Intensified prostate cancer screening in germline carriers of rare pathogenic variants: interim results from the initial screening round of the PROGRESS study
Alexandra Hunter, BA, Andrew E. Amini, BS, Aya Almashad, MD, Shelley McCormick, MS, LCGC, Linda Rodgers, MS, LCGC, Keyan Salari, MD, PhD.
Massachusetts General Hospital, Boston, MA, USA.
BACKGROUND: Men with germline pathogenic variants in prostate cancer risk genes (e.g., BRCA2) are at increased risk of developing aggressive prostate cancer and thus warrant special considerations regarding prostate cancer screening. The Prostate Cancer Genetic Risk Evaluation and Screening Study (PROGRESS) is evaluating an intensified screening program for men at high genetic risk for prostate cancer that incorporates prostate MRI-based screening for early detection of prostate cancer.
METHODS: Men between 35-75 years old with a pathogenic/likely pathogenic germline variant in one of 19 prostate cancer risk genes and no prior diagnosis of prostate cancer were prospectively enrolled. Screening paradigm included annual DRE and PSA testing and a multiparametric MRI of the prostate every three years. PSA was considered elevated using an age-adjusted threshold of >1.5 ng/mL for 35-49 years of age, >2.0 ng/mL for 50-54 years of age, and >3.0 ng/ml for 55-70 years of age. Patients with an abnormal DRE, elevated age-adjusted PSA, or a positive MRI (PI-RADS ≥3) were recommended to undergo prostate biopsy.
RESULTS: A total of 91 patients have been enrolled to date, 85 of whom have completed the first round of screening. Median age is 57 years (48-65), and median PSA is 0.87 ng/mL (0.58-1.52). Most patients harbored pathogenic variants in either BRCA2 (n=35 [41%]) or BRCA1 (n=31 [36%]). After the first round of screening, 2 (2%) patients had an abnormal DRE, 10 (12%) had an elevated age-adjusted PSA, and 12 (14%) had a positive MRI. All 12 patients with an abnormal MRI, and 2 patients with a normal MRI but elevated PSA, underwent prostate biopsy. MRI was the sole indication for biopsy in 6 of the 14 (43%) patients. Eight of the 14 (57%) patients were diagnosed with prostate cancer (3 BRCA1, 3 BRCA2, 1 ATM, 1 TP53), with clinically significant (grade group ≥2) disease present in half of patients on initial biopsy and another 2 patients on subsequent biopsy or surgical pathology. MRI-based screening did not miss any of the cancers, whereas age-adjusted PSA alone would have missed 5 of the 8 cancers (included 3 of 6 clinically significant cancers).
CONCLUSIONS: Our early findings suggest prostate cancer is prevalent among men with high-risk germline genetic variants. MRI-based screening may enhance early detection of prostate cancer beyond PSA-based strategies in this patient population. 
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