Prospective Validation of Single Nucleotide Polymorphisms as Predictors of Gastrointestinal, Genitourinary, and Sexual Patient-Reported Outcomes Following Radiotherapy for Prostate Cancer.

Abstract

Radiotherapy (RT) for localized prostate cancer (PC) can adversely impact gastrointestinal (GI), genitourinary (GU), and sexual quality of life (QoL). Biomarkers are needed to accurately predict individualized risk of toxicity and enable tailoring of therapy. Single nucleotide polymorphisms (SNPs) have been reported as potential predictors of RT-related toxicities, but have not been associated with patient-report outcomes (PRO) in prospective cohorts. In this study, we sought to validate these SNPs in a prospective registry study of RT for PC, with high-quality prospectively collected PRO data. Men with low/intermediate risk PC were consented to a multicenter companion registry study associated with the PARTIQoL Phase III Randomized Trial of proton vs. photon RT. Patients received RT to prostate/seminal vesicles per protocol. Androgen deprivation therapy and pelvic lymph node RT were not allowed. 95 patients enrolled between 2014-2020 at a single institution had blood specimens available for germline DNA analysis. 172 SNPs previously reported to correlate with GI, GU, and/or sexual RT toxicities were genotyped. PRO data through the Expanded Prostate Cancer Index Composite (EPIC) were collected prior to RT and at prespecified follow-up (FU) time points. Change of the EPIC score from baseline was compared between genotypes of previously identified SNPs using a two-sample t-test. Significant clinically meaningful QoL differences were identified by an effect size of at least 0.4σ with two-sided p<0.05, where σ represents the standard deviation of the score change. Median FU was 39 months (r, 6-89). Median age was 68 years (r, 52-83). Features at diagnosis include: 77% T1c, median PSA 5.8 (r, 1.43-15.1), 53% Gleason 7, median prostate volume 45.5cc (r, 16-142). 43% received proton RT; 53% had a rectal spacer. 40% received 79.2 Gy/44 fractions; 60% received 70 Gy/28 fractions. Between 6 to 24 months post-RT, there were 19 SNPs that were significantly associated with clinically meaningful decreases in GI QoL scores, 19 that were significantly associated with clinically meaningful decreases in GU QoL scores, and 10 SNPs that were significantly associated with clinically meaningful decreases in sexual QoL scores. Three BRCA2 SNPs (rs1801439, rs1801499, rs1799944) were significantly associated with clinically meaningful decreases in both GI and GU QoL scores. Of the 172 SNPs previously reported to be associated with GI, GU, and/or sexual toxicity after prostate RT, 23% were validated for domain-specific QoL detriment. Ongoing analyses include integrated modeling of dosimetry and SNP data for prediction of toxicities and PRO, and evaluation of potential interactions between RT modality (proton/photon) and QoL-associated SNPs.