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

Area of Science:

• Radiation Oncology
• Genetics
• Urology

Background:

• Late bladder toxicity is a significant concern for prostate cancer patients undergoing radiotherapy, impacting survivors' quality of life.
• Known risk factors for bladder toxicity are limited, primarily focusing on radiation dose and bladder volume exposure.
• A polygenic risk score (PRS) offers a potential method to identify patients genetically predisposed to developing bladder toxicity.

Purpose of the Study:

• To develop and validate a polygenic risk score (PRS) for predicting late bladder toxicity in prostate cancer patients receiving radiotherapy.
• To assess the PRS's association with specific urinary side effects, including hematuria, urinary retention, and frequency.
• To evaluate the PRS's utility in identifying patients who may benefit from personalized treatment strategies.

Main Methods:

• A PRS was constructed using genome-wide association data from the Radiogenomics Consortium (N=3,988).
• The PRS was prospectively tested in the REQUITE and URWCI studies (N=2,034), analyzing time to gross hematuria (≥G2) using Cox regression.
• External validation was performed using UK Biobank data (N=8,430) for clinically diagnosed irradiation cystitis, alongside a gene-burden test for rare variants.

Main Results:

• The 115-variant PRS significantly correlated with increased risk for hematuria (HR=1.22, P=0.009), urinary retention (HR=1.18, P=0.016), and frequency (HR=1.14, P=0.036).
• Patients in the highest PRS decile (PRShigh) exhibited over a two-fold increased risk of hematuria (HR=2.12, P=0.002) after adjusting for clinical factors.
• The PRS demonstrated similar predictive performance for clinically diagnosed irradiation cystitis in the UK Biobank (OR=2.15, P=0.026), and BOD1L1 was identified as a potential radiosensitivity gene.

Conclusions:

• The developed PRS effectively identifies patients susceptible to developing late bladder toxicity following prostate cancer radiotherapy.
• This genetic risk assessment tool can inform treatment planning, potentially guiding the selection of patients who require optimized bladder-sparing strategies.
• Implementing PRS-guided treatment could reduce the incidence and impact of bladder toxicity, improving outcomes for prostate cancer survivors.