TBCRC009: A Multicenter Phase II Clinical Trial of Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast Cancer

• Published in: Journal of clinical oncology Vol. 33; no. 17; pp. 1902 - 1909
• Main Authors: Isakoff, Steven J, Mayer, Erica L, He, Lei, Traina, Tiffany A, Carey, Lisa A, Krag, Karen J, Rugo, Hope S, Liu, Minetta C, Stearns, Vered, Come, Steven E, Timms, Kirsten M, Hartman, Anne-Renee, Borger, Darrel R, Finkelstein, Dianne M, Garber, Judy E, Ryan, Paula D, Winer, Eric P, Goss, Paul E, Ellisen, Leif W
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 10-06-2015
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor - genetics; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Carboplatin - administration & dosage; Carboplatin - therapeutic use; Cisplatin - administration & dosage; Cisplatin - therapeutic use; Class I Phosphatidylinositol 3-Kinases; Drug Administration Schedule; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomic Instability; Heterozygote; Humans; Loss of Heterozygosity; Middle Aged; Mutation; Neoplasm Staging; ORIGINAL REPORTS; Phosphatidylinositol 3-Kinases - genetics; Treatment Outcome; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2014.57.6660

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 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.
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.
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.