Inherited risk for prostate cancer (PCa): Following the natural history of men with increased genetic risk using multiparametric MRI (mpMRI).

315 Background: PCa has substantial inherited predisposition and certain germline variants like BRCA1/2 , ATM , HOXB13 , and DNA mismatch repair (MMR) genes are associated with an increased risk of PCa. This study follows men without a diagnosis of PCa, with known germline pathogenic/likely pathogenic variant (PV) in BRCA1/2 , DNA MMR genes associated with Lynch syndrome ( MLH1/PMS2 , MSH2 / MSH6 , EPCAM ), HOXB13 , ATM , CHEK2 , PALB2 , TP53 , NBN , RAD51C/D , BRIP1 , and FANCA-FANCM (NCT03805919). Methods: Up to 500 men, ages 30-75 years old (y/o) with a documented PV will enroll. Men undergo biennial mpMRI and annual PSA. Indication for prostate biopsy includes clinical, PSA, and/or MRI findings. Patients are followed at 12-month intervals to determine PSA, PCa diagnosis, and disease/survival status until death. Results: To date, 378 evaluable patients have enrolled: 353 (93%) Caucasian, 11 (3%) Hispanic, 7 (2%) Asian, 4 (1%) African-American, 2 (1%) bi-ethnic. 1 Indian-Asian. Median age was 47 y/o. The most common PV were: 180 (48%) BRCA2 , 94 (25%) BRCA1 , 22 (6%) CHEK2 , and 18 (5%) ATM . PVs in MLH1 / PMS2 , MSH2 / MSH6 , PALB2 , HOXB13 , TP53 , BRIP1 , RAD51D , EPCAM , NBN , and FANCA are <4%. Eight patients carried more than one PV. A total of 782 MRIs were performed: 378 baselines, 228 at year 2, 121 at year 4, 30 at year 6, and 25 clinical. Indication for biopsy was present in 89 (24%) patients with 37 (10%) diagnosed with PCa. Of the 90 biopsies indicated, 1 refused and withdrew and 3 are still pending. Of those with PCa, 22 had BRCA1/2 PVs, 5 had MMR PVs, and 10 had non-MMR PVs. Median age at diagnosis was 62. 24 patients were diagnosed with Grade Group (GG) 1, 8 patients with GG2, 1 patient with GG3, 3 patients with GG4, 1 patient with GG5. 21 opted for active surveillance (AS), 10 opted for prostatectomy, 6 opted for radiation therapy. 5 patients on AS converted to definitive treatment after progression was noted at 1-year follow-up. Conclusions: mpMRI screening in men with PVs is feasible and can be used for early diagnosis, PCa monitoring, and facilitates PCa diagnosis at PSA levels below conventional thresholds. Correlative studies including cfDNA, PBMCs and PRS, are ongoing. Clinical trial information: NCT03805919 . Indication for biopsy. BiopsyPositive BiopsyNegative Biopsy Pending, Refused Total = 89 PSA WNL PSA Elevated PSA WNL PSA Elevated PSA WNL PSA Elevated PIRADS 1 13 0 4 0 9 0 0 PIRADS 2 15 1 3 5 6 0 0 PIRADS 3 23 5 1 11 3 2 1 PIRADS 4 34 <jats:td colspan="1" ro