Reversion of Pathogenic BRCA1 L1780P Mutation Confers Resistance to PARP and ATM Inhibitor in Breast Cancer

This study investigates the molecular characteristics and therapeutic implications of the BRCA1 L1780P mutation, a rare variant prevalent among Korean hereditary breast cancer patients. Using patient-derived xenograft (PDX) models and cell lines (PDX-derived cell line) from carriers, sequencing analyses revealed loss of heterozygosity (LOH) at the BRCA1 locus, with one patient losing the wildtype allele and the other the mutated allele. This reversion mutation may confer resistance to homologous recombination deficiency (HRD)-targeting drugs such as PARP inhibitors (PARPi) and ATM inhibitors (ATMi). Although HRDetect and CHORD analyses confirmed a strong association between the L1780P mutation and HRD, effective initially, drug resistance developed in cases with reversion mutations. These findings underscore the complexity of using HRD prediction in personalized treatment strategies for breast cancer patients with BRCA1/2 mutations, as resistance may arise in reversion cases despite high HRD scores.