Prostate cancer biomarkers to urologists’ rescue

Dr. Shore is medical director of Carolina Urologic Research Center, Myrtle Beach, SC.

The recent AUA guideline on prostate cancer screening, combined with the USPSTF’s grade “D” recommendation regarding the use of PSA, have certainly caused the urology and primary care communities to reassess not only our reasons and concerns for screening men for prostate cancer but also the need for observation versus interventional therapies for the newly diagnosed prostate cancer patient. In other words, to paraphrase the famous Whitmore conundrum: Is cure necessary when possible, and is it possible when necessary?

Fortunately, since the initial mention of this rhetorical concern, the clinician community has benefited tremendously from advances in both localized and systemic interventions for prostate cancer. Newly diagnosed men with prostate cancer, regardless of stage, as well as men with castration-resistant disease are achieving significant increases in overall survival while maintaining their quality of life, and thus prostate cancer patients are not just living longer but they and their families are enjoying that longevity.

Nonetheless, in the U.S. there are approximately 240,000 newly diagnosed cases of prostate cancer annually. Many have suggested that approximately 40% to 50% of those newly diagnosed are classified as “low risk” by AUA classification metrics: PSA, histopathology (Gleason grade), and clinical stage (digital rectal exam). The low-risk classification implies that their disease will most likely not have an impact on their mortality. Presumably then, these same men (approximately 100,000-120,000) should be considered for the option of active surveillance, or perhaps active monitoring, as opposed to a primary interventional therapy: prostatectomy, radiation therapy, thermal ablation, or primary androgen deprivation therapy. Of course, one can debate the merits and disadvantages of the aforementioned therapeutic options and their respective attendant potential sequelae regarding voiding and sexual function, as well as the impact on the expanding U.S. health care economic consumption. The more obvious and vexing question is, why are we dramatically underutilizing active surveillance?

CaPSURE (Cancer of the Prostate Strategic Urologic Research Endeavor) and Surveillance, Epidemiology, and End Results data suggest that no more than 10% of men within the U.S. who are newly diagnosed with prostate cancer will select an initial treatment option of active surveillance, despite the growing body of literature suggesting that if this group of low-risk patients were adequately monitored, only about 25% might demonstrate disease upgrading, of which more than 95% would still be potential candidates for curative intervention.

Hence, why the underutilization of active surveillance? The more ardent cynics would allude to U.S. health care’s perverse economic incentivizations for interventional therapies, which I believe are vastly overstated and overhyped. I believe that 95% of physicians make recommendations in the best interest for their patient, based upon the data and information at their disposal. Unfortunately, the traditional metrics of PSA, histopathology, and DRE may not always inform most accurately regarding indolent versus aggressive disease pathology and the individual patient prognosis.

Fortunately, we have witnessed breakthroughs in genomic, proteomic, molecular, and biochemical pathways, which have resulted in accessibility and applicability for new biomarkers that may be obtained via tissue (stored biopsy blocks), serum, urine, and saliva. Certainly, these newly minted biomarkers must overcome two important hurdles. First, they must demonstrate clinical validation, which is typically accomplished through large-scale academic trials that are then repeated on a multi-institutional basis, inclusive of community centers, in order to demonstrate methodologic replication and consistency of findings. Second, and equally important, clinical utility studies must be performed. Essentially, our payer system now requires that ordering a new biomarker test, with its additional cost, should demonstrably alter physician and patient decision making, presumably resulting in improved patient care outcomes as well as cost efficiencies.

Three new genomic assays are now commercially available: Oncotype DX-Prostate (Genomic Health), Prolaris (Myriad Genetics), and Decipher (GenomeDx Biosciences). All three use their specific gene signature assays to evaluate previously obtained prostate biopsy blocks or prostatectomy specimen to further characterize the individual patient’s cancer aggressiveness. The reports, which are specific to each test, are designed to provide physician and patient with additional independent information, in conjunction with traditional metrics for evaluation of disease aggressiveness (PSA, DRE [stage], histopathology).

Oncotype DX-Prostate and Prolaris are indicated for the newly diagnosed prostate cancer patient, and will give additional information regarding the likelihood of disease aggressiveness and progression, which subsequently should provide greater clarity for choosing an active surveillance strategy as well as sometimes encouraging a more aggressive interventional strategy when indicated. The Prolaris and Decipher are applicable in the post-prostatectomy setting to provide additional guidance regarding potential likelihood of further disease progression, thereby assisting in decision making regarding adjuvant surveillance intensity of monitoring as well as consideration for adjuvant therapies. (Other newer tests, including ConfirmMDx, PCA3, and TMPRSS2-ERG, are indicated for a prior negative prostate biopsy to assist with the decision to rebiopsy.)

All three genomic assay providers are embarking upon prospective clinical utility trials, which are essential in order to demonstrate their ultimate impact on the clinician and patient communities. Data from all three assays were presented at this year’s AUA annual meeting in San Diego. These assays represent a breakthrough in our diagnostic capability to better inform our patients with respect to their treatment options. Molecular markers are prime time, but require prospective validation studies demonstrating their impact upon clinician/patient choices. The data should allow us to better counsel our patients.

Learn more about the details of each genomic assays established validation pathways, and consider enrolling and participating in ongoing prospective trials for them. We can do better, and avoid future “D” ratings.UT

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