DNA testing for prostate cancer – of the patients’ inherited DNA and their tumors’ somatic DNA – is increasingly used in the U.S. to determine whether and how to treat low-grade, localized prostate cancers.
Another genetic approach, known as the polygenic risk score (PRS), is emerging as a third genetic approach for sorting out prostate cancer risks.
PRS aims to stratify a person’s disease risk by going beyond rare variants in genes, such as BRCA2, and compiling a weighted score that integrates thousands of common variants whose role in cancer may be unknown but are found more frequently in men with prostate cancer. Traditional germline testing, by contrast, looks for about 30 specific genes directly linked to prostate cancer.
Essentially, “a polygenic risk score estimates your risk by adding together the number of bad cards you were dealt by the impact of each card, such as an ace versus a deuce,” said William Catalona, MD, a urologist at Northwestern University Feinberg School of Medicine, Chicago, known as the father of prostate-specific antigen (PSA) screening.
In combination, these variants can have powerful predictive value.
Having a tool that can mine the depths of a person’s genetic makeup and help doctors devise a nuanced risk assessment for prostate cancer seems like a winning proposition.
Despite its promise, PRS testing is not yet used routinely in practice. The central uncertainty regarding its use lies in whether the risk score can accurately predict who will develop aggressive prostate cancer that needs to be treated and who won’t. The research to date has been mixed, and experts remain polarized.
“PRS absolutely, irrefutably can distinguish between the probability of somebody developing prostate cancer or not. Nobody could look at the data and argue with that,” said Todd Morgan, MD, a genomics researcher from the University of Michigan, Ann Arbor. “What [the data] so far haven’t really been able to do is distinguish whether somebody is likely to have clinically significant prostate cancer versus lower-risk prostate cancer.”
The promise of PRS in prostate cancer?
, according to Burcu Darst, PhD, a genetic epidemiologist at Fred Hutchinson Cancer Center, Seattle.
Research in the area has intensified in recent years as genome-wide association studies (GWAS) have become more affordable and the genetic information from these studies has been increasingly aggregated in biobanks.
“Because the sample sizes now are so much bigger than they used to be for GWAS studies, we’re able to develop much better polygenic risk scores than we were before,” said Dr. Darst.
Dr. Darst is lead author on the largest, most diverse prostate GWAS analysis, which led to the development of a PRS that is highly predictive of prostate cancer risk across diverse populations.
In the 2021 meta-analysis, which included 107,247 case patients and 127,006 control patients, Dr. Darst and colleagues identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants.
Compared with men at average genetic risk for prostate cancer – those in the 40%-60% genetic risk score category – men in the top 10% of the risk score (90%-100%) had between a 3.74-fold to fivefold higher risk for prostate cancer. However, the team did not find evidence that the genetic risk score could differentiate a person’s risk for aggressive versus nonaggressive disease.
As Dr. Darst’s team continues to improve the PRS, Dr. Darst says it will get better at predicting aggressive disease. One recent analysis from Dr. Darst and colleagues found that “although the PRS generally did not differentiate aggressive versus nonaggressive prostate cancer,” about 40% of men who will develop aggressive disease have a PRS in the top 20%, whereas only about 7% of men who will develop aggressive tumors have a PRS in the bottom 20%. Another recent study from Dr. Darst and colleagues found that PRS can distinguish between aggressive and nonaggressive disease in men of African ancestry.
These findings highlight “the potential clinical utility of the polygenic risk score,” Dr. Darst said.
Although the growing body of research makes Dr. Catalona, Dr. Darst, and others optimistic about PRS, the landscape is also littered with critics and studies showcasing its limitations.
An analysis, published in JAMA Internal Medicine, found that, compared with a contemporary clinical risk predictor, PRS did not improve prediction of aggressive prostate cancers. Another recent study, which used a 6.6 million–variant PRS to predict the risk of incident prostate cancer among 5,701 healthy men of European descent older than age 69, found that men in the top 20% of the PRS distribution “had an almost three times higher risk of prostate cancer,” compared with men in the lowest quintile; however, a higher PRS was not associated with a higher Gleason grade group, indicative of more aggressive disease.
“While a PRS for prostate cancer is strongly associated with incident risk” in the cohort, “the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease,” the authors concluded.