Multi-level factors impacting clinical outcomes in Veterans with low-/intermediate-risk prostate cancer

Veterans diagnosed with low grade group (GG1/2) prostate cancer frequently display an indolent disease course. Consequently, these patients are encouraged to consider active surveillance or watchful waiting as an alternative to curative-intent surgical or radiation therapies that may impart long-term side effects that diminish quality of life (QOL). Although the majority of individuals with GG1/2 prostate cancer display an indolent disease course, outcomes analysis of the of a large cohort of Veterans who received longitudinal care within the VA Healthcare System between 2000-2024 (n=11M) revealed approximately 6% diagnosed with GG1/2 prostate cancer (n = 6379) experienced metastatic progression. Given the ongoing debate in the medical community that GG1 prostate cancer should no longer be considered “cancer”, it is critical to understand factors associated with metastatic progression in the diverse Veterans Affairs population. We hypothesize that multi-level factors, such as ancestry, specific common genetic variants, social determinants of health, and environmental/military exposures are associated with increased risk of metastasis in patients with GG1/2 prostate cancer. Consequently, we propose to determine the specific complement of multi-level factors associated with metastasis in patients with low grade disease, then develop and validate a prognostic tool to measure risk of metastatic progression. Such a prognostic tool could inform a risk-adapted screening approach, as well as contribute to decision-making about management of low grade prostate cancer with the goal of reducing overdiagnosis/overtreatment of indolent disease while implementing curative-intent treatment in those at highest risk of metastatic progression (an uncurable stage of PCa). To accomplish these goals, we have designed a case control study that will support our first 2 aims - Identify which known genetic variants are associated with metastasis in individuals with GG1/2 prostate cancer (Aim 1) and identify a priori non-genetic risk factors associated with metastasis in individuals with GG1/2 prostate cancer (Aim2). For Aim 3, we will train and test a multi-level prognostic model that estimates probability of metastasis by combining risk estimates for significant genetic and non-genetic variables. This new prognostic model will be highly translatable and serve an unmet need of guiding treatment-decisions for a clinical scenario that affects thousands of Veterans annually. Project Number: 1I01CX002710-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Isla Garraway (+2 co-PIs) | Institution: VA GREATER LOS ANGELES HEALTHCARE SYSTEM, LOS ANGELES, CA | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 ONCA-S (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11052413