A. Dornisch1, R. Karunamuni2, K. Maxwell3, J. A. Lynch4, I. Garraway5,6, A. Kibel7, C. Brunette8, M. Danowski9, K. M. Lee10, S. L. Duvall9, J. M. Gaziano11, B. S. Rose2, R. Hauger12, J. Vassy13, and T. M. Seibert14; 1Department of Radiation Medicine and Applied Sciences, UC San Diego, La Jolla, CA, 2Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 3University of Pennsylvania, Philadelphia, PA, 4VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, 5Department of Urology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 6Department of Surgical and Preoperative Care, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 7Brigham and Womens Hospital, Boston, MA, 8Veterans Affairs Boston Healthcare System, Boston, MA, 9VA Salt Lake City Healthcare System, Salt Lake City, UT, 10VA Informatics and Computing Infrastructure, VA Salt Lake City Healthcare System, Salt Lake City, UT, 11VA Boston Healthcare System, Boston, MA, 12UC San Diego Department of Psychiatry, La Jolla, CA, 13Division of General Internal Medicine and Primary Care, VA Boston Healthcare System, Boston, MA, 14University of California - San Diego, San Diego, CA
Purpose/Objective(s): Common tenets of prostate cancer screening (PCa) guidelines include shared decision-making and individual risk assessment. However, subjective risk assessment based on family history and race is neither accurate nor consistent. A polygenic hazard score based on 290 genomic variants (PHS290) is strongly associated with age at diagnosis of aggressive PCa in large datasets, including the racially and ethnically diverse Million Veteran Program (MVP). Moreover, PHS290, ancestry, and family history are each independently associated with lifetime risk of metastatic PCa. Here, we develop and validate a new integrated model for use in the primary care setting, called Prostate Cancer integrated Risk Evaluation (P-CARE). Materials/
Methods: Candidate genetic variants with reported association with PCa, aggressive PCa, benign prostatic hyperplasia, or benign PSA elevation were considered for inclusion in the new PHS model. We used genetic and phenotypic data from a diverse, population-based cohort (Million Veteran Program, n=648,422). We then fit a LASSO-regularized PHS model using the age at diagnosis of prostate cancer as the time to event, and all the candidate genetic variants as predictors while covarying the first 5 principal components of genetic ancestry. We combined the new PHS with family history and ancestry to create an integrated risk score, P-CARE, again using age at diagnosis of PCa as time to event. We estimated the hazard ratio (HR) performance of the new PHS model and P-CARE using 10 iterations of a 10-fold cross-validation. Results: We found 707 unique candidate variants; 601 were ultimately included in the updated polygenic score (PHS601). Risk stratification with PHS601 for any, metastatic, and fatal prostate cancer was improved over PHS290 within each ancestry group, including within the >100,000 participants of African ancestry—a group known to have elevated risk of fatal PCa. The integrated score, P-CARE, combines PHS601, ancestry, and family history. Patients in the highest 20% of P-CARE, compared to those in the lowest 20%, have a HR of 6.3 [95%CI 5.9-6.7] for any PCa and a HR of 6.7 [5.7-7.6] for metastatic PCa. Conclusion: P-CARE combines genetic ancestry, family history, and PHS601 to achieve objective risk stratification for metastatic PCa. External validation is underway in additional diverse datasets. We will use P-CARE in a nationwide randomized clinical trial to evaluate precision prostate cancer screening in the VA healthcare system (ProGRESS: the Prostate Cancer, Genetic Risk, and Equitable Screening Study; ClinicalTrials.gov ID NCT05926102).
