DNA-Based Biomarkers as Predictors of Carboplatin Response in Neoadjuvant Treatment for Hormone Receptor Positive and Triple-Negative Breast Cancer

PURPOSE: This prospective, randomized neoadjuvant study evaluated DNA-based biomarkers to identify breast cancer patients most likely to benefit from carboplatin (Cb). While Cb improves outcomes in triple-negative breast cancer (TNBC), responses vary, and its role in aggressive hormone receptor-positive breast cancer (HR+BC) remains uncertain. PATIENTS AND METHODS: Patients (N = 187) with early, high-risk, HER2-negative cT2-4 tumors received 12 weekly paclitaxel with or without Cb, followed by four cycles of epirubicin and cyclophosphamide. Pretreatment tumor whole-exome sequencing was used to calculate the complex arm-wise aberration index (CAAI), loss of heterozygosity (LOH) fraction, and homologous recombination deficiency (HRD) status. RESULTS: For TNBC patients, pathologic complete response (pCR) was obtained in 69% (24/35) with Cb versus 43% (16/37) with control (p = 0.036) whereas 74% (26/35) and 65% (24/37), respectively, acquired either pCR or recidual cancer burden class 1 (RCB 1; p = 0.45). Cb significantly prolonged event-free survival (EFS; p = 0.017). In patients with a low genomic LOH fraction, Cb improved EFS (p = 0.007). Low genomic LOH fraction also indicated an unfavourable prognosis without Cb, confirmed in an independent cohort (n = 67, p = 0.02). For HR+BC patients, pCR was 15% (9/60) with Cb versus 11% (6/55) with control (p = 0.59), but the proportion achieving low residual cancer burden (pCR and RCB 1) increased from 16% (9/55) to 35% (21/60; p = 0.033). Among patients having HR+BC tumors with HRD, 5 of 8 attained pCR with Cb compared with 4 of 47 HRD-negative tumors (p = 0.002). CONCLUSION: This study indicates distinct predictive values of complex DNA-based biomarker analyses for breast-cancer subtypes. Low genomic LOH fraction may identify TNBC patients who benefit most from Cb, while HRD may guide Cb use in HR+BC.