Better together: Synergy of germline and somatic testing in HRR pathway-driven cancers.

10571 Background: Germline and somatic pathogenic variants inform eligibility for poly (ADP-ribose) polymerase inhibitors (PARPi) in breast, ovarian, prostate and pancreatic (BOPP) cancers. The role of BRCA1/BRCA2 in BOPP cancers is well-established, but the significance of other homologous recombination repair (HRR) genes is evolving. Integrating germline and somatic data provides a comprehensive understanding of oncogenesis and informs therapeutic decisions and risk assessment. For example, patients with “two hits” (germline and somatic alteration in the same HRR gene) often exhibit exceptional responses to PARPi. Methods: Patients with BOPP cancers receiving standard of care germline genetic testing (GGT) (Labcorp Genetics, formerly Invitae) and comprehensive genomic profiling (CGP) (Omniseq Insight, Labcorp) between 2021-2024 were analyzed. CGP data was queried to determine if the germline pathogenic variant (PGV) 1) was detected in the tumor, 2) had suggestive loss-of-heterozygosity (LOH) with a variant allele fraction (VAF) of ≥ 0.6, 3) had a second hit in the same gene, or 4) had somatic mutation(s) in other HRR gene(s). These were compared between BRCA1/BRCA2 and other HRR PGVs using Fisher’s exact test with significance set at <0.05. Results: 607 patients with BOPP cancers underwent GGT and CGP; 57 (9.4%) had ≥ 1 PGV in an HRR gene. The PGV+ cohort was 51% White; mean age at GGT was 62 years (26-88). Breast cancer was the most common cancer (27), followed by ovarian (15), pancreatic (12) and prostate (4); 20 (35%) patients had a BRCA1/BRCA2 PGV and 37 (65%) patients had other HRR PGV, primarily CHEK2, ATM, PALB2 (Table). Most (88%) PGV were detected by CGP, with 100% of BRCA2 PGV identified. However, 8 (12%) of PGV+ patients would have been missed by CGP testing alone. VAF ≥ 0.6 and/or 2nd hits in the same gene were significantly more likely in those with BRCA1/2 PGV vs. other HRR. Rates of additional mutations in other HRR genes were not significantly different (p>0.05) between the groups (Table). Conclusions: BRCA1/2 PGV were frequently identified as suspected drivers of BOPP cancers compared to other HRR genes. However, one-third of patients with other HRR variants exhibited features suggestive of driving cancer pathogenesis. These findings may qualify indicated patients for targeted therapies or trials and highlight the synergistic value of combined germline and somatic testing. Tumor characteristics of patients with HRR PGV. Genes Total PGV+ patients N (%) PGV detected by CGP N (%) VAF ≥ 0.6 N (%) 2nd hit, same gene N (%) VAF ≥ 0.6 OR 2nd hit N (%) 2nd mutation, different HRR gene BRCA1/2 20 17 (85) 12 (71) a 2 (12) 14 (82) b 6 (35) BRCA1 11 8 (73) 7 (88) 0 (0) 7 (88) 2 (25) BRCA2 9 9 (100) 5 (56) 2 (22) 7 (78) 4 (44) Other HRR c 37 33 (89) 9 (27) a 4 (12) 11 (33) b 9 (27) a p=0.011; b p=0.005; c CHEK2 (14), ATM (7), PALB2 (5), BRIP1 (2), RAD51C (2); BARD1 , BLM, FANCA, FANCA/CHEK2, FANCM , NBN, RAD50 (1 each).