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Million Veterans Study Yields Prostate Cancer Risk Score With Promise for Improved Screening


NEW YORK – Genomic data from the US Department of Veteran Affairs' Million Veterans Program has yielded a novel polygenic risk score that investigators believe could help improve and personalize screening for prostate cancer by identifying individuals at higher or lower risk of developing aggressive, metastatic disease.

VA investigators reported in a poster presentation at last week's American Society of Clinical Oncology Genitourinary Cancers Symposium that the scoring algorithm, which incorporates 290 genetic variants, accurately identified individuals with high or low lifetime risks of developing metastatic prostate cancer or dying from the disease.

The risk of death was more than four times higher in people with a polygenic risk score, or PRS, in the top 20th percentile than it was for those in the bottom 20 percent.

"While most prior genetic studies have focused on men of European ancestry, our scoring algorithm is a measure of risk of dying of prostate cancer in a diverse population of military veterans," lead study author and University of California, San Diego researcher Meghana Pagadala, in La Jolla, California, said in a statement. "Even accounting for family history and ancestry, the scoring algorithm provided powerful additional information about a man's risk of death due to prostate cancer."

Tyler Seibert, a UCSD radiation oncologist and the study's senior author said in an email that although the details of how the team's PRS could be best implemented remain to be determined, the evidence from the current study suggests that it could be clinically useful.

"The results show that the genetic score is a stronger predictor of lifetime risk of prostate cancer death than the factors currently used clinically (family history and race), so this effect size is likely large enough to matter," he wrote.

Pagadala added that the ability to identify individuals with a fourfold increased risk of dying from prostate cancer even when controlling for family history and ancestry clearly marks the VA's PRS as an effective risk stratification tool.

For comparison, in data published on Myriad Genetics' PRS for breast cancer, individuals in the top 95th score percentile had a more than twofold higher risk of breast cancer development than women with an average score, with those in the lowest 10th percentile showing a nearly twofold reduction in risk of breast cancer development.

"The applications in the clinic will depend on also accounting for existing methods, such as PSA screening, Gleason scoring, and more," Pagadala said. "However, the stratification we see here is promising, especially in African American individuals as they have higher incidence and mortality from prostate cancer," she said.

According to Seibert, if clinically implemented, the genetic score could be used to help guide the decision of whether and how to screen a particular man for prostate cancer using tools like prostate-specific antigen testing and follow-up imaging.

Although it remains a mainstay in clinical practice, questions continue to emerge concerning the precision of PSA testing and its utility, considering the risk of overdiagnosis of low-risk disease and unnecessary treatment. As such, adjunct tools that can help guide the best use of imperfect screening tools could be powerful, the VA team said.

The team has also shown previously that genetic information can be combined with age to give an age-specific genetic risk of aggressive prostate cancer, Seibert added. This means the genetic score "could also help decide at what age a man should initiate prostate cancer screening."

The Million Veterans study has enrolled over 650,000 individuals so far, and the current study analyzed genetic data and clinical information for 513,997 male participants, using an algorithm that incorporates 290 previously identified gene variants associated with prostate cancer risk, along with patients' ages.

Overall, the investigators calculated that individuals with PRS scores in the top 20 percent had more than four times higher risk of death than those with scores in the bottom 20 percent. The risk for developing prostate cancer was more than five times higher and the risk for having the disease metastasize was about four times higher for those in the top 20 percent of risk scores compared to the lowest 20 percent.

Seibert said that the group hasn't worked out exactly how they will advance their predictor for clinical use, but that is the goal.

"We definitely want to see patients benefit from what we have learned. That would probably require a commercial product, though the score is published openly and could potentially be calculated by individual laboratories," he said.

In the meantime, the group is "exploring multiple options for how to implement this in real time, including within the VA."

Other next steps include working to better understand how to incorporate ancestry into estimating genetic risk.

"We want to assess the ancestry-specific effects of current prostate cancer risk variants and also [explore the possibility of] novel ancestry-specific risk variants. One limitation is that most genotyping studies are dominated by European individuals. However, as we continue to study genetics in more diverse populations, like the Million Veteran Program, we hope to gain a better understanding," Pagadala said in her email.

Beyond this, the team also wants to evaluate the score in the context of PSA screening, PSA density, and MRI, assessing whether and how elevated genetic risk translates to specific screening outcomes and observations.