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Impact of family history and germline genetic risk on biopsy upgrading in prostate cancer patients on active surveillance
Chandler Bronkema, MD, Preeti Chachlani, MA, Xiu Lui, MS, Aileen Feng, BS, Himanshu Patankar, BS, Andrew Gusev, MD, Chin-Lee Wu, MD, PhD, Jason Efstathiou, MD, DPhil, Richard Lee, MD, PhD, Anthony Zietman, MD, Douglas Dahl, MD, Michael Blute, MD, Adam Feldman, MD, MPH, Keyan Salari, MD, PhD.
Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
BACKGROUND: How family history (FH) and germline genetic risk might improve risk stratification and patient selection for active surveillance (AS) is incompletely understood. We aimed to evaluate the impact of FH, rare pathogenic mutations, and common genetic variants measured by the polygenic risk score (PRS) on biopsy grade progression (BGP) among patients on AS.
METHODS: We selected 186 men from our institutional database (1997-2023) who had undergone at least two prostate biopsies and had germline genetic data available from the MGB Biobank. A previously validated PRS derived from 400 PC risk variants was computed for each patient, and patients were stratified based on genetic risk. Cox regression was used to test the association of PRS
400 and a previously identified 19q13 high-risk locus on BGP.
RESULTS: In the cohort, 75 patients demonstrated BGP with median time to progression (IQR) of 41 (13-66) months. Median age, PSA and PSAD was 65 (61-69) years, 4.9 (4.0-6.0), and 0.110 (0.078-0.153), respectively. FH of PC and 19q13 risk allele was present in 74 (39.8%) and 37 (19.9%) individuals, respectively. Nine patients were found to have a rare pathogenic mutation of PC (e.g., BRCA2), of which five had BGP. Regression analysis showed that those with the 19q13 risk allele had a 49% higher risk of BGP (HR 1.49; 95% CI: 0.88-2.51, p=0.14). FH was associated with a higher risk of BGP (HR 1.95; 95% CI: 1.21-3.11, p=0.006). Compared to patients with low PRS, those with high PRS
400 score did not have higher risk of BGP.
CONCLUSIONS: In men with favorable-risk PC managed by AS, PRS
400 was not associated with BGP. Although patients with the 19q13 risk allele were found to have a 50 % higher risk of BGP, this did not reach statistical significance. Efforts to expand germline analysis of our AS cohort are ongoing.
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