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

Author(s): Jonathan H. Shepherd, PhD1; Karla Ballman, PhD2; Mei-Yin C. Polley, PhD3; Jordan D. Campbell, PhD2; Cheng Fan, MS1; Sara Selitsky, PhD4; Aranzazu Fernandez-Martinez, MD1; Joel S. Parker, PhD5; Katherine A. Hoadley, PhD1,6; Zhiyuan Hu, PhD1; Yan Li, PhD1; Matthew G. Soloway, MS1; Patricia A. Spears, MS1; Baljit Singh, MD7; Sara M. Tolaney, MD, MPH8; George Somlo, MD9; Elisa R. Port, MD10; Cynthia Ma, MD, PhD11; Charles Kuzma, MD12; Eleftherios Mamounas, MD, MPH13; Mehra Golshan, MD14; Jennifer R. Bellon, MD8; Deborah Collyar, BS15; Olwen M. Hahn, MD16; Clifford A. Hudis, MD17; Eric P. Winer, MD8; Ann Partridge, MD8; Terry Hyslop, PhD18; Lisa A. Carey, MD19; Charles M. Perou, PhD1,6; and William M. Sikov, MD20
Source: DOI: 10.1200/JCO.21.01506 Journal of Clinical Oncology 40, no. 12 (April 20, 2022) 1323-1334.
Lucio Gordan MD

Dr. Gordan's Thoughts

The difference in CR vs RD rates with addition of carboplatin or bevacizumab was quite impressive. It is likely that the study was simply not powered to measure other endpoints. While LTOs were not improved, pCR was associated with superior LTOs. Biological markers of response are very interesting and may help us tailor specific therapies in the future.

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.

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.

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.

Author Affiliations

1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 2Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN 3Department of Public Health Sciences, University of Chicago, Chicago, IL 4QuantBio LLC, Durham, NC 5Life Edit Therapeutics, RTP, NC 6Department of Genetics, University of North Carolina, Chapel Hill, NC 7White Plains Hospital, White Plains, NY 8Dana-Farber/Partners CancerCare, Boston, MA 9City of Hope Comprehensive Cancer Center, Duarte, CA 10Mount Sinai Medical Center, New York, NY 11Washington University School of Medicine, St Louis, MO 12FirstHealth Sanford Hematology and Oncology, Sanford, NC 13UF Health Cancer Center Orlando, Orlando, FL 14Yale Cancer Center, Yale School of Medicine, New Haven, CT 15Patient Advocates In Research, Danville, CA 16University of Chicago Medical Center, Chicago, IL 17Memorial Sloan Kettering Cancer Center, New York, NY 18Department of Biostatistics & Bioinformatics, School of Medicine, Duke University, Durham, NC 19Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 20Program in Women’s Oncology, Women and Infants Hospital of Rhode Island and Warren Alpert Medical School of Brown University, Providence, RI

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