Steven J Isakoff1, Erica L Mayer2, Lei He2, Tiffany A Traina2, Lisa A Carey2, Karen J Krag2, Hope S Rugo2, Minetta C Liu2, Vered Stearns2, Steven E Come2, Kirsten M Timms2, Anne-Renee Hartman2, Darrel R Borger2, Dianne M Finkelstein2, Judy E Garber2, Paula D Ryan2, Eric P Winer2, Paul E Goss2, Leif W Ellisen2. 1. Steven J. Isakoff, Lei He, Darrel R. Borger, Dianne M. Finkelstein, Paula D. Ryan, Paul E. Goss, and Leif W. Ellisen, Massachusetts General Hospital Cancer Center; Steven J. Isakoff, Erica L. Mayer, Lei He, Karen Krag, Steven E. Come, Darrel R. Borger, Dianne M. Finkelstein, Judy E. Garber, Paula D. Ryan, Eric P. Winer, Paul E. Goss, and Leif W. Ellisen, Harvard Medical School; Erica L. Mayer, Judy E. Garber, and Eric P. Winer, Dana-Farber Cancer Institute; Steven E. Come, Beth Israel Deaconess Medical Center, Boston; Karen Krag, Massachusetts General Hospital/North Shore Cancer Center, Danvers, MA; Tiffany A. Traina, Memorial Sloan Kettering Cancer Center, New York, NY; Lisa A. Carey, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Hope S. Rugo, University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Minetta C. Liu, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Vered Stearns, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Kirsten Timms, Myriad Genetics; and Anne-Renee Hartman, Myriad Genetic Laboratories, Salt Lake City, UT. sisakoff@mgh.harvard.edu. 2. Steven J. Isakoff, Lei He, Darrel R. Borger, Dianne M. Finkelstein, Paula D. Ryan, Paul E. Goss, and Leif W. Ellisen, Massachusetts General Hospital Cancer Center; Steven J. Isakoff, Erica L. Mayer, Lei He, Karen Krag, Steven E. Come, Darrel R. Borger, Dianne M. Finkelstein, Judy E. Garber, Paula D. Ryan, Eric P. Winer, Paul E. Goss, and Leif W. Ellisen, Harvard Medical School; Erica L. Mayer, Judy E. Garber, and Eric P. Winer, Dana-Farber Cancer Institute; Steven E. Come, Beth Israel Deaconess Medical Center, Boston; Karen Krag, Massachusetts General Hospital/North Shore Cancer Center, Danvers, MA; Tiffany A. Traina, Memorial Sloan Kettering Cancer Center, New York, NY; Lisa A. Carey, The University of North Carolina at Chapel Hill, Chapel Hill, NC; Hope S. Rugo, University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Minetta C. Liu, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC; Vered Stearns, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD; Kirsten Timms, Myriad Genetics; and Anne-Renee Hartman, Myriad Genetic Laboratories, Salt Lake City, UT.
Abstract
PURPOSE: The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates. PATIENTS AND METHODS: Patients with mTNBC received first- or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers. RESULTS: Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores. CONCLUSION: Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted.
PURPOSE: The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates. PATIENTS AND METHODS: Patients with mTNBC received first- or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers. RESULTS:Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores. CONCLUSION:Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted.
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