Genetic Score Predicts Lifetime Risk of Prostate Cancer Death

Roxanne Nelson, RN, BSN

February 23, 2022

SAN FRANCISCO ― A novel gene score algorithm was able to accurately identify men who had a high or low lifetime risk of developing metastatic prostate cancer or dying from the disease.

The novel algorithm (PHS290) incorporates 290 inherited genetic variants associated with prostate cancer and was used on blood samples from more than half a million veterans.

The findings were presented here at the Genitourinary Cancers Symposium (GUCS) 2022.

"This study represents the largest and most ancestry diverse validation of polygenic association with lifetime risk of fatal prostate cancer," said lead study author Meghana Pagadala, from the VA Health Care System, La Jolla, California. She is an MD/PhD candidate at the University of California, San Diego.

"It might inform decisions about screening and early cancer detection," she added.

Commenting on the study, ASCO Expert Robert Dreicer, MD, noted that while current prostate cancer screening recommendations rely on family history as well as race and ethnicity, these are "factors which often don't fully capture a person's risk of developing or dying from prostate cancer.

"This new study suggests that an extensive genetic risk score could be an effective tool to guide screening decisions by identifying people at high or low risk of developing metastatic prostate cancer," he said.

"Importantly, this tool been validated in a diverse population," he added.

Routine screening of healthy men for prostate cancer remains somewhat controversial because of possible overdiagnosis and unnecessary treatment of low-risk disease.

Genetic scores may provide an objective measure of assessing the risk of dying from prostate cancer, note the authors, and may be particularly useful for men of African ancestry, who have a higher average risk of prostate cancer death but are often treated homogeneously with the general population.

Study Details

The authors used participants from the Million Veteran Program, which over the past decade has enrolled over 650,000 people who are receiving medical care at 63 facilities that are part of the Veterans Health Administration system.

About 600,000 of the enrollees were male, and clinical information was obtained for nearly 97% of those men. About 425,000 were of European ancestry, and about 105,000 had an African ancestry. The remaining participants were of either Asian or Hispanic heritage. The median age of the participants was 69 years, and all had consented to donate blood for genotyping.

Genotype data were used to calculate the genetic score.

In addition, the team collected information on any family history of prostate cancer (first-degree relative) and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian).

A total of 582,515 men were included in the analysis.

After assessing ancestry and risk, the results showed that men of African ancestry had a 1.84 times' greater risk of developing prostate cancer as compared with those of European ancestry. The risks of metastatic disease and death were 2.27 times and 1.97 times higher, respectively.

Men with Hispanic ancestry had scores that were similar to those of European background, and while the study included men of Asian ancestry, a reliable estimate of risk could not be determined because of the small population size in the analysis.

In addition to ancestry, family history of prostate cancer also conferred a greater risk for disease development (hazard ratio [HR] = 1.9) and related death (HR = 1.67).

The results for the polygenic score showed that men with scores in the top 20% had a 4.4 times' higher risk of death as compared with men who had a score in the lowest 20%. The risk of developing prostate cancer was 5.6 times higher among men in the top 20%, and the risk of having metastatic disease was 4.18 times higher compared to individuals in the lowest 20%.

"We demonstrated the effectiveness of polygenic hazard scores in stratifying risk in a multi-ancestry cohort. Even when accounting for family history and ancestry group, the polygenic score remained a strong independent predictor of dying from prostate cancer," Pagadala commented.

The PHS290 algorithm is not yet commercially available, and Pagadala and her team hope to identify more ancestry-specific prostate cancer risk variants and better understand how to incorporate ancestry into estimating genetic risk. In addition, they plan to look at the interaction of genetic risk and environmental factors.

Approached for comment, Camille Ragin, PhD, MPH, from the cancer prevention and control program at Fox Chase Cancer Center, described the new findings as "quite promising."

"Prostate cancer is the leading cause of cancer death among men, and, in particular, Black men have the highest incidence and mortality rates," Ragin commented. "Previous studies focusing on the development of polygenic risk scores for prostate cancer have been predominantly Euro-centric and have not taken into account the genetic diversity among non-White prostate cancer patients.

"The study by Pagadala et al focused on the evaluation of a polygenic risk score using a diverse study population that incorporates genetic ancestry. While further work appears to be needed for better prediction of lethal and metastatic prostate cancer among Asian men, the findings have the potential to improve precision medicine for predicting lethal or metastatic prostate cancer, especially among Black men," she told Medscape Medical News.

The study received funding from the Million Veteran Program. Pagadala was supported by NIH grants. Several co-authors were supported by an NIH/NIBIB grant, the Prostate Cancer Foundation, and a University of California grant. Dreicer has relationships with Astellas Pharma AstraZeneca, AVEO, Bayer, Bristol-Myers Squibb, EMD Serono, Exelixis, Hinova Parmaceuticals, Infinity, Janssen Oncology, Merck, Myovant Myovant Sciences, Pfizer, Propella, Seattle Genetics, Very, Bristol-Myers Squibb (inst), Exelixis (inst), Novartis (inst), and Seattle Genetics (inst).

Genitourinary Cancers Symposium (GUCS) 2022: Abstract 155. Presented February 17, 2022

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