In an analysis from the phase II CALGB 40603/Alliance trial reported in the Journal of Clinical Oncology, Shepherd et al found that the addition of carboplatin or bevacizumab to neoadjuvant chemotherapy was not associated with improved long-term outcomes in patients with stage II or III triple-negative breast cancer. Achievement of pathologic complete response was associated with improved outcomes.
The 2 × 2 randomized trial showed that the addition of neoadjuvant carboplatin or bevacizumab to weekly paclitaxel followed by doxorubicin and cyclophosphamide significantly increased pathologic complete response rate.
Study Details
The analysis included 443 study patients and had a median follow-up of 7.9 years. Among all patients, estimated 5-year event-free survival was 70.3% and 5-year overall survival was 75.0%. Genomic predictors of treatment response and outcomes were assessed by mRNA sequencing in pretreatment tumor samples.
Key Findings
Among baseline characteristics, only clinical stage of III vs II was significantly associated with event-free survival (hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.53–3.01) and overall survival (HR = 2.42, 95% CI = 1.68–3.50). No associations with age, race, or tumor grade were observed.
No significant difference was observed in 5-year event-free survival among 222 patients who received bevacizumab vs 221 who did not (70.9% vs 69.6%, HR = 0.92, 95% CI = 0.66–1.29); no significant difference was observed in overall survival rates either (HR = 0.97, 95% CI = 0.67–1.40). No significant difference in event-free survival (70.4% vs 70.1%, HR = 0.94, 95% CI = 0.67–1.32) or overall survival (HR = 1.12, 95% CI = 0.77–1.61) was observed among 225 patients who received carboplatin vs 218 who did not. No significant differences in outcomes with either agent were observed in analysis among the subgroup of patients with basal-like subtype cancers.
Patients with pathologic complete response (n = 205, 46.3% of population) had significantly greater 5-year event-free survival (85.5% vs 56.6%, HR = 0.29, 95% CI = 0.19–0.42) and overall survival (87.9% vs 63.4%, HR = 0.28, 98% CI = 0.18–0.43) compared with patients with residual disease. Pathologic complete response was associated with significantly improved 5-year event-free survival when comparison was limited to patients with residual disease with residual cancer burden class I (67.0%; HR = 2.49, 95% CI = 1.46–4.25).
Among clinical and genomic features of pretreatment biopsies, evidence of immune activation (including tumor-infiltrating lymphocytes and low B-cell receptor evenness) was associated with both increased likelihood of pathologic complete response and improved event-free survival.
The investigators concluded, “Despite higher pathologic complete response rates, neither carboplatin nor bevacizumab appeared to improve long-term outcomes, although the study was not powered to assess these secondary endpoints. Pathologic complete response was associated with superior long-term outcomes even when compared with minimal residual disease. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pathologic complete response rates and improved survival.”
William M. Sikov, MD, of Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by National Cancer Institute grants, the Breast Cancer Research Foundation, Susan G. Komen, Genentech, and others. For full disclosures of the study authors, visit ascopubs.org.
