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

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.

Trial registration: ClinicalTrials.gov NCT00483223.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.

(A) Progression-free survival and (C) overall survival estimates for all 86 enrolled patients. (B) Progression-free survival and (D) overall survival of BRCA1/2 mutation (MUT) carriers versus BRCA1/2 wild type (WT). Hazard ratios (HRs) and 95% CIs estimated by the Kaplan-Meier method. Patients were censored at last follow-up or at time of change in therapy without progression.

Fig 2.

High homologous recombination deficiency–loss of heterozygosity (HRD-LOH) and homologous recombination deficiency–large-scale state transition (HRD-LST) scores are associated with BRCA1/2 mutation and with platinum sensitivity. Primary tumor DNA was analyzed for two distinct genomic aberration patterns (HRD-LST, HRD-LOH) as described in Results. Higher scores indicate increased aberrations. Horizontal lines show mean values ± SEM. (A) BRCA1/2-mutant (MUT) versus wild-type (WT) tumors. (B) Tumors of responding patients (complete response [CR] plus partial response [PR]) versus nonresponding patients (stable disease [SD] plus progressive disease [PD]), excluding BRCA1/2-mutant tumors. Unpaired t test (Welch's correction) was used to calculate P values. Gray circle indicates germline BRCA1 mutation; blue circle indicates patient without germline or tumor somatic BRCA1/2 mutation, BRCA1 methylation, or long-term response; gold diamond indicates somatic BRCA1 mutation; red diamond indicates germline BRCA2 mutation; gold triangle indicates BRCA1 promoter methylation; gold star indicates long-term responder.

Fig 3.

Summary of gene expression and mutational analysis. Each column represents one patient. Row 1: Progression-free survival (PFS) in days. Row 2: The four RECIST response categories shown here are complete response (light blue), partial response (gray), stable disease (gold), and progressive disease (red). Row 3: Germline BRCA1 (1) and BRCA2 (2); no mutation (blank). Row 4: Tumor p53 mutation analyses; no mutation (blank); missense mutation ([solid dot]); nonsense/splice-site mutation ([solid star]). Row 5: Tumor PIK3CA mutation analyses; no mutation (blank); missense mutation ([solid dot]). Row 6: ΔNp63:TAp73 messenger RNA expression ratio (ie, p63:p73) > 2 ([solid dot]); < 2 (blank). Row 7: PAM50 basal signature according to Nielson et al; basal ([solid dot]); nonbasal (blank). Row 8: Gene expression signatures derived from Lehmann et al: unstable (dark blue), immunomodulatory (orange), mesenchymal stem-like (yellow), basal-like 1 (brown), basal-like 2 (light blue), luminal androgen receptor (black), and mesenchymal (green). (L) Long-term responders; (X) not available.