Nucleotide excision repair deficiency identified by mutational signatures is associated with cisplatin response in triple-negative breast cancer

In triple-negative breast cancer (TNBC), platinum-based chemotherapy increases pathological complete response rates relative to non-platinum neoadjuvant chemotherapy, but its potential toxicity underscores the need for predictive biomarkers. While homologous recombination deficiency (HRD) has been proposed as a platinum sensitivity marker, FDA-approved HRD testing has shown only modest predictive power in TNBC clinical trials. Nucleotide excision repair (NER) deficiency is an alternative mechanism of platinum sensitivity identified in bladder cancer using next-generation sequencing-based mutational signatures. Here, we apply the ERCC2mut score, derived from bladder cancers with inactivating ERCC2 mutations, to identify potential NER-deficient breast cancers and evaluate their association with platinum response. In the Cancer Genome Atlas (TCGA) breast cancer cohort ( n = 943), 4.7% of cases showed indications of NER deficiency without concurrent HRD. In a cisplatin-treated TNBC cohort ( n = 50), both ERCC2mut ( p = 0.0077) and HRDetect ( p = 0.036) were associated with pathological response, but the two biomarkers identified largely non-overlapping patients. In the TBCRC030 randomized trial ( n = 54 cisplatin, n = 45 paclitaxel), multiple signatures associated with NER deficiency were significantly associated with response to cisplatin, but not to paclitaxel. These findings demonstrate that NER deficiency-associated mutational signatures can identify a subset of platinum-sensitive TNBC patients missed by HRD testing alone, supporting a combined biomarker strategy.