Measures of Inherited Prostate Cancer Risk in the Management of Low-Grade Prostate Cancers on Active Surveillance

Fred Hutchinson Cancer Center, Seattle WA

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Abstract

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 21-100. The proposal herein outlines a 3-year career development plan with the overarching scientific goal of making active surveillance (AS) safe for men with low-grade prostate cancers who have inherited high genetic risk for the disease. With this award, the candidate wants to build on her prior research and clinical experience in AS and in prostate cancer germline genetics, with the guidance of her mentors Drs Daniel Lin, Heather Cheng and Burcu Darst. This mentorship team has complementary expertise in AS, clinical management of inherited high-risk prostate cancers and genetic epidemiology, which will allow her to study germline genetics in AS by integrating three measures of inherited risk – high-risk family history, rare pathogenic mutation carrier status and polygenic risk scores. The research plan, didactic courses and career development goals outlined in the proposal are designed for the candidate to become an independent investigator and surgeon scientist with unique expertise in the management of high-risk patients on AS. AS is the standard of care for low-grade prostate cancers, irrespective of inherited genetic risk, as many of these cancers never need to be treated, and for those that do progress during surveillance, treatment can be safely delayed without missing the window of opportunity for cure. Little is known however about optimal management of men who inherit high genetic risk for prostate cancer after diagnosis of low-risk localized disease. In the metastatic setting, certain germline variants are significant drivers of disease and are associated with poor survival. Currently there is limited data on the role these same variants play in the biology of low-grade cancers. Some studies suggest these patients can be safely monitored on AS and others suggest the opposite. The central hypothesis of this proposal is that most men who carry one or more measures of inherited risk can be safely surveilled; and the tumor features of these patients can help in their risk stratification. This hypothesis will be tested by pursing two specific aims: 1) Identify associations between the three measures of inherited risk and outcomes during and after AS; and 2) Evaluate the tumor characteristics of the carriers of one or more measures of inherited risk. In the first aim, associations between any combination of the three measures and upgrading during surveillance or recurrence after delayed treatment will be evaluated. The second aim will serve to identify tumor specific mutations, molecular alterations and histopathological patterns associated with AS outcomes in low-grade tumors of men with high genetic risk. This is an innovative approach because it will take into account all three measures of inherited risk and identify potential links between the germline and the tumor. The research is significant because it will generate clinically actionable results allowing providers to better counsel their patients with high genetic risk considering AS.