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NEW ORLEANS -- Adjusting prostate-specific antigen (PSA) levels for normal genetic variations showed potential for making PSA testing more useful, including reducing unnecessary prostate biopsies, a large genome-wide association study (GWAS) suggested.

A "polygenic score" (PGS) that accounted for noncancerous variations in PSA values explained 7.3%-8.8% of the variation in baseline PSA values in two large prostate cancer prevention studies. Correcting PSA values for noncancerous variations would have led to almost 20% fewer negative biopsies in men without cancer and 15.7% fewer biopsies in men with low-risk disease.

Genetics-adjusted PSA values also had a stronger association with aggressive prostate cancer than did unadjusted values, reported Linda Kachuri, PhD, of the University of California San Francisco, at the American Association for Cancer Research (AACR) meeting.

"I think our findings are exciting because we're able to show that we can use these genetic discoveries that are coming out of genome-wide association studies to actually improve, potentially, the detection of prostate cancer and hopefully try to make a PSA a more useful and accurate screening biomarker," said Kachuri, during an AACR press briefing. "This is only the first step. It's absolutely important to validate these findings in additional patient populations."

However, she cautioned that "the data that I'm showing really includes predominantly 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 and individuals of all ancestries to really represent our target patient population."

Though widely used in the diagnosis and management of prostate cancer, PSA remains controversial because of its poor sensitivity and specificity, which leads to overdiagnosis and overtreatment of prostate cancer. Kachuri and colleagues hypothesized that the accuracy of PSA testing could be improved by accounting for inherent variations that are unrelated to prostate cancer.

Although GWAS investigations often focus on identifying genetic variations associated with a disease, Kachuri's group conducted a study to identify genetic changes in PSA values unrelated to cancer. The study involved more than 95,000 men from the U.S., England, and Sweden. The analysis identified 128 PSA-related variants, including 82 not previously recognized.

Data from the analysis formed the basis for developing a PGS that accounted for the variants' contributions to PSA values. The score, individualized to each patient, represented the sum of genotypes across the 128 variants, weighted to reflect the variants' effect on PSA levels. A personalized adjustment factor was applied to a patient's PSA value, which was adjusted up or down to account for patient's unique PSA profile.

To validate the PGS, they applied the score to PSA values of participants in the and the prostate cancer prevention studies. The studies involved a combined total of almost 28,000 men who did not have prostate cancer at enrollment. The analysis showed that the score explained 7.3% of variation in PSA values in PCPT and 8.8% of the variation in SELECT. Moreover, the analysis showed the PGS was not associated with prostate cancer in the PCPT (OR 0.98) or SELECT (OR 1.04), confirming that the score reflected benign PSA variation.

The investigators used the individual PGS values to evaluate the potential impact on referral for biopsy. By substituting the PGS for patients' measured PSA values, Kachuri and colleagues estimated that 19.6% of negative biopsies potentially could have been avoided. In a separate analysis, the PGS was applied to men who had indolent, low-grade prostate cancer. The results suggested that 15.7% of biopsies could have been avoided in those men.

"This is another indication that genetically adjusted PSA could potentially be very useful for reducing overdiagnosis of prostate cancer," said Kachuri.

A final objective of the study was to examine the PGS utility for recognizing aggressive prostate cancer. The results showed that the corrected PSA values outperformed (as reflected in area under the curve) measured PSA levels, as well as a validated PGS for prostate cancer, for identifying aggressive disease in both the PCPT and SELECT studies. Combining the PGS for PSA and the PGS for prostate cancer provided the best results.

If the promising preliminary results are confirmed by further evaluation, the PGS could establish a new paradigm for providing clinicians with useful information about prostate cancer, said press briefing moderator Louis Weiner, MD, of Georgetown Lombardi Comprehensive Cancer Center in Washington.

"I think the polygenic score, added to the information that we get from a variety of different PSA determinations...can create more precise knowledge or information," said Weiner. "It's important that all information be transmuted into knowledge, which then becomes actionable...How do you integrate this with issues such as environmental modifiers of PSA, like inflammation, prostatitis, or age? How do you integrate the polygenic score into a more holistic interpretation of what PSA might be?"

"This is a tool, and I think that tools that give us more precision typically turn out to have value," he stated. "If this is validated -- and it seems to be getting validated right now -- it could create a new paradigm for giving clinicians useful, actionable information to inform their patients."

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