3401 - External Validation of a Germline Genetic Risk Score for Genitourinary Adverse Events after Prostate Radiotherapy
Presenter(s)
G. Xu1,2, R. Karunamuni1,2, S. L. Kerns3, W. A. Hall3, A. K. Bryant4, R. Hauger5,6, J. A. Lynch7,8, H. Patel9, J. M. Stark10, J. Vassy11,12, and T. M. Seibert1,2; 1Research Service, VA San Diego Healthcare System, San Diego, CA, 2Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, 3Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI, 4Department of Radiation Oncology, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, 5VA San Diego Healthcare System, San Diego, CA, 6UC San Diego Department of Psychiatry, La Jolla, CA, 7VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT, 8Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, CA, 9Northwestern University Feinberg School of Medicine, Chicago, IL, 10University of California San Diego, San Diego, CA, 11VA Boston Healthcare System, Boston, MA, USA, Boston, MA, 12Division of General Internal Medicine and Primary Care, VA Boston Healthcare System, Boston, MA
Purpose/Objective(s):
Genitourinary (GU) adverse events (AEs) can impact patient quality of life after radiation therapy (RT) for prostate cancer. Few risk factors are known beyond RT dose and baseline urinary function. We sought to evaluate a germline polygenic risk score (PRS) for GU AEs in prostate cancer patients treated with prostate RT. We hypothesized that higher PRS is associated with increased risk of GU AEs after RT.Materials/Methods:
We previously developed a 115-SNP germline PRS trained for association with risk of post-RT grade 2+ gross hematuria using a prospective cohort study of 2,034 patients. Here, we identified a cohort of participants in the Million Veteran Program who had available genotype data and underwent definitive RT or post-prostatectomy RT for prostate cancer. GU AEs of interest included gross hematuria and radiation cystitis, identified by ICD-9 and ICD-10 codes in electronic medical records. Logistic regression was used to model associations between GU PRS and AEs, adjusting for age at prostate cancer diagnosis and prior prostatectomy. GU PRS was modeled as a continuous variable and as a categorical variable comparing the top 10th percentile and bottom 90th percentile of patients. Results were reported as odds ratios (OR). ORs for continuous GU PRS were calculated per standard deviation increase.Results:
20,493 participants met eligibility criteria. Median follow-up after radiation therapy was 6.24 years (IQR 2.80 – 10.74). Following prostate cancer diagnosis and radiation treatment, 20.2% and 4.8% of patients experienced gross hematuria and radiation cystitis, respectively. After adjusting for age at diagnosis and prostatectomy, GU PRS was significantly associated with gross hematuria (continuous GU PRS: adjusted OR [aOR]=1.07, 95% CI: 1.03-1.11, categorical GU PRS: aOR=1.16, 95% CI: 1.04-1.30). GU PRS was significantly associated with radiation cystitis (continuous GU PRS: OR=1.07, 95% CI: 1.00-1.14), but this association was diminished after adjusting for age at diagnosis and prostatectomy (continuous GU PRS: aOR=1.02, 95% CI: 0.95-1.08).Conclusion:
Germline genetic risk, as calculated by GU PRS, is associated with risk of gross hematuria after prostate irradiation, independent of age at prostate cancer diagnosis and prostatectomy history. Our findings support previous work suggesting that germline genetics may play a role in post-radiation GU AE risk. The observed effect sizes are unlikely to justify immediate changes for clinical decision-making. Risk stratification may be improved by integrating genetic risk with clinical and treatment factors, such as dose-volume parameters, that were not available in this cohort but improved model performance in the training cohort. Further studies are also needed to clarify the biological mechanisms underlying these adverse events which may inform development of targeted interventions for those at elevated risk.