DNA Linked to Genitourinary Toxicity Risk With Radiation in Prostate Cancer

Amar Kishan, MD

Newly designed predictive models demonstrated high accuracy in predicting late grade 2 or higher genitourinary (GU) toxicity following either conventionally fractionated radiotherapy (CF-RT) or stereotactic body radiotherapy (SBRT), according to data recently published in Radiotherapy & Oncology.¹

Specifically, research demonstrated that germline variants in single nucleotide polymorphisms disrupting microRNA targets (mirSNPs) are highly accurate in predicting late-grade genitourinary toxicity. A predictive model, which used 22 mirSNPs, is able to accurately predict GU toxicity following CF-RF and a model using 32 mirSNPs predicts GU toxicity following SBRT. Notable, the model used to predict SBRT–related toxicities cannot predict CF-RT–related toxicity, and vice versa.

“Given the high effectiveness of definitive treatments for localized prostate cancer, quality of life following treatment is a paramount factor in patient-physician shared decision-making,” lead author Amar Kishan, MD, of the University of California, Los Angeles, and co-investigators stated in the study. “After definitive radiotherapy, a major quality of life­–limiting toxicity is late genitourinary toxicity, which could manifest as increased urinary frequency, retention, pain, and bleeding.”

Currently, the 5-year grade 2 GU toxicity rate ranges from 12% to 15% following modern radiotherapy. These rates appear to be consistent across both CF-RT (1.8–2.0 Gy per fraction over 39-45 treatment sessions) and SBRT (>7 Gy per fraction over ≤5 sessions). Despite the similarities in rates, researchers believe that select patients exhibit fraction-dependent radiosensitivity and might consequently experience higher rates of toxicity after high dose per fraction vs low dose per fraction radiation.

miRNS are known to regulate the stress response pathways, which include the local and system responses to radiations. Furthermore, germline SNPs, which disrupt their target binding or regulatory regions, are highly influential in determining radiation response.

Researchers performed a translational study of germline DNA from 201 prospectively treated patients. These included patients who were treated with 2 forms of definitive radiotherapy for prostate cancer at 2 institutions: Oslo University Hospital and University of California, Los Angeles (NCT01059513 and NCT02296229).

Among evaluable participants, 108 men received CF-RT and 93 received SBRT. Their germline DNA was assessed for the presence of functional mirSNPs. After evaluation, researchers compiled random forest, boosted trees, and elastic net models, to predict toxicity in accordance with the radiation therapy oncology group (RTOG) scale.

The median follow-up period was 8.5 years. Findings revealed that the late grade 2 or higher GU toxicity rate was 16% after CF-RT and 15% after SBRT. The elastic net model utilizing the 22 mirSNPs identified CF-RT patients at high risk for toxicity (71.5%) vs low risk (7.5%), with an area under the curve (AUC) values of 0.76-0.81. Similarly, the elastic net model utilizing mirSNPs identified SBRT patients at high risk for toxicity (64.7%) vs low risk (3.9%), with an area under the curve (AUC) values of 0.81-0.87.

Based on these findings, an ongoing clinical trial (NCT04624256) will seek to test the model on a new set of patients and further validate the results. In this novel trial, the results from the DNA analysis will be shared with each patient and information’s role in shared decision making will be evaluated alongside group toxicity rates.

“This research may ultimately guide a prostate cancer patient’s treatment plan,” Kishan noted in a press release.² "If we can know ahead of time who will tolerate radiation treatment and who may suffer these side effects, we can do a better job of assuring not only the best treatment but the one with least impact on quality of life."

References

1. Kishan AU, Marco N, Shulz-Jaavall MB, et al. Germline variants disrupting microRNAs predict long-term genitourinary toxicity after prostate cancer radiation. Radiotherapy and Oncology.2022;167:226-232. doi:10.1016/j.radonc.2021.12.040
2. Genetics predicts toxic side effects to prostate cancer radiotherapy. UCLA Health. News release. January 13, 2022. Accessed January 25, 2022. https://bit.ly/3KUkbeD