Polygenic Risk Scores Predict Cancer Cases, but Not Aggressiveness in Prostate Cancer

A new report casts doubt on the usefulness of polygenic risk scores for assessing the risk of aggressive prostate cancer in men suspected of having the disease.

In a research letter published today in JAMA Internal Medicine, investigators said there is a significant need to improve risk assessment in men with potential prostate cancer because a high rate undergo prostate cancer biopsies only to find they have clinically insignificant cancer (grade group [GG] 1) or no cancer.

Polygenic risk scores (PRS) are scores based on an assessment of an individual’s burden of risk-associated single-nucleotide polymorphisms. Investigators have suggested such scores might be useful in helping to identify the highest-risk patients, but previous studies have failed to find an association between PRS and aggressive disease.

“Although polygenic risk scores have been associated with prevalent and incident disease, prior studies have shown that they do not improve risk prediction for aggressive prostate cancers with the potential to be fatal,” the study authors said.

They decided to compare polygenic risk scores, specifically the PRS₂₆₉ assessment, with the Prostate Biopsy Collaborate Group’s (PBCG) risk calculator, a tool designed to assess the likelihood of finding any cancer and finding high-grade cancer (GG2 and above) on biopsy.

They retrospectively analyzed a cohort of 655 men aged 40 to 80 years who underwent a prostate biopsy. The median age was 63 years, and 8.2% of participants were of African ancestry (the remaining patients were of European ancestry). Patients were scored using the PRS₂₆₉ assessment and the PBCG’s risk calculator, the latter of which is based on age, prostate-specific antigen (PSA) levels, digital rectal examination findings, ancestry, and family medical history.The patients in the study had a median PSA of 5.3 ng/mL.

About half of the men were found to have prostate cancer on biopsy (52%), and 27% had cancers of GG2 or higher. Scores on the PRS₂₆₉ assessment were found to be associated with a finding of any cancer. The age-adjusted odds ratio per standard-deviation increase in the PRS269 was 2.0 (95% CI, 1.6-2.4). When PRS₂₆₉ was combined with the PBCG tool, the authors said prediction of any cancer was improved. However, the same was not true for prediction of high-risk (GG2 and above) cancers (C-statistic, 0.74 vs 0.74; difference, 0.002; 95% CI, −0.011 to 0.012).

“A prostate cancer polygenic risk score did not improve risk prediction of aggressive prostate cancer compared with a contemporary clinical risk predictor,”the study authors wrote. “Although the PRS₂₆₉ improved model discrimination for all cancers, improvement was less than has been observed for other validated prostate cancer biomarker predictors such as the Prostate Health Index.”

In an accompanying invited commentary, Robert J. Klein, PhD, of the Icahn School of Medicine at Mount Sinai, said the new study helps demonstrate the considerable work left to do if PRS is to become a meaningful tool in a clinical setting. He said a PRS that could discriminate between indolent and potentially lethal prostate cancers would be helpful in reducing the risk of overdiagnosis. However, he added there are logistical challenges, such as the need to include a sufficient number of cases to identify potentially lethal cancers in studies and the need for a lengthy follow-up period.

“Because even higher-grade cancers may not progress to metastasis or death, studies with sufficient longitudinal follow-up will be necessary to build a PRS that can predict mortality outcomes,” he wrote.

He said future studies should include rare coding variants in their PRS, since those rare variants appear to be associated with aggressive, potentially fatal disease.

“Given the experience with PSA testing, where a marker for any prostate cancer resulted in detection of many indolent cancers that did not need treatment, care will need to be taken that any PRS that makes it to the clinic can discriminate between indolent and potentially lethal prostate cancer,” he concluded.

Reference

Schaffer KR, Shi M, Shelley JP, et al. A polygenic risk score for prostate cancer risk prediction. JAMA Intern Med. Published online March 6, 2023. doi:10.1001/jamainternmed.2022.6795