Researchers Devise ‘Genetic Correction’ to Improve PSA Test Ability to Gauge Prostate Cancer Risk
By analyzing four gene markers linked to prostate-specific antigen levels, researchers have devised a method that could potentially be combined with PSA testing to provide doctors a more accurate picture of a man’s risk for prostate cancer and help avoid unnecessary biopsies.
Researchers led by Brian Helfand at Northwestern University tested nearly 1,000 men for four SNPs that have been shown in previous studies to impact increases or decreases in a person’s PSA levels. These men were recruited in Chicago for a PSA screening study between 2003 and 2009 and were prostate cancer-free at the time of enrollment.
Screening for PSA – a glycoprotein enzyme encoded by the KLK3 gene and produced by the epithelial cells of the prostate gland – has shown in some cases to reduce prostate cancer-related mortality. However, enzyme levels can fluctuate based on factors not associated with cancer, and as such many experts feel that PSA isn’t very precise as a prognostic marker for the disease.
The US Preventative Services Task Force last year issued guidelines recommending against PSA-based screening for prostate cancer and concluded that “many men are harmed as a result of prostate cancer screening and few, if any, benefit.” Based on data from several large, randomized trials on prostate cancer screening, the USPSTF estimated that for every 1,000 men between ages 55 and 69 years old who were screened for PSA every one to four years for a decade, only one death from prostate cancer would be avoided, and more than 100 men would have false-positive results that lead to unnecessary biopsies.
In the latest study, Helfand and colleagues aimed to improve the prognostic value of PSA testing with the help of genetic testing. They used genetic factors linked to PSA levels to adjust trial participants’ PSA concentrations, and to gauge more accurately whether they had a heightened risk of prostate cancer and needed more aggressive action. “We hypothesized that genetic factors that are associated with increases or decreases in serum PSA concentrations may provide improved specificity for early detection and aid in determining whether a prostate biopsy is warranted,” the study authors wrote in the paper published recently in the Journal of Urology.
According to one estimate, there are 1 million prostate biopsies performed in the US each year. As such, a method that would enable doctors to avoid unnecessary biopsies in patients who aren’t likely to develop cancer could impart significant cost savings to the healthcare system.
Previous studies have shown that up to 45 percent of the variability in PSA levels among men are due to genetic factors. Furthermore, genome-wide association analyses have identified four SNPs in or near genes – TERT, FGFR2, TBX3, and KLK3 – that influence a man’s serum PSA concentrations.
After study participants were tested for these four SNPs, Helfand and colleagues calculated the genotypic effect on serum PSA concentrations for each SNP a patient carried and adjusted the overall PSA value relative to the median in the population. The investigators then determined the percentage of men who would meet commonly used PSA thresholds (2.5 ng/ml or greater or 4.0 ng/ml or greater) for determining if a patient should undergo biopsy before and after “genetic correction” of their PSA concentrations.
“Since the variants increase PSA levels, we have to decrease the measured PSA to account for them,” Helfand told PGx Reporter, explaining the rationale behind the “genetic correction” performed in the study. “Similarly, in their absence, we have to increase the PSA levels to account for the lack of genetic affect.” The correction process is complicated by the fact that not all the alleles influence PSA in the same way.
“Individuals carry different combinations of the genetic variants,” Helfand explained. “Therefore, just because a man may have three alleles, he may have many different combinations.”
In the paper, Helfand and colleagues reported that before genetic correction 9.7 percent of study participants had PSA levels of 2.5 ng/ml or greater, which would have made them candidates for prostate biopsy. However, after genetic correction, 8.2 percent of the men in the trial met this threshold, resulting in a 15.5 percent relative risk reduction for biopsy. Additionally, genetic correction imparted a 3 percent reduction in potentially delayed biopsies by identifying the subset of patients who are “genetically low PSA producers” – those who didn’t meet the biopsy threshold by PSA testing but crossed it after genetic adjustment.
Based on a biopsy threshold of 2.5 ng/ml or greater, “one of every 57 men undergoing PSA screening could be spared a biopsy,” the study authors wrote.
Using a biopsy threshold criteria of 4.0 ng/ml or greater, 6.6 percent of study participants met this criteria before genetic correction and 5.3 percent met this criteria after adjustment, resulting in a nearly 20 percent relative risk reduction for biopsy. At this threshold, one out of 69 men undergoing PSA screening could avoid an unnecessary biopsy with the help of genetic testing, the study showed.
“Our data suggest that the traditional single cutoff [for] PSA screening (eg 2.5 ng/ml or greater or 4.0 ng/ml or greater) might be improved by genetic correction,” Helfand and colleagues said in the paper.
In the study, genetic correction identified 17 men whose PSA levels fell below the 2.5 ng/ml cutoff, 13 of whom had a prostate biopsy but none had cancer. Comparatively, there were 76 study participants whose PSA levels remained above the 2.5 ng/ml threshold, 43 of whom had biopsies, which revealed the presence of cancer in eight.
For the 4.0 ng/ml cutoff, 14 men fell below this threshold with genetic correction, of whom seven had biopsies but none had cancer. Meanwhile, 50 men had PSA levels above this mark, 32 underwent biopsy, seven of whom have been diagnosed with cancer to date.
In the current study, Helfand and colleagues have so far shown that their four PSA-SNP genetic correction method can yield a personalized PSA value, which could potentially be used to avoid unnecessary biopsies. However, their findings need further validation before such a method could be part of standard prostate cancer screening.
Helfand told PGx Reporter that his research team is planning to test this genetic correction strategy in a larger prospective study, as well as in other ethnic populations since the current study involved only Caucasian men. For example, in a separate study, Helfand and his research team also tested the ability of the four PSA-SNPs to adjust PSA levels in African American men and found “significant differences” in how these markers impact PSA levels in this population compared to Caucasian men. While genetic testing did not identify any unnecessary biopsies in the African-American cohort, it found a proportion of men who would not have met the threshold for biopsies based on PSA testing alone and therefore would have had their biopsies delayed.
The researchers will also follow patients in the current study to gauge long-term outcomes in those who initially met the biopsy criteria, but then fell above and below the cut off after genetic correction. The paper notes that to date not all healthy volunteers in the study who met the biopsy criteria have been biopsied.
If validated, by genetically correcting PSA levels using the four PSA-SNPs, healthcare providers can hope to prevent between 15 percent and 20 percent of unnecessary prostate biopsies, Helfand and colleagues wrote. Given there are nearly 1 million prostate biopsies performed in the US each year, the study authors estimated that their method could avoid between 150,000 and 200,000 biopsies annually and reduce procedure-related adverse events, such as infections, sepsis, and hospitalizations.
“The cost of genetic testing is very inexpensive,” Helfand said. In the paper, the study authors gauged that it would cost less than 60 cents to test for the four PSA-SNPs for labs that have the equipment already in place. Helfand envisions that a genetic correction test of this kind would be marketed broadly to healthcare providers performing PSA testing and serve as an adjunct tool they can use to guide decisions about whether to biopsy a patient’s prostate tissue based on corrected and uncorrected PSA values.
The researchers estimated that 60 men need to be screened with PSA and genetic testing to prevent one unnecessary biopsy. However, given the low price of testing, “the cost-to-benefit ratio appears favorable,” they stated.
Helfand noted, however, that he and his colleagues haven’t yet reached out to any test developers to gauge their interest in developing a genetic correction PSA test.
The current study was funded by the Urologic Research Foundation, which is headed up by Northwestern’s William Catalona, one of the authors of the paper and a PSA testing pioneer. Study participants’ blood samples were analyzed by Decode Genetics, an Icelandic firm that last year was purchased by drug maker Amgen.