Platinum-based neoadjuvant chemotherapy and the predictive role of DNA damage response biomarkers in TNBC: the NeoCarbo study.

Platinum-containing neoadjuvant chemotherapy increases pathological complete response (pCR) rates in triple-negative breast cancer (TNBC), but predictive biomarkers remain incompletely defined. In the multicenter NeoCarbo cohort, we assessed a carboplatin-containing neoadjuvant regimen and examined whether germline homologous recombination deficiency (HRD) and baseline tumor DNA damage response (DDR) activation predict pCR and outcomes. Stage I-III TNBC patients at three centers received carboplatin (AUC6 q3w×4) plus weekly paclitaxel (×12), followed by dose-dense epirubicin/cyclophosphamide (q2w×4) and surgery. The primary endpoint was pCR (ypT0/is ypN0); secondary endpoints were disease-free survival (DFS) and overall survival (OS). Germline HRD was defined by pathogenic/likely pathogenic variants in BRCA1/2 and other homologous recombination genes, and DDR activation was assessed centrally by phospho-DDR immunohistochemistry. Among 128 patients, pCR occurred in 77 (60.2%; 95% CI 51.1-68.7%). HRD status was available in 80 patients (28 HRD-positive), with pCR rates of 78.6% in HRD-positive versus 57.7% in HRD-negative tumors (Fisher p = 0.086). In a bivariable analysis restricted to patients with complete biomarker data, HRD positivity independently predicted pCR (adjusted OR 2.68; 95% CI 1.16-6.85; p = 0.027), whereas DDR tertiles were not independently associated with pCR. At a median follow-up of 60.4 months, pCR was associated with improved DFS (HR 0.29; 95% CI 0.12-0.72; p = 0.008) and OS (HR 0.30; 95% CI 0.12-0.81; p = 0.017). Grade ≥3 toxicity occurred in 14.4% during carboplatin-paclitaxel and 18.9% during epirubicin-cyclophosphamide, predominantly hematologic. These findings support high pCR rates with this regimen and suggest that HRD may identify patients more likely to achieve pCR, whereas baseline tumor phospho-DDR lacked predictive value; future evaluation may require dynamic DDR assessment in larger studies.