New scoring system tunes out the 'noise' in PSA testing to spare 30% of patients from biopsies
Also, register: ASPI program "Pissed Off: The Many ways Urination Can Go Wrong."
By Howard Wolinsky
Are you a heavy producer of PSA who has not beeen diagnosed with prostate cancer? Could your PSA sending out a misleading signal in deciding whether you need a biopsy?
A new genetics scoring system with data from a group that included men with and without prostate cancer confirmed by biopsy, found that roughly 30% of men could have been spared a biopsy, researchers reported in a major new study appearing in the journal Nature Medicine on June 1.
“The biggest take-home message from the study is that it is possible to improve PSA screening by accounting for genetic factors that affect PSA production even in the absence of prostate cancer,” said co-senior author Rebecca E. Graff, ScD, assistant professor, Department of Epidemiology and Biostatistics, University of California, San Francisco, in an e-interview.
(Rebecca E. Graff, ScD, UCSF)
It turns out that some of us secrete extra amounts PSA (prostate-specific antigen). If this could be confirmed through genetic testing, it would impact interpreting our PSAs and help determine whether we need a biopsy.
Genes determine the level at which we secrete PSA.
“We know from previous studies that PSA levels are highly heritable, so there is a genetic basis to PSA regulation. Our study identified over 120 regions across the genome that are associated with PSA levels,” said co-author Linda Kachuri, PhD, an assistant professor of epidemiology and population health at Stanford and the lead author of the study.
(Linda Kachuri, PhD, Stanford Medicine.)
“We looked at the association between genetically adjusted PSA and prostate cancer, and found that genetic adjustment makes PSA more predictive. In order to perform this genetic adjustment, we identified factors that influence constitutive (non-cancer) PSA variation. This means that if some men are high PSA producers simply because of their genetics, their PSA values would get corrected downward and help them avoid excessive diagnostic work-ups,” she said.
Kachuri said PSA measurements “can be noisy, such that elevated PSA levels don’t always indicate the presence of a tumor. Genetic factors also play a role. Our approach tries to improve the signal-to-noise ratio for PSA.”
Genetic researcher Brian Helfand, MD, PhD, a urologic oncologist and a molecular biologist at NorthShore University HealthSystem outside Chicago, who was not involved in the study, said the new approach attempts ”to understand and adjust for the genetic basis of PSA expression. There is a large genetic component, and by adjusting for this, we can make PSA screening more accurate.”
Genomic testing is more widely accepted in the U.S. than in Canada, Europe or Australia.
Jeremy Grummet, MBBS, urologic surgeon and director of the Clinical Research Urology Unit, Alfred Health, Monash University and a member of European Association of Urology, Guidelines Prostate Cancer Panel Member, was not impressed with the polygenic score.
He said, “MRI already does this. And its advantage is that when it’s positive, it then allows you to perform a targeted biopsy. Not sure these genetic tests add much. MRI has been standard next test after elevated PSA in EAU Guidelines for several years.
William Catalona, MD, the PSA pioneer from Northwestern University' Feinberg SChool of Medcine in Chicago, said: “Current prostate MRI scans are far from perfect in assessing the risk for aggressive disease. The reasons include variability in equipment, technique, and the experience and skill of the readers. There are many false positives and a considerable proportion of false negatives in which the MRI scan fails to detect an aggressive cancer.
“Authors from the United Kingdom in general have tended to lend more credibility to MRI scans than many in the United States. And I acknowledge that it is possible that new artificial intelligence-assisted scans may reduce the variability and improve the accuracy. However, genetic biomarkers do not share the same limitations, and there is increasing evidence that they provide independent information for risk assessment. At this juncture, I believe that it would be short-sighted to totally dismiss the possible contribution of polygenic risk scores to multi-parameter risk-prediction algorithms.”
The experimental polygenic scoring system tested in the study, funded by the National Cancer Institute/National Institutes of Health, could be used someday to set a baseline level to determine who is a big PSA secreter. But there are no immediate plans to commercialize it, the researchers told me.
“Additional research is required before our findings can be leveraged commercially. Were our findings and future research ultimately translated into a commercial test, it would theoretically be used to adjust PSA levels prior to determining whether or not someone should have a biopsy,” Graff said.
(John Witte, PhD, Stanford Medicine)
“Some men have higher PSA levels due to their genetics,” said John Witte, PhD, a professor of epidemiology and population health and of biomedical data sciences at Stanford and co-senior author. “They don’t have cancer, but the higher PSA level leads to a cascade of unnecessary medical interventions like biopsy.”
In addition to the regular blood-based PSA test, such personalized screening would require a germline genetic test, typically done on saliva, blood or cheek swab samples, to look for inherited genetic variants that affect PSA levels.
Elevated PSA levels can be a sign of a cancerous prostate tumor, but also can be caused by factors unrelated to cancer, such as inflammation, infection, an enlarged prostate, or simply older age.
By one estimate, fewer than one-third of men with elevated PSA levels were confirmed by a biopsy to have prostate cancer. Moreover, 15% of men with normal PSA levels were later found to have prostate cancer.
The researchers aimed to refine PSA testing by plugging in genetic factors and, as they put it, tune out “background noise.”
The researchers said the trouble with current PSA screening can be compared to a signal-to-noise problem in engineering, in which the desired output is mixed with background noise.
“To improve the signal, which is the variation in PSA levels caused by a prostate tumor, we subtract out the noise, which in this case comes from genetics,” said Kachuri.
The adjusted PSA levels particularly improved detection of the more aggressive forms of prostate cancer, although the benefit was noticeable only in men of European ancestry.
“What we’re really worried about are those aggressive cases, so the fact that we’re able to show that genetically adjusted PSA is more predictive of aggressive disease is really promising,” Kachuri said.
The adjusted PSA levels are not perfect either. They would have missed approximately 9% of positive biopsies. The majority of these overlooked cases were slow-growing tumors, which may not require treatment, but the misclassifications point to room for improving the score.
The testing concept is aimed at men who have not yet been diagnosed. So this would not apply to those of us already on AS or those who have undergone treatment.
Kachuri said, “Our study examines PSA testing use in the context of screening. The tests are meant for healthy men for the purpose of cancer prevention (regardless of the surveillance or treatment protocol they would follow were they diagnosed with prostate cancer).”
The polygenic scoring was more effective in men of European ancestry, a population focused on in earlier research.
Because the polygenic score was developed using data predominantly from men of European ancestry, the team is working on a larger study in collaboration with the Million Veteran Program, which will include more men from diverse ancestral populations.
The researchers identified 128 sites in the genome that can impact a person’s inherent PSA level. They calculated PSAs that accounted for an individual’s normal genetic variations at these sites — known as a PSA polygenic score.
“A polygenic score is a quantitative way of summarizing someone’s genetic predisposition for a trait in a single value,” Kachuri said. In this case, the trait is a higher baseline PSA level.
The researchers evaluated the PSA polygenic score on data from a separate group of nearly 32,000 men without prostate cancer. They found that the score could predict close to 10% of variation in PSA levels, though it was much more effective among men of European ancestry than among men of East Asian or African ancestry.
Kachuri said, “This approach is applicable to all men, but at the moment, our genetic score for PSA is less predictive in men of African and East Asian ancestry. We are already working on additional studies that aim to improve prediction in men of non-European ancestry.
“Ideally, we want to come up with a single score that works well for everybody, across the spectrum of ancestry.”
ASPI on July 1: ‘Pissed Off: The Many Ways Urination Can Go Wrong’
By Howard Wolinsky
Dean Elterman, MD, an academic urologist at the University of Toronto, is presenting a free webinar, “Pissed Off: The Many Ways Urination Can Go Wrong” to Active Surveillance Patients International at 12-1:30 p.m. Eastern on July 1, 2021.
Click here to register: https://tinyurl.com/5d7ypd8k
He’ll be covering the waterfront of topics, from BPH to incontinence to overactive bladder.
The session will be followed with a live Q&A.
(Dean Elterman, MD, University of Toronto.)
Elterman’s research interests include voiding dysfunction, benign prostate enlargement, and men’s health.
He is the medical director of the Prostate Cancer Rehabilitation Clinic at Princess Margaret Cancer Centre.
Elterman trained at the University of Toronto, Memorial Sloan-Kettering Cancer Center, and Weill Cornell Medical Center. He lectures internationally on the topics of novel technologies for BPH and teaches courses at the American Urological Association.