Polygenic score-adjusted PSA may improve screening accuracy in prostate cancer

Investigators have developed a polygenic score for patients with prostate cancer that accounts for non-cancer related genetic variants that cause changes to prostate-specific antigen (PSA) levels, showing a potential for the tool to improve screening accuracy.¹

The investigators analyzed PSA levels among a total of 95,768 cis-gender men who had never been diagnosed with prostate cancer.

The results were published in Nature Medicine.

“We showed that genetic correction of PSA levels has the potential to both reduce unnecessary biopsies and improve our ability to detect tumors with a more aggressive profile. We hope that our findings represent a step forward in developing informative screening guidelines and reducing the diagnostic gray area in PSA screening,” said lead author Linda Kachuri, PhD, MPH, in a news release on the findings.² Kachuri is an assistant professor of epidemiology and population health at Stanford University School of Medicine in Stanford, California.

Using data from 5 previously published studies, the investigators analyzed PSA levels among a total of 95,768 cis-gender men who had never been diagnosed with prostate cancer. Nearly 90% of participants included in the study were predominantly of European ancestry. PSA levels had a cutoff of 10 ng mL⁻¹ or lower.

A genome-wide analysis yielded 82 novel genetic variants that are associated with PSA. With that data, the investigators developed a genome-wide polygenic score, which was set to calculate patients’ individual risk for high PSA levels based on genetic variation. The score was found to have no association with prostate cancer incidence (P = .83).

“The polygenic score was strongly associated with PSA levels in validation cohorts and was not associated with prostate cancer, confirming that it reflects benign PSA variation,” said senior author Rebecca Graff, ScD, in the news release. Graff is an assistant professor of epidemiology and biostatistics at the University of California, Los Angeles.

The investigators found that when the score adjusted patients’ PSA levels based on genetic risk, the accuracy of biopsy referral decisions was improved. Data showed that 31.7% of men of European ancestry who were biopsy-negative were found to be below the threshold for recommending a biopsy, according to the polygenic score. With 2.5% of these participants found to be eligible for biopsy, the adjusted score had a net reclassification of 29.3% of patients.

However, positive biopsies would have been missed in approximately 9% of participants with the adjusted PSA levels. Among these patients, most had tumors of less than Gleason 7.

In men of African ancestry, 4.6% of men had PSA levels that were reclassified as being below the threshold, and 3.1% had PSA levels that were reclassified upward.

In 106 cases and 23,667 controls, the genetically adjusted PSA score was also more predictive of aggressive prostate cancer compared with unadjusted PSA.

The authors note that further analysis is needed in order to include a more diverse study population.

References

1. Kachuri L, Hoffmann TJ, Jiang Y, et al. Genetically adjusted PSA levels for prostate cancer screening. Nat Med. Published online June 1, 2023. Accessed June 2, 2023. doi:10.1038/s41591-023-02277-9

2. Personalizing prostate cancer screening may improve the accuracy of detection. News releasee. University of California, San Francisco. May 31, 2023. Accessed June 2, 2023. https://www.newswise.com/articles/personalizing-prostate-cancer-screening-may-improve-the-accuracy-of-detection