The use of a polygenic score incorporating variations in prostate-specific antigen (PSA) values that are not due to cancer may allow for more precise PSA screening, according to findings of a large genome-wide association study presented at the American Association for Cancer Research (AACR) Annual Meeting 2022.1,2 Investigators performed a meta-analysis of a large group of men without prostate cancer and identified 128 variants associated with elevated PSA values but not due to cancer. They reported on developing a polygenic score for PSA variation that could help in identifying whether elevated PSA levels are an indicator of disease risk or the result of benign PSA variations. PSA values using the polygenic score could help to identify aggressive vs nonaggressive prostate cancer, reduce unnecessary biopsies, and prevent overdiagnosis of low-risk prostate cancer, the investigators reported.
In the study, a polygenic score accounting for noncancerous variations in PSA values explained 7.3% to 8.8% of the variation in baseline PSA values in two large prostate cancer prevention studies. Correcting PSA values for noncancerous variations would have led to almost 20% fewer negative biopsies in men without cancer and 15.7% fewer biopsies in men with low-risk disease.
PSA values adjusted for noncancerous variations were more strongly associated with aggressive prostate cancer than PSA values not adjusted for these variations, noted lead author Linda Kachuri, PhD, MPH, a postdoctoral scholar in the Department of Epidemiology and Biostatistics at the University of California San Francisco.
“Our findings are exciting because we’re able to show we can use these genetic discoveries from genome-wide association studies to potentially improve the detection of prostate cancer and hopefully make PSA a more useful and accurate screening biomarker. This is only the first step, and it’s absolutely important to validate these findings in additional patient populations,” Dr. Kachuri stated at a press conference.
PSA testing is widely used in the diagnosis and management of prostate cancer, but its use remains controversial due to limitations. Dr. Kachuri and co-investigators hypothesized that the accuracy of PSA testing could be improved and personalized by accounting for genetic variations that are unrelated to prostate cancer.
The large genome-wide association study included about 95,000 men from the United States, England, and Sweden. The analysis identified 128 PSA-related variants not associated with cancer, including 82 not previously recognized.
These data were used to develop a polygenic score that accounted for the variants’ contributions to PSA values. The score was individualized to each patient and represented the sum of genotypes across the 128 variants, weighted to reflect the variants’ effect on PSA values. A personalized adjustment factor was applied to a patient’s PSA value to account for the patient’s unique PSA profile.
The polygenic score was validated by applying the score to the PSA values of men who participated in the Prostate Cancer Prevention Trial (PCPT, n = 5,725) and SELECT (n = 25,917) prostate cancer prevention studies of men who did not have prostate cancer at enrollment. The polygenic score explained 7.3% of variation in PSA values in PCPT and 8.8% of the variation in SELECT. Of note, the polygenic score was not associated with prostate cancer in the PCPT or SELECT trial, confirming that the score reflected benign PSA variation.
Additional Study Objectives
Next, individual polygenic score values were substituted for participants’ measured PSA values to reclassify patients. As a result, the investigators estimated that 19.6% of negative biopsies could potentially have been avoided if polygenic scores were used. In a separate analysis, the polygenic score was applied to men who had indolent, low-grade prostate cancer. The results suggested that 15.7% of biopsies could have been avoided in those men. “This is another indication that genetically adjusted PSA values could potentially be useful for reducing overdiagnosis of prostate cancer,” Dr. Kachuri told listeners.
A final objective of the study was to examine the use of the polygenic score in recognizing aggressive prostate cancer. The results showed that the adjusted PSA values outperformed measured PSA levels and a validated polygenic score for identifying aggressive disease in both the PCPT and SELECT studies. The best prediction tool was identified as a combination of the polygenic score and the genetically adjusted PSA measure.
Dr. Kachuri noted that these data were based mainly on men of European ancestry. “In our subsequent efforts, we want to focus on having larger and much more diverse studies. Thus, we can comprehensively examine PSA genetics and individuals of all ancestries to represent our target patient population,” she added.
Expert Point of View
Louis M. Weiner, MD
If these preliminary results are confirmed by further evaluation, the polygenic score could provide clinicians with useful information about prostate cancer, said press conference moderator Louis M. Weiner, MD, Director of the Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. “Added to the information we get from a variety of different PSA [prostate-specific antigen] determinations, the polygenic score may create more precise knowledge or information,” he stated.
Dr. Weiner continued: “It’s important that all information be transmuted into knowledge, which then becomes actionable…. How do you integrate this with issues such as environmental modifiers of PSA, like inflammation, prostatitis, or age? How do you integrate the polygenic score into a more holistic interpretation of what PSA might be?”
“This is a tool, and I think any tool that gives us more precision typically turns out to have value,” he stated. “If this is validated—and it seems to be getting validated right now—it could create a new paradigm for giving clinicians useful, actionable information to inform their patients.”
DISCLOSURE: Dr. Kachuri reported no conflicts of interest. Dr. Weiner reported financial relationships with Jounce Therapeutics, Celldex Therapeutics, Cytomx Therapeutics, Immunome, BioXcel Therapeutics, Tessa Therapeutics, and Samyang.
1. Kachuri L, Graff RE, Berndt SI, et al: Genetic determinants of PSA levels improve prostate cancer screening. AACR Annual Meeting 2022. Abstract 1441/8. Presented April 11, 2022.
2. Kachuri L, Hoffmann TJ, Jiang Y, et al: Incorporating genetic determinants of prostate-specific antigen levels improves prostate cancer screening. medRxiv, April 21, 2022 (Preprint available at https://www.medrxiv.org/content/10.1101/2022.04.18.22273850v1).