By ecancer reporter Janet Fricker

The preoperative combination of gemcitabine, carboplatin, and iniparib is active and well tolerated in the treatment of early-stage triple negative breast cancer (TNBC) and BRCA1/2 mutation-associated breast cancer, finds the PrECOG0105 study published in Journal of Clinical Oncology.

Sporadic TNBC shares many pathologic and molecular features with breast cancer caused by hereditary BRCA1 germline mutations.

Such observations led to the hypothesis that sporadic TNBC may possess similar DNA repair defects and similar chemosensitivity profiles to BRCA1/2 mutation associated breast tumours.

In the current study Melinda Telli and colleagues, from Stanford University School of Medicine, set out to investigate a neoadjuvant combination chemotherapy regimen (gemcitabine, carboplatin, and iniparib targeting DNA repair defects in early-stage TNBC and BRCA1 /2 mutation associated breast cancer.

Although initially investigated as a PARP1 inhibitor, iniparib’s mechanism of action is now believed to be involved with uncoupling of electro transport from oxidative phosphorylation, producing reactive oxygen species at cytotoxic levels.

A major goal of the study was to identify markers of response among patients with TNBC.

In the single-arm phase II neoadjuvant study, 93 patients with stage I to IIIA oestrogen receptor-negative or BRCA1/2 mutation-associated breast cancer received intravenous (IV) neoadjuvant gemcitabine (1,000 mg/m2 on days one and eight); IV carboplatin (at an area under curve of 2 on days one and eight) and IV iniparib (5.6 mg/kg on days one, four, eight and 11).

The protocol was administered every 21 days for four cycles, but was later amended to six cycles.

Altogether 80 patients received six cycles.

The primary endpoint was pathologic complete response (i.e. no invasive carcinoma in breast or axilla).

For the study homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies.

Among the patients 19 (24%) had germline BRCA1 or BRCA2 mutations.

Results showed that the overall pathologic complete response in the intent-to-treat population was 36% (90% CI, 27 to 46).

Additionally, results showed that mean HRD-LOH scores were higher in responders compared with non responders (P=.02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P=.021).

The most common treatment-related adverse events for those treated with four and six cycles respectively were fatigue (84.9% for four cycles, and 85.0% for six cycles); nausea (81.7% for four cycles and 81.3% for six cycles); and neutropenia or neutrophil count decreases (49.5% for four cycles and 53.8% for six).

Grade 4 adverse events only occurred among those receiving six cycles.

“Our results do not have direct impact on clinical practice today, but they strongly suggest that patient selection based on underlying DNA repair deficiency in future randomized trials of standard versus DNA repair defect-targeted therapy in TNBC should be pursued,” write the authors.

The study, they add, represents the first assessment to their knowledge of HRD-LOH biomarkers in TNBC.

Reference: M Telli, K Jensen, S Vinayak, et al. 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: PrECOG0105. JCO doi: 10.1200/JCO.2014.57.0085