Clinico-genomic characterization of <i>PALB2</i> -mutated pancreatic adenocarcinoma.

4169 Background: Pancreatic adenocarcinoma (PDAC) with germline (g) or somatic (s) mutations in BRCA1/2 and PALB2 exhibit unique molecular characteristics and predict response to platinum-based chemotherapy and PARP inhibition. However, distinct features of PALB2 and PDAC are not well described. Herein, we characterize distinct clinico-genomic features of patients (pts) with g/s PALB2 and PDAC. Methods: Institutional databases and cBioPortal were queried to identify pts with g/s PALB2 and PDAC. Pts with PALB2 variants of unknown significance (VUS) were excluded (annotation from OncoKb, ClinVar). Demographic data and clinical outcomes abstracted from medical record. Detailed mutational analysis obtained from cBioPortal. Zygosity determined with FACETS. Progression-free survival (PFS) and overall survival (OS) estimated with Kaplan-Meier Method. Results: N = 29 pts with pathogenic/oncogenic g/s PALB2 and PDAC identified between 2011-2024. N = 25 (86%) g PALB2 (+/- s PALB2 ) and N = 4 (14%) s PALB2 (no g PALB2 ); N = 13 s PALB2 excluded as VUS. Median age (range): 57 years (38-78) g PALB2 and 63 years (43-73) s PALB2 . N = 23 (79%) white; N = 16 (55%) female. Stage IV at diagnosis: N = 11 (44%) g PALB2 ; N = 2 (50%) s PALB2 cohort. In g PALB2 cohort (N = 25), 4 (16%) had personal history of cancer (N = 2 thyroid, N = 1 uterine, N = 1 CLL) and N = 17 (68%) had family history of cancer (N = 7 breast/prostate/ovarian, N = 1 pancreas). KRAS and TP53 variants co-occurred in 84% and 36% of g PALB2 and 50% and 50% of s PALB2 cases, respectively. N = 9 (56%) of patients with a gPALB2 mutations showed biallelic loss of PALB2 (N = 6 by LOH, N = 3 somatic LOH). None of four patients in s PALB2 cohort (negative g PALB2 ) had biallelic loss. Median TMB (mt/Mb): 4.10 (0.80-9.10) g PALB2 ; 3.85 (2.00-5.80) s PALB2 . For stage IV g PALB2 (N = 11), median PFS 4.2 months (95% CI 2.4, NR) and median OS 12 months (95% CI 5.5, NR). N = 10 (90%) received platinum therapy, with N = 6 in the first line setting. Durable disease control on PARPi was observed for patients with g PALB2 and s PALB2 , including N = 1 s PALB2 with 7 months on 4 th -line olaparib and N = 1 g PALB2 with 6 months on 6 th line Olaparib. Conclusions: gPALB2 and sPALB2 mutations are seen in a small % of PDAC. gPALB2 PDAC presents earlier and is linked to family history of cancer. g PALB2 compared to s PALB2 had higher biallelic loss; oncogenic s PALB2 are uncommon. Identification of g/s PALB2 has implication for therapeutics and screening. Loss of heterozygosity, TMB, telomeric allelic imbalance, large-scale state transitions, and implications for treatment will be presented. gPALB2 = 25 Putative driver mut (%) 21 (84) Truncating mut 13 (62) Structural Variant 4 (19) Splice mut 4 (19) Zygosity Biallelic 9 (56) Monoallelic 6 (44) Unknown 10