SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease.
PSA is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on Prostate Specific Antigen (PSA) levels remains controversial and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer. PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy.
The researchers in this study hypothesized that the accuracy of PSA screening for prostate cancer could be improved by accounting for genetic factors that cause changes in PSA levels not associated with prostate cancer. The aim of this study was to characterize genetic determinants of PSA levels in cancer-free men, in order to personalize prostate cancer screening.
The researchers conducted a large Genome Wide Association Study of PSA, to improve Prostate cancer screening, by accounting for genetic factors that cause noncancer-related variations in PSA levels, thereby personalizing prostate cancer screening. This study involved 95,768 men without a diagnosis prostate cancer from the US, UK and Sweden. The researchers identified 128 PSA-related variants across the genome, including 82 novel variants that were not previously recognized, and created a polygenic score for PSA levels. This polygenic score provided a cumulative measure of each individual’s genetic predisposition to high PSA levels.
The authors validated the polygenic score by applying the score to PSA values of 5,725 individuals enrolled in the Prostate Cancer Prevention Trial (PCPT) and the 25,917 individuals enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The analysis showed that the score explained 7.3% of variation in baseline PSA values in PCPT trial and 8.8% of variation in baseline PSA values in the SELECT cohort, and the polygenic score was not associated with prostate cancer in both the prevention trials, confirming that the score reflected benign PSA variation.
The researchers next tested the ability of the polygenic score’s ability to improve detection of clinically significant prostate cancer and reduce over diagnosis among a real-world cohort at Kaiser Permanente. They adjusted each individual’s PSA values based on his unique polygenic score and estimated the impact of this adjustment on the PSA thresholds that trigger biopsy referrals. The authors estimated that by substituting the patient’s polygenic score for measured PSA values, 19.6% of negative biopsies in men without prostate cancer potentially could have been avoided, and 15.7% of biopsies could have been avoided in men who had indolent, low-grade prostate cancer (Gleason score <7), which represented 71% of all men.
The researchers then evaluated whether genetically adjusted polygenic score would better detect aggressive prostate cancer (Gleason score 7, PSA 10 ng/mL, T3-T4 stage and/or distant nodal metastases). It was noted that in both the PCPT and the SELECT cohorts, polygenic score was more strongly associated with aggressive prostate cancer than measured unadjusted PSA values. The polygenic score also exceeded the performance of the 269-variant genetic risk score.
The authors from this study concluded that genetically adjusted PSA (polygenic score) could reduce unnecessary testing and overdiagnosis of low-risk prostate cancer, and increase detection of aggressive tumors and thus make PSA a more useful and accurate screening biomarker. The researchers pointed out that the population studied, were primarily European descent, and the polygenic score will need to be validated in more diverse populations.
Genetic determinants of PSA levels improve prostate cancer screening. Kachuri L, Graff RE, Berndt SI, et al. Presented at: AACR Annual Meeting 2022; April 8-13; New Orleans, Louisiana. Abstract 1441/8.