The Next Generation of Prostate Cancer Diagnostics
By Genna Rollins

The shortcomings of prostate-specific antigen (PSA) as a screening test for prostate cancer have long been obvious to scientists, to clinicians, and most of all to men who have had elevated levels and faced difficult decisions about what to do next. A considerable scientific enterprise has been devoted to improving on or replacing the PSA test, which detects prostate disease but not necessarily prostate cancer. Even as studies continue and controversy roils around how to make the most of the PSA test, a large contingent of researchers is seeking better biomarkers for prostate cancer that take advantage of genomic technologies. However, even as some genomic tests are making their way into the marketplace, leading researchers have sounded a note of caution.

“It’s a very daunting task, introducing a biomarker that’s going to impact clinical care. That’s really the important issue at hand,” said Mark Rubin, MD, a professor of pathology and laboratory medicine at Weill Cornell Medical College in New York City. “In developing biomarkers for prostate cancer, a major clinical question to be addressed is distinguishing between aggressive versus indolent disease. Conceptually, this is easy and the terms indolent and aggressive are easily spoken, but are much more difficult to define.”

Rubin spoke recently at the annual meeting of the American Association for Cancer Research (AACR) as part of a panel exploring prostate cancer screening now and in the future. He went on to add that next-generation sequencing has the potential to address the many demands placed on biomarkers for prostate cancer, from diagnosis all the way to personalizing drug therapies of the future. However, he also warned against being beguiled by the novelty of this technology if it doesn’t decisively answer key clinical questions.

Knowing which men have indolent disease that merely deserves active surveillance and which have aggressive cancer that must be acted on, has, in fact, been at the heart of the PSA debate. Quite a number of different strategies for using PSA and its various forms have been proposed to address this issue, including: PSA density, PSA velocity, PSA doubling time, free PSA (fPSA), proPSA, and complexed PSA. All of these have been found to be complementary to PSA in certain circumstances, and the FDA has cleared fPSA for use in men with total PSA in the diagnostic gray zone between 4–10 µg/L.

Different cutoffs also have been proposed to fine-tune PSA’s sensitivity and specificity. A cutoff of 4 µg/L has been commonly adopted and used in major screening studies, and an ACS literature review found this threshold to have an estimated sensitivity of 21% for detecting any prostate cancer and 51% for detecting high-grade cancer. Lowering the cutoff to 3 µg/L boosts these sensitivities to 32% and 68%, respectively, but at the cost of specificity, which drops from 91% to 85%. However, lower thresholds have not been endorsed formally by professional organizations. In fact, the National Academy of Clinical Biochemistry Laboratory Medicine Practice Guideline on the use of tumor markers recommends not using age-specific reference intervals and notes that the reported benefits from lowering the clinical decision limit below 4 µg/L are too uncertain to make a blanket Researchers and clinicians who hoped clarity about the role of PSA in screening would come from two major clinical trials—the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the European Randomized Study of Screening for Prostate Cancer (ERSPC)—were disappointed. PLCO, a study of 77,000 men at 10 U.S. centers, did not identify a significant reduction in prostate cancer-specific mortality. However, this study has been criticized because half of the men assigned to the control group also underwent screening by virtue of receiving usual care. “PLCO does not provide an answer to value of screening—it compares screening to the current U.S. practice of screening,” contended AACR panelist, Fritz Schröder, MD, PhD, a professor of urology at Erasmus University in Rotterdam, the Netherlands and one of the lead ERSPC investigators.recommendation (Clin Chem 2008:54:e11–79).