Germline gene-specific associations in a large prostate cancer cohort.

person Hiba M Khan University of Washington/Fred Hutch Cancer Center, Seattle, WA info_outline Hiba M Khan, Sarah M. Nielsen Young, Emily M. Russell, Ed Esplin, W. Michael Korn, Heather H. Cheng

Authors person Hiba M Khan University of Washington/Fred Hutch Cancer Center, Seattle, WA info_outline Hiba M Khan, Sarah M. Nielsen Young, Emily M. Russell, Ed Esplin, W. Michael Korn, Heather H. Cheng Organizations University of Washington/Fred Hutch Cancer Center, Seattle, WA, Invitae Corporation, San Francisco, CA, Division of Hematology & Oncology, University of Washington & Fred Hutchinson Cancer Center, Seattle, WA Abstract Disclosures Research Funding No funding sources reported Background: Identification of pathogenic germline variants (PGV) in patients (pts) with prostate cancer (PC) enables precision therapy and cascade testing. Equitable advances in precision PC management require more detailed understanding of gene-level associations. Herein we describe PC gene-specific demography in a large cohort of PC pts. Methods: Germline genetic testing (GGT) (Invitae Corp.) and insurance claims (Komodo Healthcare Map) data were linked for PC pts from 2015-2023. ICD/CPT codes were used to define PC personal and family history and disease stage (early-stage = codes for active surveillance or definitive local treatment; advanced = remaining pts). PC genes analyzed were those in NCCN PC guidelines with >100 PGV+ pts: ATM, BRCA1, BRCA2, CHEK2, HOXB13 and mismatch repair (MMR) genes ( EPCAM, MLH1, MSH2, MSH6, PMS2 ). Two sample t-tests were used for age and chi-square tests were used for other variables, with a Bonferroni correction for post hoc analysis. Results: 14,979 pts had GGT: 68% with advanced disease (enriched for BRCA2 ) and 32% with early-stage. Mean diagnosis age was 64, and significantly younger for ATM / BRCA2 / HOXB13 + pts (p<0.04) (Table). BRCA2 was the most common PGV but was not enriched in any clinician-reported race/ethnicity. CHEK2/ MMR+ pts were more likely to be White ( post hoc p<0.001). The Midwest had the highest frequency of PGV (12%). A lower proportion of CHEK2+ pts resided in the South ( post hoc p<0.001). 26% of PGV+ pts had documented PC family history, which was significantly associated with BRCA2/ HOXB13, and negatively correlated with MMR (p<0.02 for both). Conclusions: In this cohort of ~15,000 PC pts, gene-specific associations were detected that warrant further study. Three-quarters of pts with PGV had no claims for family PC history, highlighting the importance of GGT in all pts meeting criteria, independent of family history. Further analysis of linked data will assess real-world treatment decisions and outcomes by GGT result. N (%) Total Cohort 14979 ATM 260 (1.7) BRCA1 115 (0.8) BRCA2 438 (2.9) CHEK2 328 (2.2) HOXB13 136 (0.9) MMR 178 (1.2) No Germline Findings 7881 (53) Mean age at diagnosis (yrs) (SD) 64.4 (9) 63.5 (9) 64.2 (11) 63.7 (9) 64.5 (9) 62.2 (9) 63.5 (10) 64.7 (9) Black 1568 (11) 11 (0.7)* 7 (0.4) 40 (2.6) 11 (0.7)^ 15 (1) 5 (0.3)^ 784 (50) Hispanic 636 (4) 13 (2) 5 (0.8) 19 (4) 7 (3) 0 5 (0.7) 312 (49) White 9930 (66) 176 (2) 75 (0.8) 290 (3) 264 (3)^ 102 (1) 140 (1)^ 5261 (53) Northeast 3191 (21) 71 (2) 24 (0.8) 101 (3) 76 (2) 16 (0.5) 36 (1) 1760 (55) Midwest 3506 (23) 72 (2) 39 (1) 117 (3) 102 (3) 41 (1) 50 (1) 1927 (55) South 4470 (30) 64 (1) 30 (0.7) 128 (3) 66 (2) # 45 (1) 38 (0.9) 2390 (53) West 3644 (24) 53 (2) 22 (0.6) 87 (2) 83 (2) 34 (0.9) 47 (1) 1712 (47) Family history of PC 3728 (25) 62 (2) 19 (0.5) 130 (4) 83 (2) 53 (1) 29 (0.8) 1925 (52) Bolded values are significant (p<0.05) compared to “no germline findings” group Only most common race/ethnicity categories included Significant post hoc: *Black; ^Black, White; # South.