Homologous recombination (HR) facilitates error-free repair of double-strand DNA breaks and interstrand crosslinks.1 Mutations in BRCA1, BRCA2, and other genes responsible for HR are prevalent among human cancers and cause HR deficiency (HRD) and genomic instability.2 Recent evidence has shown that BRCA1 and BRCA2 mutations are associated with improved outcomes on platinum-based chemotherapy in pancreatic cancer,3-5 which mirrors more-established findings from breast cancer.6
Whole-genome sequencing (WGS) efforts have identified mutational and structural rearrangement signatures linked to BRCA1 and BRCA2 mutations in breast and other cancers,7 which may predict response to platinum-based chemotherapy8 and poly (ADP-ribose) polymerase inhibitors.9 However, the role signature timing plays in treatment response has not been elucidated but could help to distinguish currently active, actionable mutational processes from historically active ones.
We present the first clinical application of HRD dynamics across spatially and temporally distinct biopsy specimens of a pancreatic ductal adenocarcinoma (PDAC). This approach helped to reconcile the following paradoxical findings: genomic stability and low HRD mutation signature despite a germline BRCA1 mutation and exceptional response to fluorouracil, oxaliplatin, leucovorin, and irinotecan (FOLFIRINOX). The findings highlight the potential value of considering timing in the clinical interpretation of mutation signatures.