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. 2022 Feb:167:226-232.
doi: 10.1016/j.radonc.2021.12.040. Epub 2022 Jan 3.

Germline variants disrupting microRNAs predict long-term genitourinary toxicity after prostate cancer radiation

Amar U Kishan  1 , Nicholas Marco  2 , Melanie-Birte Schulz-Jaavall  3 , Michael L Steinberg  4 , Phuoc T Tran  5 , Jesus E Juarez  4 , Audrey Dang  4 , Donatello Telesca  2 , Wolfgang A Lilleby  3 , Joanne B Weidhaas  4
Affiliations

Germline variants disrupting microRNAs predict long-term genitourinary toxicity after prostate cancer radiation

Amar U Kishan et al. Radiother Oncol. 2022 Feb.

Abstract

Background and purpose: The purpose of this study was to determine whether single nucleotide polymorphisms disrupting microRNA targets (mirSNPs) can serve as predictive biomarkers for toxicity after radiotherapy for prostate cancer and whether these may be differentially predictive depending on radiation fractionation.

Materials and methods: We identified 201 men treated with two forms of definitive radiotherapy for prostate cancer at two institutions: 108 men received conventionally-fractionated radiotherapy (CF-RT) and 93 received stereotactic body radiotherapy (SBRT). Germline DNA was evaluated for the presence of functional mirSNPs. Random forest, boosted trees and elastic net models were developed to predict late grade ≥2 GU toxicity by the RTOG scale.

Results: The crude incidence of late grade ≥2 GU toxicity was 16% after CF-RT and 15% after SBRT. An elastic net model based on 22 mirSNPs differentiated CF-RT patients at high risk (71.5%) versus low risk (7.5%) for toxicity, with an area under the curve (AUC) values of 0.76-0.81. An elastic net model based on 32 mirSNPs differentiated SBRT patients at high risk (64.7%) versus low risk (3.9%) for toxicity, with an area under the curve (AUC) values of 0.81-0.87. These models were specific to treatment type delivered. Prospective studies are warranted to further validate these results.

Conclusion: Predictive models using germline mirSNPs have high accuracy for predicting late grade ≥2 GU toxicity after either CF-RT or SBRT, and are unique for each treatment, suggesting that germline predictors of late radiation sensitivity are fractionation-dependent. Prospective studies are warranted to further validate these results.

Keywords: Germline; IMRT; Prostate; SBRT; SNPs; Toxicity.

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Conflict of interest statement

Conflict of interest disclosures Dr. Kishan reported receiving personal fees from ViewRay, Inc, Varian Medical Systems, Inc, and Janssen Pharmaceuticals outside the submitted work, as well as research funding from ViewRay. Dr. Weidhaas is a co-founder of MiraDx, a molecular diagnostics company that owns IP related to microRNA binding site variants, some of which were studied in this paper.

Figures

Fig. 1.
Fig. 1.
Bar Chart of Toxicity Percentage Based on Risk-Stratification. The percentage of patients experiencing grade ≥2 genitourinary toxicity in the conventional radiotherapy (CF-RT) and stereotactic body radiotherapy (SBRT) cohorts based on single nucleotide polymorphisms disrupting microRNA targets (mirSNPs).
Fig. 2.
Fig. 2.
Toxicity-Free Survival Curves. Curves depict the predicted toxicity over time for men predicted to have a low or high risk of toxicity by the indicated mirSNP signature. p-values derived from the log-rank test.
See this image and copyright information in PMC

References

    1. Hoffman KE, Penson DF, Zhao Z, Huang L-C, Conwill R, Laviana AA, et al. Patient-reported outcomes through 5 years for active surveillance, surgery, brachytherapy, or external beam radiation with or without androgen deprivation therapy for localized prostate cancer. JAMA 2020;323:149. 10.1001/jama.2019.20675. - DOI - PMC - PubMed
    1. Michalski JM, Moughan J, Purdy J, Bosch W, Bruner DW, Bahary J-P, et al. Effect of standard vs dose-escalated radiation therapy for patients with intermediate-risk prostate cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial. JAMA Oncol 2018;4:e180039. 10.1001/jamaoncol.2018.0039. - DOI - PMC - PubMed
    1. Meier RM, Bloch DA, Cotrutz C, Beckman AC, Henning GT, Woodhouse SA, et al. Multicenter trial of stereotactic body radiation therapy for low- and intermediate-risk prostate cancer: survival and toxicity endpoints. Int J Radiat Oncol Biol Phys 2018;102:296–303. - PubMed
    1. Widmark A, Gunnlaugsson A, Beckman L, Thellenberg-Karlsson C, Hoyer M, Lagerlund M, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet 2019;394:385–95. - PubMed
    1. Kishan AU, Dang A, Katz AJ, Mantz CA, Collins SP, Aghdam N, et al. Long-term outcomes of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer. JAMA Network Open 2019;2:e188006. - PMC - PubMed