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Impact of Polygenic Risk Scores on Prostate Cancer Detection in the Prostate Cancer Genetic Risk Evaluation and Screening Study (PROGRESS)
Katherine Merport, BA1, Himanshu Patankar, BS2, Rajveer Kaur, BA2, Aileen J. Feng, BA2, Andrew E. Amini, MD2, Margaret R. O'Dea, CNP2, Shelley R. McCormick, MS, CGC3, Linda H. Rodgers-Fouche, MGC, CGC3, Keyan Salari, MD, PhD2.
1UMass Chan Medical School, Worcester, MA, USA, 2Department of Urology, Mass General Brigham, Boston, MA, USA, 3Center for Cancer Risk Assessment, Mass General Brigham Cancer Institute, Boston, MA, USA.
BACKGROUND: Individuals with rare germline pathogenic variants (PV) carry increased risk of prostate cancer (PCa). Polygenic risk scores (PRS) estimate an individual's genetic predisposition for developing PCa based on common genetic variants. This study investigates how PRS impacts PCa risk and diagnostic performance of MRI among rare PV carriers enrolled in a prospective PCa early detection study.
METHODS: Participants in cohort A of PROGRESS (NCT05129605) underwent germline SNP array or Blended Genome-Exome sequencing to derive a PRS based on 400 PCa-associated variants. All participants were screened with annual PSA, prostate exam, and triennial multiparametric MRI. Participants with abnormal screening tests underwent prostate biopsy. PRS risk categories were defined using PRS distribution among 20,635 participants in the Mass General Brigham Biobank. Cumulative incidence of PCa and clinically significant PCa (csPCa; grade group ≥2) and positive predictive value (PPV) of MRI by PRS category were estimated. Impact of PRS on time to diagnosis was evaluated by Cox proportional hazard models.
RESULTS: PRS were determined for 163 participants, who underwent 228 MRIs leading to 17 PCa (13 csPCa) diagnoses. PRS was not associated with PSA or MRI positivity. High PRS correlated with younger age at csPCa diagnosis (rho = -0.69, p=0.01). Cumulative incidence of PCa and csPCa was highest in the fourth quartile of PRS and lowest in the first quartile. PRS did not significantly affect PPV of MRI PI-RADS scores. Adjusting for MRI positivity, higher PRS was associated with an increased hazard of csPCa (PRS HR 2.27 [0.94-5.48], p=0.07) suggesting a potential, though not statistically significant, effect.
CONCLUSIONS: Among rare PV carriers, higher PRS was associated with an increased hazard of csPCa at a younger age but did not impact the PPV of MRI. PRS may refine risk stratification for high-risk populations. Ongoing enrollment and follow-up will improve statistical power.
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