	Medical Director, Carolina Urologic Research Center

	Distinguished Professor of Surgery, Urology, and

	University of Colorado Anschutz Medical Campus

	Smilow Cancer Hospital at Yale-New Haven 

Although prostate cancer (PC) is the most common solid tumor malignancy among men in the Western Hemisphere, disease-specific mortality remains low, primarily due to optimized screening, diagnosis, and treatment.

Despite this recent success, decision-making challenges remain for patients and clinicians, including whether or not to perform an initial prostate biopsy; whether or not to elect interventional treatment for low-risk disease; and whether or not to perform a repeat prostate biopsy following an initial negative result.

Clinically applicable and validated risk-analysis tools, beyond those traditionally used, are needed to assist with informing treatment decisions for patients and physicians regarding the aforementioned challenges. Biomarkers are required which can provide both prognostic and predictive information. Specifically, regarding prognostic variables, such as the historic clinical features currently used today (serum PSA [prostate-specific antigen], DRE [digital rectal exam], Gleason primary/secondary patterns, number of positive cores, and percent involvement of positive cores), there is an unmet need to inform decisionmaking optimization.

	Group 1: Biomarkers to Determine Whom to Biopsy

Given that traditional clinical risk-assessment tools may be less than optimal, patients with early-stage PC may benefit from more precise, personalized assessment of their tumor biology. Prognostic and predictive tools based on PCa biomarkers are already available, and more are in development. The tools now available can be roughly organized into four groups (

), each with its own unique goals for assessing clinical decision-making. Collectively, the biomarkers that fall within these four groups should be utilized to enhance risk assessment, guide diagnostic strategies, and improve treatment outcomes by allowing more targeted screening, more accurate diagnosis, and improved risk stratification. The ultimate goal is to improve treatment recommendations and subsequent selection of therapy, thereby maximizing patient outcomes and concomitantly stabilizing, or reducing, healthcare costs.

After its approval by the US Food and Drug Administration (FDA) more than 20 years ago, PSA dramatically influenced PC screening and diagnosis,

 with approximately 19 million men receiving yearly testing and more than 1.3 million biopsy procedures being conducted annually. The result was nearly 240,000 findings of newly diagnosed PC.

Nonetheless, the interpretation of PSA has inherent challenges, including the potential for false-positive or falsenegative results regarding its assessment for malignancy. For example, most men with a PSA level above 4.0 ng/mL

 do not have PC and only about 40% of men undergoing biopsy for an elevated PSA level will actually have PC. Additionally, PSA testing does not adequately differentiate low-risk from highrisk disease;

 many newly diagnosed patients with PC may be overtreated for low-risk cancer.

 Such limitations contributed to the US Preventive Services Task Force’s recommendation against continued routine PC screening.

In the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (which was designed to assess the effects of screening on cancer-related mortality), there was no evidence of a survival benefit for organized annual PC screening compared with usual care, which sometimes included screening, after 13 years of follow-up.

The PLCO findings were followed with more positive results from other studies. For example, the Goteborg trial (20,000 men born between 1930 and 1944), demonstrated that the benefit of PC screening compared favorably to other cancer screening programs. PC mortality was reduced by nearly half over 14 years of follow-up.

 Then, in 2011, Crawford et al reported a survival benefit for screening in men without significant comorbidities.

 The following year, Schroder and colleagues demonstrated that screening significantly reduced death from PC.

In order to increase the sensitivity and specificity of serum PSA as a marker for PC detection, various PSA ratios and protein derivatives have been interrogated.

The PHI score, a blood test approved by the FDA in 2012, is a diagnostic tool designed to reduce the burden of overbiopsying men with serum PSA values between 4 and 10 ng/ mL.

 The PHI score (calculated as [−2] proPSA/fPSA × PSA1/2; proPSA is a PSA subtype and fPSA is free PSA) has been described as a marker of specificity in the 2014 NCCN [National Comprehensive Cancer Network] guidelines for early detection of PC, along with percent free PSA and PCA3.

 Furthermore, some publications have suggested that the PHI may also be useful as a marker for predicting aggressive disease, guiding biopsy decisions, and predicting the likelihood of progression during active surveillance.

	Group 2: Biomarkers to Determine Whom to Re-Biopsy

4KScore is a newly available commercial assay panel that is designed to enhance prediction of which men with an elevated PSA will have high-grade disease upon tumor biopsy. By combining measures of total, free, and intact PSA with human kallikrein 2 (hK2) and other clinical parameters (eg, DRE, age), a large US multicenter trial assessing the 4KScore blood test demonstrated improved detection of high-grade disease upon biopsy in comparison to the Prostate Cancer Prevention Trial (PCPT) calculator tool.

ConfirmMDx is a tissue-based assay designed to help improve decision-making for patients considering a repeat biopsy. The false-negative rate for first-time prostate biopsy approximates 25%, and many of these men have persistent PSA elevations or other concerns indicating that a repeat biopsy might be useful.

Thus, further stratifying the likelihood for detecting cancer upon a repeat biopsy versus avoiding a second negative biopsy (with its attendant inconvenience, cost, and risks) is warranted.

 Using archived paraffin-embedded tissues from previous negative biopsies, ConfirmMDx detects an epigenetic field effect, which results from increased hyper-methylation of PCspecific genes. Because the field effect may be detected despite the normal histologic appearance of cells, use of ConfirmMDx may effectively extend the coverage of the biopsy. When the ConfirmMDX report results are negative, the negative predictive value (NPV) approximates 90%, as reported in two separate large-scale multicenter trials.

					Biomarkers to determine whom to biopsy

					Biomarkers to determine whom to rebiopsy

					Biomarkers to stratify whom to treat or not to treat

					Biomarkers to help assess response to treatment

The PCA3 test (a urine-based assay detecting a non-coding mRNA and its ratio to PSA) was approved by the FDA as a diagnostic tool in the setting of a previous negative biopsy. The utility of PCA3 lies in its ability to help patients and physicians decide when to re-biopsy or avoid doing so, thereby adding to the diagnostic information obtained from PSA testing alone.

 One caveat is that PCA3 testing may fail to identify transition-zone cancers because the DRE does not exude cells into the urine. This test has received a billable Centers for Medicare & Medicaid Services (CMS) code.

The PCMT is designed to assist identification of men who do not require a repeat biopsy.

 Deletions in mitochondrial DNA indicate cellular changes associated with PC, detecting field-effect abnormalities correlative with cancer. PCMT is designed to detect the presence of malignant cells in normalappearing histopathology.

 In an earlier published trial, the NPV approximated 92%. Further validation trials of this test are pending.

The PTEN is a prognostic assay that detects partial or complete deletions of the tumor suppressor gene, which is a fairly ubiquitous event for many solid tumor malignancies. Because dysregulation of PTEN has been associated with poor prognosis in PC, this tissue test, which may be ordered in conjunction with prostate biopsy tests, can detect disease with higher Gleason grade, risk of progression, and recurrence after therapy.

 Additionally, PTEN dysregulation has been shown to be associated with locally advanced and metastatic disease.

 Large-scale, multicenter trials further interrogating the utility of this test are pending.

	Group 3: Biomarkers to Stratify Whom to Treat or Not To Treat

Oncotype DX is a tissue-based assay which can be utilized along with standard clinical parameters to improve risk stratification of disease aggressiveness for newly diagnosed PC patients, thereby assisting with decision-making about active surveillance versus interventional therapy. The assay has been validated in several contemporary cohorts as an accurate predictor of adverse pathology in men with clinically very low-, low-, and low-intermediate- risk PC.

		Table 2. Commonly Utilized Biomarkers in PC: Indications/Cost Considerations

					To help determine the need for repeat prostate biopsies in men who have had a previous negative biopsy

					This test has received a billable CMS code

					Identification of patients (aged 50+ years, with total PSA 2-10 ng/mL and DRE) with a high likelihood of having a positive prostate biopsy result

					For finding a high-grade (Gleason score 7 or higher) prostate cancer upon biopsy

					Biopsy tissue-based test of NCCN Very Low-, Low- & Intermediate-Risk PCs; provides personalized risk assessment

					Other ins: If estimated out-of-pocket cost >$100, company will contact the patient to offer financial assistance program.

E. David Crawford, MD, Neal D. Shore, MD

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