e16424 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with 5-year survival below 13% and rising incidence. Most patients present with advanced disease unsuitable for resection. DNA damage repair (DDR) alterations, including BRCA1/2, PALB2, RAD51 paralogs, ATM, ATR, CHEK1/2, and Fanconi anemia genes, occur in 25% of PDAC and confer platinum-sensitivity and PARP inhibitor responsiveness. Olaparib demonstrated significant benefit as maintenance therapy in germline BRCA-mutated metastatic PDAC, establishing biomarker-driven treatment. Here, we characterize the molecular landscape and develop an OS nomogram for DDR-altered PDAC. Methods: We analyzed data from 4,132 PDAC patients with DDR alterations from cBioPortal (2012-2025). We investigated BRCA1/2, PALB2, RAD51B/C/D/54L, BARD1, BRIP1, ATM, ATR, CHEK1/2, FANCA, FANCL, PTEN, NBN, MRE11, STK11, CDH1, CDK12 , and interacting oncogenes ( KRAS , BRAF , PIK3CA ), reflective relevant HRR NGS panels used in clinical practice. We evaluated copy number alterations, mRNA expression, clinicopathological factors, and OS. Transcriptomic profiling identified survival-associated signatures. A nomogram integrating clinical, pathological, and molecular features was constructed for OS prediction. Results: Genomic analysis of 4,024 PDAC samples revealed mutations in BRAC2 (3%), BRAC1 (1.5%), TP53 (68%), STK11 (2%), KRAS (87%), PIK3CA (2%) and ATM (3%). Notably, DDR alterations were associated with inferior OS (log-rank P < 0.001; mOS altered vs wild-type 18.28 vs 26.24 months) and DFS (log-rank P = 0.041; mDFS altered vs wild-type 14.95 vs 27.30 months). Transcriptomic and GSEA profiling linked these alterations to changes of oncogenic pathways, including dysregulated homologous recombination, base excision repair, Fanconi checkpoint control, cell cycle regulation, epithelial-mesenchymal transition, and immune pathways. The prognostic nomogram incorporated age, stage, differentiation, and top 5 most significantly identified transcriptomic signatures. Conclusions: This study characterizes DDR-altered PDAC, revealing distinct genomic and transcriptomic profiles. DDR alterations identify patients benefiting from platinum-chemotherapy and PARP inhibitors, with superior outcomes versus unselected populations. The validated nomogram provides a precision tool for OS prediction, guiding treatment selection, surveillance, and trial stratification. These findings emphasize universal DDR screening importance and support molecular profiling integration to improve outcomes through biomarker-driven strategies.
Laliotis et al. (Thu,) studied this question.