CALGB 40603 (Alliance): Long-Term Outcomes and Genomic Correlates of Response and Survival After Neoadjuvant Chemotherapy With or Without Carboplatin and Bevacizumab in Triple-Negative Breast Cancer.

Abstract

PURPOSE:

CALGB 40603 (NCT00861705), a 2 × 2 randomized phase II trial, demonstrated that adding carboplatin or bevacizumab to weekly paclitaxel (wP) followed by doxorubicin and cyclophosphamide significantly increased the pathologic complete response (pCR) rate in stage II-III triple-negative breast cancer. We now report long-term outcomes (LTOs) and correlative science end points.

PATIENTS AND METHODS:

The Kaplan-Meier method was used to estimate LTOs in 443 patients who initiated study treatment. Log-rank tests and Cox proportional hazards models evaluated the impact of clinical characteristics, pathologic response, calculated residual cancer burden (RCB) in patients with residual disease (RD), treatment assignment, and dose delivery during wP on LTOs, including event-free survival (EFS). Genomic predictors of treatment response and outcomes were assessed on pretreatment tumor samples by mRNA sequencing.

RESULTS:

Among baseline characteristics, only the clinical stage was associated with LTOs. At a median follow-up of 7.9 years, LTOs were not significantly improved with either carboplatin or bevacizumab, overall or in patients with basal-like subtype cancers by genomic analysis. Patients with pCR (n = 205, 46.3%) had significantly higher 5-year EFS (85.5% v 56.6%, log-rank P < .0001) and overall survival (87.9% v 63.4%, P < .0001) rates compared with patients with RD, even those with RCB class I. Among clinical and genomic features, evidence of immune activation, including tumor-infiltrating lymphocytes and low B-cell receptor evenness, was associated with pCR and improved EFS.

CONCLUSION:

Despite higher pCR rates, neither carboplatin nor bevacizumab appeared to improve LTOs although the study was not powered to assess these secondary end points. pCR was associated with superior LTOs even when compared with minimal RD. Markers of immune activation in pretreatment tumor biopsies were independently associated with higher pCR rates and improved survival.

• Authors: Jonathan H Shepherd, Karla Ballman, Mei-Yin C Polley, Jordan D Campbell, Cheng Fan, Sara Selitsky, Aranzazu Fernandez-Martinez, Joel S Parker, Katherine A Hoadley, Zhiyuan Hu, Yan Li, Matthew G Soloway, Patricia A Spears, Baljit Singh, Sara M Tolaney, George Somlo, Elisa R Port, Cynthia Ma, Charles Kuzma, Eleftherios Mamounas, Mehra Golshan, Jennifer R Bellon, Deborah Collyar, Olwen M Hahn, Clifford A Hudis, Eric P Winer, Ann Partridge, Terry Hyslop, Lisa A Carey, Charles M Perou, William M Sikov
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 40 Issue 12 Pg. 1323-1334 (04 20 2022) ISSN: 1527-7755 [Electronic] United States
• PMID: 35044810 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bevacizumab
• Carboplatin
• Paclitaxel

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (therapeutic use)
• Breast Neoplasms (drug therapy, genetics)
• Carboplatin (therapeutic use)
• Female
• Humans
• Neoadjuvant Therapy (methods)
• Neoplasm, Residual (drug therapy)
• Paclitaxel (therapeutic use)
• Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)