis of Asian pts in the phase III MONALEESA (ML) trials, which tested ET ± RIB in pts with hormone receptor–positive/human epidermal growth factor receptor-2–negative advanced breast cancer.

Methods

ML-2 and ML-3 enrolled postmenopausal pts; ML-7 enrolled pre/perimenopausal pts. To pool a homogenous population and reflect health authority recommended treatment, this analysis included all pts from ML-2, first-line pts from ML-3 and pts treated with a nonsteroidal aromatase inhibitor from ML-7.

Results

Pts were assigned to ET + PBO (118 Asian; 562 non-Asian) or ET + RIB (136 Asian; 651 non-Asian). In Asian pts, median PFS was 12.7 mo (95% CI, 9.1-15.6) with PBO vs not reached (NR; 95% CI, 16.6-NR) with RIB (hazard ratio [HR], 0.49 [95% CI, 0.34-0.70]). In non-Asian pts, median PFS was 16.5 mo (95% CI, 14.5-18.2) with PBO vs 25.3 mo (95% CI, 23.8-27.7) with RIB (HR, 0.59 [95% CI, 0.50-0.69]). In 182 Asian pts with visceral mets, median PFS was 12.7 mo (95% CI, 8.8-16.0) with PBO vs 23.9 mo (95% CI, 14.8-NR) with RIB (HR, 0.54 [95% CI, 0.36-0.82]). In 687 non-Asian pts with visceral mets, median PFS was 13.0 mo (95% CI, 11.1-14.9) with PBO vs 23.9 mo (95% CI, 19.9-29.6) with RIB (HR, 0.55; 95% CI, 0.44-0.68). In Asian pts, overall response rate (ORR) was 33.1% (95% CI, 24.6-41.5) with PBO vs 49.3% (95% CI, 40.9-57.7) with RIB (P = 0.005). In non-Asian pts, ORR was 27.8% (95% CI, 24.1-31.5) with PBO vs 38.2% (95% CI, 34.5-42.0) with RIB (P < 0.001). Among pts with visceral mets, ORR was 37.6% (95% CI 27.3-47.9) with PBO vs 52.6% (95% CI, 42.6-62.5) with RIB (P = 0.022) in Asian and 34.5% (95% CI, 29.3-39.7) with PBO vs 44.3% (95% CI, 39.2-49.4) with RIB (P = 0.004) in non-Asian pts. The most common grade 3/4 adverse event (AE) was neutropenia (preferred term) in Asian (47.1%) and non-Asian (45.6%) RIB-treated pts. In the Asian subgroup, 1 pt receiving PBO (0.8%) and 3 pts receiving RIB (2.2%) discontinued due to AEs; in non-Asian pts, 16 receiving PBO (2.8%) and 46 receiving RIB (7.1%) discontinued due to AEs.

Conclusions

Significant improvements in PFS and ORR were observed in Asian pts with RIB vs PBO. Discontinuation rates due to AEs were lower in Asian pts.

Clinical trial identification

NCT01958021; NCT02422615; NCT02278120.

Legal entity responsible for the study

Novartis Pharmaceutical Corporation.

Funding

Novartis Pharmaceutical Corporation.

Disclosure

S-A. Im: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eisai. Y-S. Yap: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Eisai; Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Roche. K.S. Lee: Advisory / Consultancy: Lily; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Research grant / Funding (self): Dong-A Socio. L.M. Tseng: Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (self), Travel / Accommodation / Expenses: Roche Pharma AG; Research grant / Funding (self): MSD; Travel / Accommodation / Expenses: GlaxoSmithKline. S.C. Lee: Honoraria (self): ACT Genomics; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Eisai; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Research grant / Funding (self): Taiho Pharmaceutical; Travel / Accommodation / Expenses: Amgen. Y.H. Park: Honoraria (self), Travel / Accommodation / Expenses: Merck; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Eisai. I. Gounaris: Non-remunerated activity/ies: PharmaMar; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. M. Sondhi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. A. Ridolfi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. J.P. Zarate: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. Y-S. Lu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Clinical trial study fee; Grant for clinical study for ESR1 mutation detected by cell free DNA;: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (self): Roche; Research grant / Funding (self): Merck Sharp & Dohme; Research grant / Funding (self): GlaxoSmithKline. All other authors have declared no conflicts of interest.

Background

Resistance to endocrine therapy in ABC has been linked to the activation of the PI3K/AKT/mTOR pathway.¹ Pivotal phase 3 studies such as BOLERO-2 has shown that treatment (tx) with EVE+EXE (vs EXE+ placebo [PBO]) improves PFS in postmenopausal women with HR+,HER2– ABC progressing on nonsteroidal aromatase inhibitors (NSAIs).² However, the BOLERO-2 trial included <10% of the pts from Middle East, Africa, and Asia Pacific nations. The tx outcomes of anticancer agents may vary based on ethnicities, thus it is key to evaluate the safety and efficacy of EVE+EXE in these populations.³ Here, we report the final safety and efficacy outcomes from the EVEREXES trial.

Methods

EVEREXES is a single-arm, phase IIIb study assessing the safety and efficacy of EVE+EXE in postmenopausal pts with HR+, HER2– ABC progressing on/after prior NSAI tx. Pts received EVE (10 mg QD) and EXE (25 mg QD). The primary outcome included safety and tolerability of EVE and the secondary objectives included PFS, ORR and CBR.

Results

A total of 235 pts received EVE+EXE therapy. The overall safety analysis were similar to results previously reported for EVE+EXE. AEs were the main reason for dose reduction/interruption. The most common grade 3/4 AEs were stomatitis (10.2%), non-infectious pneumonitis (4.3%), infections (2.1%), hyperlipidemia (1.7%), hypophosphatemia (1.7%) and increased creatinine (1.7%). The table depicts the final efficacy outcomes.Table: 40O

Overall efficacy results

Conclusions

The efficacy and safety profile of EVE+EXE in this predominantly Asian patient population is consistent with the BOLERO-2 study, thus validating the use of this combination therapy in Asian pts with HR+, HER2– ABC progressing on/after prior NSAIs. References Baselga J, et al. N Engl J Med 2012;366(6):520-529. Yardley DA, et al. Adv Ther 2013;30(10):870-884. Noguchi S, et al. Breast Cancer 2014;21(6):703714.

Clinical trial identification

NCT03176238.

Editorial acknowledgement

The authors would like to thank the patients who participated in the EVEREXES study and their families.

We acknowledge Susmita Bhattacharjee (Novartis Pharmaceuticals Corporation) for editorial assistance with this abstract. This presentation is the intellectual property of the author/presenter.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

B. Karabulut: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche, Merck Serono, Amgen, Pfizer, Novartis, MSD, BMS, J&J, Astellas, Sanofi, Bayer. K.S. Lee: Honoraria (self): Roche; Non-remunerated activity/ies: Dong-A Pharm; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Pfizer. All other authors have declared no conflicts of interest.

Background

The use of antracycline in breast cancer has been associated with adverse cardiac events and its prevention remains an important challenge in cancer. The aim of this study was to evaluate the efficacy of bisoprolol in preventing acute cardiac events caused by anthracycline drugs in breast cancer patients.

Methods

70 consecutive breast cancer patients planned to receive anthracycline chemotherapy were enrolled in this double blind, randomized clinical trial. Patients randomly assigned to receive either bisoprolol (2.5 mg daily) or placebo starting from day before chemotherapy up to 14 days after completion of chemotherapy course. One day before the start of chemotherapy and 14 days after the last chemotherapy, the level of Pro-BNP and troponin, CPK, CK-MB and EF (based on MUGA scan) were measured and changes were compared between the two groups.

Results

There was no significant difference in the level of EF (P = 0.160), CPK (P = 0.295), CK-MB (P = 0.073) or Pro-BNP (P = 0.066) in the bisoprolol group, but a significant decrease was observed in EF in the control group (P = 0.015). There was a significant increase in CPK and Pro-BNP (P = 0.03l; P = 0.048); however, no statistically significant difference in CK-MB was observed (P = 0.710) in the control group. troponin levels were not increased in any patients.

Conclusions

Our results showed that bisoprolol may have an appropriate preventive effect on the acute complications of anthracycline drugs in patients with breast cancer, thus its use can be recommended to reduce cardiac complications in this group of 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

Dysregulated metabolism is a hallmark of cancer and targeting specific metabolic pathways of cancer cells is a promising therapeutic strategy. Despite recent studies identified triple-negative breast cancer (TNBC) molecular subtypes, its metabolic pathway dependencies and metabolic classification has not been fully understood.

Methods

We applied an integrative analysis on transcriptomic and genomic data of TNBC (n = 360) from Fudan University Shanghai Cancer Center to explore the metabolic heterogeneity of TNBC. We conducted gene set variation analysis to calculate the relative enrichment score of 86 metabolic pathways in each sample. Furthermore, K-means clustering method was performed to classify the TNBC metabolic enrichment levels into heterogeneous subtypes. In addition, we systematically explored the metabolic differences and prognostic significance of the metabolic pathway based subtypes (MPS). A subset of TNBC cell lines were used to identify the different metabolites and metabolic phenotypes produced by the subtypes.

Results

We identified three heterogeneous subtypes in TNBC: MPS1, the lipidic subtype, with upregulated lipid metabolism; MPS2, the glycolytic subtype, with upregulated carbohydrate and nucleotide metabolism; MPS3, the mixed subtype, with part of pathways dysregulated. We found that MPS2 patients have worse prognosis, high homologous recombination deficiency score and are characterized by an amplification in chr12p12-12p13 genomic region. This amplification resulted in the over-expression of GAPDH, TPI1, ENO2, LDHB and DERA. TNBC cell lines belonging to MPS1 and MPS2 showed striking differences in fatty acid uptake, oxygen consumption and glucose utilization, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis. Moreover, knockdown of TPI1 in MPS2 TNBC cells inhibited cell growth, migration and invasion.

Conclusions

We identify three metabolic pathway based subtypes of TNBC with different prognosis outcomes which showed distinct sensitivities to metabolic inhibitors. Our study suggests opportunities for personalized therapies and TPI1 might serve as a potential therapeutic target.

Legal entity responsible for the study

The authors.

Funding

The National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.