Phase II Study of Gemcitabine, Carboplatin, and Iniparib As Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer With Assessment of a Tumor-Based Measure of Genomic Instability: PrECOG 0105

Abstract

Purpose: This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.

Patients and methods: This single-arm phase II study enrolled patients with stage I to IIIA (T ≥ 1 cm) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m(2) intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies.

Results: Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021).

Conclusion: Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

Trial registration: ClinicalTrials.gov NCT00813956.

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.

Homologous recombination deficiency–loss of heterozygosity (HRD-LOH) score distribution among responders (residual cancer burden, 0 or 1) and nonresponders (residual cancer burden, 2 or 3). Plot shows distribution of HRD-LOH scores among responders in blue (BRCA1/2 mutant and wild type) and nonresponders in gold. Size of each dot corresponds to number of patients with that score; larger dot indicates more patients with that HRD-LOH score.

Fig 2.

Rate of favorable response (residual cancer burden [RCB], 0 or 1) by homologous recombination deficiency–loss of heterozygosity (HRD-LOH) score, germline BRCA1/2 status, and their combination (n = 65). Proportion of patients achieving favorable response, defined as RCB index score of 0 or 1 based on (A) HRD-LOH score low (< 10) versus high (≥ 10), (B) germline BRCA1/2 status wild type (WT) versus mutant, and (C) combination of HRD-LOH low (< 10) and germline BRCA1/2 WT versus HRD-LOH high (≥ 10) or germline BRCA1/2 mutant. Total of 65 of 80 patients in six-cycle protocol had HRD-LOH data available.