Genomic landscape of ERCC alterations in breast and gynecological cancers: implications for targeted therapy and VUS reclassification.

The Excision Repair Cross-Complementation (ERCC) gene family is critical for the Nucleotide Excision Repair (NER) pathway, yet its clinical utility in solid tumors remains underexplored. Impaired DNA repair via ERCC alterations drives tumorigenesis and influences response to DNA-damaging therapies. This study maps the clinical and genomic landscape of ERCC mutations to highlight their potential as predictive biomarkers. A retrospective analysis of cancer patients (2017-2024) was conducted utilizing a hereditary cancer Next-Generation Sequencing (NGS) panel. Excluding dominant variants like BRCA1/2, the study analyzed tumor characteristics, metastatic status, and receptor expression in patients harboring ERCC mutations. ERCC gene mutations were identified in 5.8% (32/550) of the cohort. The predominant malignancies were breast (40.7%), endometrial (22.2%), and ovarian cancers (7.4%), with metastasis present in 15.6% of cases. Mutations were most frequent in ERCC2 (43.8%) and ERCC4 (25%), primarily presenting as missense variants (68.8%). Notably, 87.5% of the identified alterations were classified as Variants of Uncertain Significance (VUS). ERCC alterations represent a critical, yet clinically underutilized, genetic factor in breast and gynecological malignancies. The remarkably high VUS rate in this cohort underscores an urgent need for international database updates and functional reclassification. Accurately profiling ERCC mutations offers a promising avenue for expanding personalized treatment strategies, particularly in leveraging platinum-based therapies and PARP inhibitors for non-BRCA carriers.