A Polygenic Risk Score for Late Bladder Toxicity Following Radiotherapy for Non-Metastatic Prostate Cancer

BACKGROUND: Late bladder toxicity is a concern for patients receiving prostate cancer radiotherapy and negatively impacts survivors. Few risk factors are known beyond the radiation dose and volume of bladder exposed. A polygenic risk score (PRS) could identify susceptible patients. METHODS: A PRS was built using genome-wide association results from the Radiogenomics Consortium (N=3,988), then tested in the prospective REQUITE and URWCI studies (N=2,034). The primary outcome was time-to-patient-reported gross (= grade 2, G2) hematuria analyzed using Cox proportional hazards regression. Secondary outcomes were =G2 urinary retention and frequency. The PRS was externally validated for clinically-diagnosed irradiation cystitis in the UK Biobank (N=8,430). A gene-burden test evaluated rare coding variants. RESULTS: A 115-variant PRS was associated with significantly increased risk of =G2 hematuria (hazard ratio [HR] per standard deviation [SD]=1.22, p=0.009) as well as urinary retention (HR-per-SD=1.18, p=0.016) and frequency (HR-per-SD=1.14, p=0.036). When binarized, men in the upper decile (PRShigh) had >2-fold increased risk of hematuria after adjusting for clinical risk factors (HR=2.12, p=0.002; Harrel's c-index 0.71 [95%CI=0.65 to 0.76]). A similar effect size was seen in the UK Biobank for clinically-diagnosed irradiation cystitis (OR=2.15, p=0.026). The burden test identified BOD1L1 as a putative novel radiosensitivity gene. CONCLUSIONS: This PRS identifies susceptible patients and could guide selection of those needing re-optimized treatment plans that spare the bladder beyond currently recommended constraints. IMPACT: PRS-guided treatment planning in radiation oncology could lower the incidence of clinically relevant bladder toxicity and reduce the impact of this outcome on prostate cancer survivors.