Clinical Predictors of Germline DNA Damage Repair Gene Mutations in Patients with Advanced Prostate Cancer

Abstract

Abstract Background: There is a need to identify patients with advanced prostate cancer harboring an inherited mutation in selected DNA damage repair (DDR) genes, as there are prognostic, treatment, and familial risk implications. We aimed to develop a model to predict an individual risk of harbouring a germline DDR gene mutation in patients with metastatic and/or castration resistant prostate cancer (CRPC) disease. Patients and Methods: A retrospective multicenter cohort study was performed on 499 patients with metastatic and/or CRPC, who were tested for germline DDR gene mutations. Clinical and pathologic characteristics were compared between patients with and without a germline DDR mutation. Multivariable logistic regression was employed to develop a prediction model, which was internally validated using a bootstrapping method. Results: Eight predictors (age at diagnosis, time to CRPC, Gleason score, intraductal/cribriform histology, family history, visceral, bone, and lymph node metastases) were included in a logistic model to predict the probability of a germline DDR mutation. A formula to calculate an individual patient’s mutation risk is provided. Two optimal risk cut-offs were explored. Conclusion: We provide a predictive model of germline DDR gene mutation status in patients with metastatic and/or CRPC, using eight clinical-pathologic parameters. Predictive models such as this could be used to estimate a patient’s risk of harbouring a germline DDR mutation to determine prioritization for germline testing.