First Of Its Kind Test Uses microRNAs to Predict Toxicity from Cancer Therapy

Many men with early-stage prostate cancer receive stereotactic body radiotherapy (SBRT), a highly precise form of radiation treatment that is completed in just five sessions. Compared to traditional radiation, which typically requires daily treatments over several weeks, SBRT is faster and more convenient. However, like all radiation therapies, SBRT can still lead to side effects. While severe side effects are rare, some patients experience moderate toxicity that may require medication and impact their quality of life. Currently, there are no known methods to prevent, slow, or reverse the late effects of radiation toxicity. A common issue after radiation is urinary side effects, such as frequent urination, pain, and an urgent need to urinate, which may not always be manageable in time. These side effects can occur immediately (acute toxicity), develop later (late toxicity), or start early and persist (chronic toxicity). Even with advanced radiation techniques, some patients still face these issues, and predicting how individuals will react to radiation remains difficult.

Researchers at the UCLA Health Jonsson Comprehensive Cancer Center (Los Angeles, CA, USA) have validated a test that can accurately predict which prostate cancer patients are more likely to experience long-lasting urinary side effects following radiation therapy. This test, named PROSTOX, is the first of its kind to use microRNAs to predict toxicity resulting from cancer treatment. By identifying patients most at risk before therapy begins, the test could help reduce the burden of long-term complications. In a study published in Clinical Cancer Research, the UCLA team validated PROSTOX's ability to predict urinary side effects, which can include urinary tract pain, blood in the urine, frequent urination, and urgency or leakage. The research also revealed that various genetic factors are linked to different side effects, highlighting the need for personalized treatment approaches.

Earlier studies by the team had identified that specific inherited genetic differences, especially in areas related to microRNAs, which regulate gene function, could predict the likelihood of developing these side effects. Using this information, they developed the PROSTOX genetic test, which identifies 32 unique mirSNPs (genetic variants in microRNAs) associated with radiation-related side effects. The test categorizes patients into low-risk and high-risk groups for developing severe, long-term urinary issues after SBRT. Their findings showed that patients in the high-risk group were 10 to 12 times more likely to experience these problems. The new study aimed to validate PROSTOX in a separate group of 148 prostate cancer patients who were undergoing either MRI- or CT-guided SBRT as part of the MIRAGE phase III clinical trial at UCLA. Additionally, the team employed machine learning, a form of artificial intelligence, to create models that could predict acute and chronic urinary toxicity.

The results confirmed that PROSTOX can accurately predict which patients will experience significant late urinary toxicity, regardless of whether MRI or CT guided the radiation treatment. Furthermore, the test was unaffected by other clinical factors like age or radiation dose, suggesting that it detects an independent, genetic risk for toxicity. The study also distinguished between two types of radiation-induced urinary side effects: chronic toxicity and late toxicity. Genetic analysis revealed that these two forms of toxicity have distinct genetic signatures, implying different underlying biological mechanisms. Late toxicity appears to be associated with immune system dysfunction and long-term inflammation, while chronic toxicity may be more influenced by the advancements in radiation technology, indicating that improved techniques could reduce these side effects. Based on these findings, the researchers emphasize the importance of integrating genetic testing with modern radiation therapy to personalize prostate cancer treatments further. The team is now working to expand the validation of PROSTOX in larger patient populations and is also investigating similar genetic biomarkers to predict side effects in other cancers treated with radiation and immunotherapy.

“We’ve always known that some men develop these life-altering side effects that they will carry through the remainder of their lives, but until now, we didn’t have a way to predict who,” said Joanne Weidhaas, MD, PhD, professor of radiation oncology and vice chair of molecular and cellular oncology at the David Geffen School of Medicine at UCLA, and senior author of the study. “What makes PROSTOX different is that it looks at a patient’s unique genetics to estimate their personal risk of developing side effects from radiation. This helps doctors and patients choose the safest treatment and avoid unnecessary toxicities.”

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