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.

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.