Prospective validation of single nucleotide polymorphisms as predictors of gastrointestinal, genitourinary, and sexual toxicities following radiation therapy for prostate cancer.
Authors: Kamran Sophia C. , Yeap Beow Y. , Soetan Zainab , Pompa Isabella R , Muise STacey , Cowan Jessica , Moteabbed Maryam , Silvia Brenda Lee , Olsen Christine Cecilia , Zietman Anthony L. , Efstathiou Jason A. , Miyamoto David Tomoaki 
Published: March 2023

385 Background: Radiation therapy (RT) for localized prostate cancer (PC) may result in long-term gastrointestinal (GI), genitourinary (GU), and sexual toxicities that adversely impact quality of life. Biomarkers are needed to accurately predict individualized RT toxicity risk and enable tailoring of treatment. Single nucleotide polymorphisms (SNPs) have been reported as predictors of RT-related toxicities, but have not been independently validated in prospective, prostate-specific cohorts. In this study, we sought to validate these SNPs in a prospective registry study of RT for PC, with high-quality prospectively collected toxicity data. Methods: 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/pelvic lymph node RT were not allowed. 95 patients enrolled between 2014-2020 at a single institution had whole blood specimens available for analysis. 172 SNPs previously reported to correlate with GI, GU, and/or sexual RT toxicities were genotyped. CTCAEv4 physician-reported toxicity was collected at prespecified follow-up (FU) time points. Association of previously identified SNP genotypes with the worst toxicity grade was analyzed using two-sided Fisher’s exact test. Results: 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. By 24 months post-RT, 21 (22%) patients experienced grade 1-2 Gl toxicity, 33 (35%) experienced grade 1-2 GU toxicity, and 68 (72%) experienced grade 1-3 sexual toxicity. Of the 172 SNPs examined, significant associations were detected for rs1805794 with a higher incidence of grade 1-2 late GI toxicity (P=0.006), rs1800872 with a higher incidence of grade 1-2 late GU effects (P=0.005) and rs25489 with a higher incidence of grade 1-3 sexual dysfunction (P=0.003). rs3749191, rs4073, rs2243250, and rs7356945 were significantly associated with grade 2 late GU toxicity (all P≤0.008). Significant associations were also observed between other SNPs and late toxicity: 4 SNPs GI, 9 SNPs GU, 7 SNPs sexual (all 0.01≤P≤0.05). Conclusions: Of the 172 SNPs previously reported to be associated with GI, GU, and/or sexual toxicity after prostate RT, 16% were validated by conventional statistical criteria. Ongoing analyses include integrated modeling of dosimetry and SNP data for prediction of toxicities and PROs, and evaluation of potential interactions between RT modality (proton/photon) and toxicity-associated SNPs.