Abstract B047: DNA Damage Repair (DDR) Variants Beyond BRCA/PALB2 in Pancreatic Adenocarcinoma (PDAC): Evaluation of Significance

Abstract Background: Approximately 10–20% of patients (pts) with PDAC harbor a germline pathogenic variant (gPV), many involving the DDR pathway. The associated clinico-genomic features of DDR gPVs beyond BRCA is not characterized. We present a cohort of pts with DDR gPVs and PDAC, describing key clinical characteristics and outcomes, DDR zygosity, and illustrative family histories. Methods: Institutional databases queried to identify pts with PDAC and DDR gPVs (excluding BRCA, PALB2, ATM) diagnosed between 01/2012–12/2024. Data abstracted from medical records. Zygosity determined with FACETS. Homologous Recombination Deficiency (HRD) score determined with TAI, LST, and LOH. Median progression-free survival (mPFS) and overall survival (mOS) estimated via Kaplan-Meier. Results: We identified 124 pts with PDAC and rare DDR variants: MUTYH (N=36), CHEK2 (N=15), BLM (N=13), FANCA/C (N=19), RECQL/RECQL4 (N=12), BRIP1 (N=8), RAD50 (N=6), RAD51B/C/D (N=5), MRE11A (N=4), NBN (N=4), and BARD1 (N=2). Overall, 62 pts (50%) male; 109 (88%) white. Median age for whole cohort 69 years, with subgroup medians from 57 (RAD51B/C/D) to 75 years (FANCA/C). At diagnosis, 48 pts (39%) with stage IV disease, including 1 (13%) BRIP1, 2 (15%) BLM, and 5 (33%) CHEK2 gPVs pts. Notably, no pts diagnosed through screening, and PDAC head tumors more frequently observed in subgroups with higher proportion of early-stage disease (head tumors: 54% BRIP1, 75% BLM, 67% CHEK2). Among 64 pts with zygosity data, biallelic DDR variants (via somatic loss) identified in 10 (16%). Median tumor mutational burden (TMB) for whole cohort 3.5 mt/Mb, ranging from median 2.95 (MUTYH) to 5.3 mt/Mb (NBN). Median HRD score 23, ranging from 11 (RAD50) to 46.5 (RAD51C/B/D). Whole-genome doubling (WGD) present in 20 (26% of pts with WGD data). KRAS mutations detected in 91.4% of pts, with lowest prevalence in BARD1 (66%) and FANCA/C (80%). Ten pts had family history of PDAC: 6 MUTYH, 2 MRE11A, 1 CHEK2, 1 RECQL4. One pt with biallelic MRE11A gPV had 4 siblings with PDAC; another pt with monoallelic CHEK2 gPV had a father, 3 aunts, and grandmother with PDAC. Among pts with de novo stage IV disease (N=44), mOS 14 months (95% CI, 9–20); for stage III, mOS 19 months (95% CI, 15–35); and for stage II, 40 months (95% CI, 32–73). In stage IV cohort, first-line (1L) mPFS 5.9 months (95% CI, 3.5–12.6); 1L platinum mPFS 9.2 months (95% CI, 3.5–NR), vs 4.9 months (95% CI, 2.5–13.3; P=0.5) for non-platinum regimens. In stage IV MUTYH cohort (N=13), mPFS 12.6 months (95% CI, 5.9–NR) and mOS 21.1 months (95% CI, 8.5–NR). Conclusion: This analysis highlights the molecular heterogeneity of DDR gPVs beyond BRCA1/2. RAD51, BLM, and RECQL gPVs are associated with earlier PDAC onset. BLM, BRIP1, and CHEK2 gPV pts presented more frequently with earlier-stage disease, potentially reflecting higher prevalence of symptomatic head tumors. Biallelic loss of DDR genes was rare. HRD scores demonstrated variability across DDR subgroups. MUTYH gPVs may be associated with a more favorable prognosis in PDAC. Citation Format: Catherine A. O'Connor, Jonathan W. Lee, Emily Harrold, Allison L. Richards, Daniel Muldoon, Florencia Velez-Cortes, Matteo Repetto, Antoine Desilets, Joshua Schoenfeld, Marc Hilmi, Anupriya Singhal. Singhal, Fiyinfolu Balogun, Anna Varghese, Kenneth Yu, Chaitanya Bandlamudi, Yonina R. Murciano-Goroff, Wungki Park, Diana Mandelker, Zsofia Stadler, Eileen M. O'Reilly. DNA Damage Repair (DDR) Variants Beyond BRCA/PALB2 in Pancreatic Adenocarcinoma (PDAC): Evaluation of Significance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B047.