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

Abstract

390 Background: PCa has inherited risk factors including high genetic risk variants such as BRCA1/2, HOXB13, and DNA mismatch repair genes. mpMRI has been shown to be effective for detection and staging of localized PCa. This study follows participants (prts), born biologically male, without a diagnosis of PCa with known germline pathogenic or likely pathogenic variants (PV) in BRCA1/2, MLH1, MSH2, MSH6, PMS2, EPCAM, HOXB13, ATM, NBN, TP53, CHEK2, PALB2, RAD51C/D, BRIP1, or FANCA-FANCM (NCT03805919). Methods: Up to 500 eligible prts 30-75 years old (yo) with a documented germline PV will enroll. Prts undergo biennial clinical exam and mpMRI, and annual PSA monitoring and are followed at 12-month intervals to determine PSA, prostate cancer diagnosis, and/or disease/survival status until death. Indication for prostate biopsy includes clinical or imaging findings. Biopsy specimens undergo molecular analyses. Results: To date, 175 prts have been enrolled: 169 (97%) White, 3 Hispanic (2%), 1 African American (1%), 1 Asian (1%), and 1 biethnic (1%). Median age is 47 yo. The most common monoallelic PV are: 48.6% BRCA2, 25.1% BRCA1, 6.3% CHEK2 and 5.7% MSH2. PVs in ATM, PALB2, HOXB13, PMS2, MLH1, MSH6, BRIP1, EPCAM and RAD51D are ≤4%. One subject carries three distinct PVs ( BRCA2, CHEK2, BRIP1). Indication for biopsy was found in 26.3% of prts with 22/46 (47.8%) with a PIRADS 4 lesion, 6/46 (13.0%) PIRADS 3 lesion, 12/46 (26.1%) elevated PSA (median=2.8 ng/mL) or 6/46 (13.0%) due to clinical discretion. Adenocarcinoma was diagnosed on 13/39 (33.3%) biopsies with median age at diagnosis=59 yo. 9/13 (69%) prts had a PSA <3 ng/ml at diagnosis. Nine prts were diagnosed with ISUP Grade Group (GG) 1, 3 with GG2, and 1 with GG3. Eight prts opted for active surveillance (AS), 2 for radiation therapy (RT), and 3 for prostatectomy (RP). Two prts on AS converted to definitive treatment (one RP and one RT) due to progression in GG on the year 1 AS biopsy. Conclusions: mpMRI screening in men with germline PV can be used for diagnosis and monitoring of PCa and facilitates detection below conventional PSA thresholds in a high genetic risk setting. Access to genetic testing and other variables need to be addressed in underrepresented minorities. Correlative studies, including cfDNA and PBMCs, are ongoing. Clinical trial information: NCT03805919 . [Table: see text]