Chemotherapy For HER2-negative Breast Cancer Research Articles

Genomic patterns resembling BRCA-mutated breast cancers and benefit of intensified carboplatin-based chemotherapy in HER2-negative breast cancer.

10505 Background: The inability of breast cancer (BC) cells deficient in homologous recombination to repair DNA double strand breaks (DSBs), such as BRCA1/-2-mutated cells, offers a target for DNA crosslinking agents, e.g. bifunctional alkylating agents or platinum compounds. Our group previously employed array Comparative Genomic Hybridization (aCGH) to assess the genomic patterns of breast cancers with loss of BRCA1- or BRCA2. We hypothesized that these patterns might be present in some sporadic BCs as well and might predict sensitivity to DNA crosslinking agents. Methods: BRCA-likeCGH status, defined as positive when the previously published BRCA1-likeCGH and/or BRCA2-likeCGH pattern was present, was assessed in 249 stage-III BC patients, who had participated in a randomized controlled trial studying adjuvant high-dose (HD) cyclophosphamide-thiotepa-carboplatin (CTC) versus conventional 5-fluorouracil-epirubicin-cyclophosphamide (FE90C) chemotherapy. We evaluated whether the effect on recurrence-free and overall survival (RFS, OS) of HD-CTC compared to conventional FE90C differed by BRCA-likeCGH status, stratified for number of lymph nodes and triple negative status, and adjusted for tumor size and grade. Results: 81 patients (81/249, 32%) were shown to have BRCA-likeCGH tumors and had a significant benefit of HD-CTC compared to conventional FE90C regarding OS (adjusted HR 0.19, 95%CI: 0.08-0.48), while HD-CTC was not superior among patients with a Non-BRCA-likeCGH tumor (adjusted HR 0.90, 95%CI: 0.53-1.54). The difference was statistically significant (p-interaction: 0.004). Similar results were found for RFS. Sensitivity analyses showed that the aCGH test was robust and not dependent on small changes in tumor percentage or thresholds. Half of all BRCA-like tumors were ER-positive; 14% of BRCA1-like ones and 69% of the BRCA2-like ones. Twelve cases were both BRCA1- and BRCA2-like. Conclusions: aCGH genomic patterns identify both ER-positive and triple negative BC patients who derive a marked survival benefit from intensified DNA crosslinking chemotherapy.