Genetic adjustment of PSA values could improve prostate cancer screening
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Prostate cancer screening could be improved through accounting for genetic factors that cause noncancer-related variations in PSA levels, according to study results presented at American Association for Cancer Research Annual Meeting.
Genetic adjustment of PSA could reduce unnecessary testing and overdiagnosis of low-risk prostate cancer and increase detection of aggressive tumors, researchers wrote.
“PSA is one of the most widely used prostate cancer biomarkers and is used for detection and also in disease management,” Linda Kachuri, MPH, PhD, postdoctoral scholar in the department of epidemiology and biostatistics at University of California, San Francisco, said during a press conference. “Its use when it comes to prostate cancer screening and detection remains controversial.”
Methodology
Several factors other than prostate cancer can cause PSA elevation, such as older age, infection, inflammation and benign prostatic hyperplasia. PSA screening currently is not recommended for systematic use at the population level.
Kachuri and colleagues sought to identify genetic determinants of PSA levels among men without cancer that could be used to personalize prostate cancer screening.
The genome-wide association study included data of 95,768 prostate cancer-free men in the United States, United Kingdom and Sweden. The study revealed 128 PSA-associated variants across the genome, including 82 novel variants, which researchers used to create a polygenic score — a cumulative measure of genetic predisposition to a particular PSA level.
They validated the score among 5,725 men in the PCPT and 25,917 men in the SELECT cancer prevention trials.
The score explained 7.3% of baseline PSA variation in the PCPT cohort and 8.8% in the SELECT cohort but had no association with prostate cancer in the cohorts, which confirmed it represented benign PSA variation.
Next, researchers tested the polygenic score’s ability to improve detection of clinically significant prostate cancer and reduce overdiagnosis among a real-world cohort at Kaiser Permanente. They adjusted each man’s PSA values based on his polygenic score and estimated the impact of the reclassification on PSA thresholds that trigger biopsy referrals.
“The observed PSA value is a little bit noisy,” Kachuri said. “It can reflect variation in PSA due to cancer, but it can also capture other factors that influence PSA, and one of these factors is genetics. So, what we’re effectively doing is using this genetic score to try to correct some of that noise.”
Key findings, implications
Results showed using genetically adjusted PSA values would have avoided 19.6% of negative biopsies in men without cancer and reclassified 15.7% fewer biopsies in cases of low-grade prostate cancer (Gleason score <7), which represented 71% of all men for whom biopsy would have been avoided.
Researchers then evaluated whether genetically adjusted PSA would help better detect aggressive prostate cancer (Gleason score 7, PSA 10 ng/mL, T3-T4 stage and/or distant nodal metastases). They found the adjusted PSA exceeded the performance of both observed PSA and a 269-variant genetic risk score for prostate cancer. Researchers achieved the best prediction performance with a combination of the genetic risk score and genetically adjusted PSA measure, resulting in an area under the curve of 0.732 among men in the PCPT trial and 0.803 among those in the SELECT trial.
“Our findings are exciting because we’re able to show that we can use genetic discoveries that are coming out of genome-wide association studies to potentially improve the detection of prostate cancer and, hopefully, try to make PSA a more useful and accurate screening biomarker,” Kachuri said.
Limitations, next steps
Kachuri noted study limitations, including that the cohorts consisted mostly of men of European ancestry.
“In our subsequent efforts, we’re really trying to focus on having larger and much more diverse studies so we can really comprehensively examine PSA genetics in individuals of all ancestries,” Kachuri said.
“The reason I’m optimistic about the translation of this is because the complicated part is calculating the genetic risk score, but the implementation is straightforward because we’re still using PSA, which is a biomarker that people are very familiar with and clinicians are familiar with,” she said.
Perspective
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Elisabeth McCauley King, MSN, RN, FNP, AGN, AOCNP
Approximately 1 in 8 men will be diagnosed with prostate cancer in their lifetime, and the disease disproportionally impacts Black men. Studies have shown early diagnosis leads to better outcomes, so screening is imperative. Unfortunately, prostate cancer screening with PSA remains controversial due to poor sensitivity and specificity.
The U.S. Preventive Services Task Force recommends individualized decisions regarding prostate cancer screening with PSA for men aged 55 to 69 years based on discussions of risk vs. benefit. USPSTF notes that prostate cancer screening with PSA offers small potential benefit and lists several possible harms from false-positive results, including additional testing and biopsy, overdiagnosis and overtreatment, and treatment complications such as incontinence and erectile dysfunction.
This study includes two very exciting findings. By using polygenic scores to adjust PSA, the authors projected they could both decrease the frequency of negative prostate biopsies and improve detection of more aggressive prostate cancers, improving the specificity and sensitivity of prostate cancer screening. Unfortunately, all genetics research continues to suffer from overrepresentation of participants of European ancestry, and this study is no different. Like many other genome-wide association studies, the authors utilized a population of primarily European descent. And because Black men are more likely to be diagnosed with prostate cancer and more likely to die of the disease, this was a major weakness of this study.
If validated in more diverse populations, the implications of this study could be tremendous. Using polygenic scores to adjust PSA values in prostate cancer screening may significantly improve early detection and decrease the potential harms that can result from false-positive results.
Reference:
Final recommendation statement. Prostate cancer: Screening. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/prostate-cancer-screening. Published May 8, 2018. Accessed April 10, 2022.
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Kachuri L, et al. Abstract 1441. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans.
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