Triple Negative Breast Cancer: Presurgery Chemotherapy Benefits

Dr. Sikov MedicalResearch.com Interview with:
William M. Sikov, MD

Associate Chief of Clinical Research Program in Women’s Oncology
Women & Infants Rhode Island
Associate professor of Medicine
The Warren Alpert Medical School of Brown University

Medical Research: What is the background for this study? What are the main findings?

Dr. Sikov: The data presented at San Antonio this year are the first results from correlative studies performed on pretreatment tissue samples from patients treated on CALGB 40603, a 2 x 2 factorial randomized phase II study which tested the addition of carboplatin or bevacizumab to a standard neoadjuvant chemotherapy regimen consisting of weekly paclitaxel followed by dose-dense AC in patients with stage II-III triple breast cancer. Last year at San Antonio (and subsequently published in the JCO) we presented the primary endpoint of the study – pathologic complete response (pCR) – and reported that the addition of either carboplatin or bevacizumab significantly increased pCR rates compared to the control regimen. This year we reported results of a preplanned analysis which assessed the impact of intrinsic subtype (based on mRNA expression analysis) – especially the basal-like subtype – on the impact of the two agents on pCR rates. We also reported the effects of a number of previously published mRNA expression signatures on pCR rates and the benefits of adding carboplatin or bevacizumab.

The findings reported were as follows: We had a higher percentage of basal-like cancers than we anticipated when the study was designed (87% vs. 70-80% expected), which we hypothesize is due to improvements in the ways we assess hormone receptor and HER2 status, and thus define triple-negative breast cancer, compared to 10-15 years ago. When we limit our analysis to the subset of patients with basal-like cancers, we continue to see a statistically significant increases in pCR rates with both carboplatin and bevacizumab. However, while the 13% of patients with non-basal-like cancers get essentially the same increase in pCR rates with carboplatin as do the basal-likes, non-basal-likes actually had a reduction in their pCR rates with the addition of bevacizumab – thus, there was a significant interaction between subtype and pCR benefit for bevacizumab but not for carboplatin. Among the mRNA signatures we assessed, higher expression of immune signatures (indicating more tumor-infiltrating lymphocytes) correlated with higher pCR rates, but not greater pCR increments with either carboplatin or bevacizumab. Higher proliferation, lower estrogen, and higher TP53 mutation signaturss also correlated with higher pCR rates overall, and also with greater pCR increments with bevacizumab, but not carboplatin.

Medical Research: What should clinicians and patients take away from your report?

Dr. Sikov: In patients with TNBC for whom neoadjuvant chemotherapy is indicated, there is no apparent benefit to assessing subtype by mRNA expression array as we have yet to identify a subset of patients in whom the addition of carboplatin does not increase the likelihood of pCR; while such an analysis might influence a clinician’s decision as to whether to add bevacizumab, there is little interest in this agent in this setting, based on negative long-term results from other neoadjuvant and adjuvant trials. We do not have long-term outcomes (relapse-free and overall survival) from either CALGB 40603 or GeparSixto, so we do not yet know whether the increase in pCR rates with the addition of carboplatin seen in both of these studies will translate into substantial long-term benefits for patients with stage II-III TNBC.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Sikov: A number of further analyses are pending on tissue and blood samples obtained from the patients treated on CALGB 40603, including BRCA mutation status, assessment of homologous recombination deficiency (HRD) and looking at both tumor and germline mutations that could identify clinically relevant subsets of patients by response or resistance to neoadjuvant chemotherapy +/- carboplatin or bevacizumab. We also look forward to a study planned by NRG that will test the addition of carboplatin to standard adjuvant chemotherapy (dose-dense AC followed by weekly paclitaxel) in patients with TNBC.

Citation:

2014 SABCS San Antonio Breast Cancer Symposium abstract:

Positive Results for Triple-Negative Breast Cancer Presurgery Chemotherapy Benefits