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Pathologic complete response to neoadjuvant chemotherapy predicts survival in triple-negative breast cancer
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SAN ANTONIO — Patients with stage II or stage III triple-negative breast cancer who achieved pathologic complete response to standard neoadjuvant chemotherapy experienced longer EFS and OS than patients who had more than minimal residual invasive disease at the time of surgery, according to study results presented at San Antonio Breast Cancer Symposium.
The randomized phase 2 CALGB/Alliance 40603 trial — a 2 x 2 factorial, open-label, randomized phase 2 study — assessed whether the addition of carboplatin and/or bevacizumab (Avastin, Genentech) to standard neoadjuvant chemotherapy — weekly paclitaxel followed by doxorubicin/cyclophosphamide — increased pathologic complete response (pCR) among 443 patients with stage II or stage III triple-negative breast cancer who received standard neoadjuvant chemotherapy.
Initial results published in Journal of Clinical Oncology showed the study met its primary endpoint, as the addition of each agent significantly increased pCR in the breast. The addition of carboplatin also significantly increased pCR in the breast and axilla, whereas the effect of bevacizumab on pCR in the breast and axilla was borderline significant.
William M. Sikov
In the current analysis, William M. Sikov, MD — associate director of clinical research in the Program in Women’s Oncology at Women and Infants Hospital of Rhode Island and associate professor at Warren Alpert Medical School of Brown University — and colleagues analyzed the effects of pCR on the pre-defined secondary endpoints of EFS and OS.
Researchers performed this analysis after 110 EFS events and 77 deaths. Median follow-up was 39 months.
At 3 years, EFS was 74.1% and OS was 83.2%. Three-year EFS rates were higher among patients who achieved pathologic complete response (84.8% vs. 61.8%).
Results revealed a statistically significant improvement in EFS among patients who achieved pCR in the breast (HR = 0.33; 95% CI, 0.22-0.5), as well as pCR in the breast and axilla (HR = 0.3; 95% CI, 0.19-0.46). Researchers also reported a statistically significant improvement in OS among patients who achieved pCR in the breast (HR = 0.28; 95% CI, 0.17-0.46), as well as pCR in the breast and axilla (HR = 0.2; 95% CI, 0.11-0.36).
The amount of residual invasive disease also may be important, Sikov said.
Thirteen percent of the study population achieved minimal residual invasive disease, defined as Residual Cancer Burden Class I (RCB I). When researchers added the RCB I group to those who achieved pCR in the breast and axilla, they observed no reduction in prognostic significance for EFS (HR = 0.29; 95% CI, 0.2-0.43) or OS (HR = 0.21; 95% CI, 0.13-0.34).
At 3 years, patients who achieved pCR in the breast and axilla demonstrated lower rates of ipsilateral invasive breast recurrence (2.9% vs. 13.3%), other locoregional recurrence (1.5% vs. 6.6%), distance recurrence (9.2% vs. 26.5%), death from any cause (6.8% vs. 28.3%) or breast cancer-attributed death (5.8% vs. 25.2%).
When researchers examined survival outcomes by agent, they observed no statistically significant difference at 3 years between patients who received carboplatin (HR for EFS = 0.84; 95% CI, 0.58-1.22; HR for OS = 1.15; 95% CI, 0.74-1.79) or bevacizumab (HR for EFS = 0.8; 95% CI, 0.55-1.17; HR for OS = 0.76; 95% CI, 0.49-1.19) compared with those who did not receive either agent.
Sikov acknowledged the study was underpowered to determine whether the addition of carboplatin or bevacizumab would improve EFS despite the increase in pathologic complete response rates, Sikov said.
“It is important not to over-interpret the results,” Sikov said during a press conference. “If you look at the confidence intervals for event-free survival for carboplatin, for example, it ranges from a benefit of 45% to an actual worsening of 22%, and there is a 95% chance that the truth lies somewhere in that range. If I said to you, ‘We can prove there is a 20% improvement with carboplatin,’ if you have a large enough study to do so, that may be we worth considering. It is important not to take this as a negative study. It was a study that was underpowered to prove an advantage or to rule out an advantage.”
Prior studies failed to demonstrate improvement in long-term outcomes with the addition of bevacizumab to a control regimen in stage I to stage III triple-negative breast cancer, Sikov said. Results from the GeparSixto study, scheduled for presentation at San Antonio Breast Cancer Symposium, should help clarify whether the addition of carboplatin benefits patients with early-stage triple-negative breast cancer, he said.
“Our results need to be considered alongside data from prior and ongoing studies with these agents in triple-negative breast cancer,” Sikov said in a press release. “Going forward, the question is whether we want to commit the additional patients and resources necessary to answer this question or instead focus our research efforts in triple-negative breast cancer on other opportunities to improve outcomes.” – by Mark Leiser
Reference:
Sikov WM, et al. Abstract S2-05. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.
Disclosure: The research was supported by Breast Cancer Research Foundation, Genentech and NCI’s Cancer Therapy Evaluation Program.
Perspective
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Virginia Kaklamani, MD
It is extremely important for us to complete ongoing adjuvant clinical trials that are powered to look at EFS and OS so we actually get the data and they are reliable. However, this study shows we have a group of patients who are doing pretty well — actually significantly well, because they have triple-negative breast cancers, which are the hardest ones to treat — when they achieve pathologic complete response. Then you have a group of patients who do not achieve pathologic complete response, and their outcomes are much worse. We need to identify those patients so we can offer them studies where we are giving them more chemotherapy, different chemotherapy or — hopefully in the future — targeted therapies so we can improve their outcomes. These are the women who are going to have recurrence of their cancers and develop metastatic disease. It is extremely important to know who they are so we can individualize care for those patients. That is why this study is so important.
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