Beyond PSA: A Summary Review of Predictive/Prognostic Biomarkers in Prostate Cancer

Neal D. Shore, MD, FACS

Medical Director, Carolina Urologic Research Center

Partner, Atlantic Urology Clinics

Myrtle Beach, South Carolina

Karen H. Ventii, PhD

Atlanta, Georgia

E. David Crawford, MD, FACS

Distinguished Professor of Surgery, Urology, and

Radiation Oncology

Head, Section of Urologic Oncology

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 (Table 1), 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.¹PSA

After its approval by the US Food and Drug Administration (FDA) more than 20 years ago, PSA dramatically influenced PC screening and diagnosis,^2,3 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.⁴

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/mL⁵ 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;⁵ many newly diagnosed patients with PC may be overtreated for low-risk cancer.⁶ Such limitations contributed to the US Preventive Services Task Force’s recommendation against continued routine PC screening.⁶

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.⁷ Then, in 2011, Crawford et al reported a survival benefit for screening in men without significant comorbidities.⁸ The following year, Schroder and colleagues demonstrated that screening significantly reduced death from PC.⁹

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.¹⁰

Prostate Health Index (PHI)

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.¹¹ 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 PCA3.¹¹ 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.^12,13

4KScore

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.¹⁴ConfirmMDx

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.^15,16 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.^17,18

Table 1. Summary of PC Biomarkers

Group 1

Group 2

Group 3

Group 4

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

PSA

PHI

4KScore

ConfirmMDx

PCA3

PCMT

PTEN

Oncotype DX

PSA

CTC

PCA3

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.¹⁹ 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.

Prostate Core Mitomic Test (PCMT)

The PCMT is designed to assist identification of men who do not require a repeat biopsy.²⁰ 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.²¹ In an earlier published trial, the NPV approximated 92%. Further validation trials of this test are pending.²¹

Phosphatase and Tensin Homolog (PTEN)

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.²² Additionally, PTEN dysregulation has been shown to be associated with locally advanced and metastatic disease.²³ 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

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.²⁴

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

Test

Indication

Cost Estimates^a and Other Considerations

PCA3

PROGENSA

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

$375

This test has received a billable CMS code

(800) 523-5001

PHI

Beckman Coulter

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

$112

(800) 526-3821

4KScore

Opko Health Inc

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

$395

(305) 575-4100

Oncotype DX

Genomic Health

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

$3820

Medicare = No ABN required^b

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

(866) 662-6897

Prolaris

Myriad Genetics

Biopsy tissue-based test for patients who are active surveillance candidates

-or-

Post-prostatectomy tissue-based test to determine relative risk of BCR

$3400

Medicare = No ABN required^b

Other ins: If estimated out-of-pocket cost >$375, company will contact patient to make arrangements. They have a financial assistance program.

(800) 469-7423

Decipher

GenomeDx

Biosciences

Post-prostatectomy tissue-based test used for patients who are candidates for secondary therapy; post-prostatectomy pT2 with positive margins or pT3 or BCR

$4250

Medicare = No ABN required^b

Other ins: Financial assistance program available for out-of-pocket expenses.

(888) 792-1601

ConfirmMDx

MDxHealth

Biopsy tissue-based test for patients who are repeat biopsy candidates

Provides risk stratification on decision for repeat biopsy Eligibility: Prior negative or HGPIN biopsy result in past 24 months

$2473 ($206 core/block)

Medicare = No ABN required^b

Other ins: Financial assistance program is available for out-of-pocket expenses.

(866) 259-5644

^aCosts listed in this table are estimates and vary by region and institution

^bWithout an Advanced Beneficiary Notification (ABN), the patient is not held responsible for any unreimbursed expenses

This table was created by E. David Crawford and Clifford Jones with support from Wendy Poage.

Prolaris

Prolaris is a tissue-based test that assesses a cell-cycle progression signature to provide risk assessment of PC-specific progression and 10-year disease-specific mortality when combined with standard pathologic parameters. The test is designed as a risk-stratification tool to further refine treatment and monitoring strategies for both newly diagnosed PC patients and post-prostatectomy patients; the test has been validated with multiple trials in both the post-radical prostatectomy and biopsy settings.²⁵ A large-scale prospective clinical utility trial has been completed and is pending presentation.

Decipher

Decipher is a genomic assay classifier that measures the biological risk for metastatic PC following a radical prostatectomy. By assessing tissue for the activity of 22 genetic markers associated with metastatic disease, the assay has been shown to be independently prognostic of PC metastases and mortality in a high-risk surgical cohort.²⁶ This assay may better enable application of directed, multimodal, or adjuvant therapy for patients with high-risk PC following radical prostatectomy.

ProMark

Group 4: Biomarkers to Help Assess Response to Treatment

ProMark is a tissue-based PC test which became commercially available in 2014. By using immunofluorescent imaging analysis to quantify protein biomarker expression and classify patients’ tumors, ProMark can differentiate indolent from aggressive disease.²⁷ Further assay validation trials are planned.PSA

Beyond its use in PC screening and diagnosis, PSA may be used to monitor responses to therapy and as a therapeutic target itself.²⁸ Studies indicate that, for cytotoxic chemotherapies or some of the newer oral targeted hormonal therapies, PSA responses may correlate with clinical response to therapy, although radiographic progression and symptomatology remain key parameters for consideration of changing anti-cancer therapy.²⁹ There is a need for newer biomarkers that can predict response to treatment.

Circulating Tumor Cells (CTCs)

The number of CTCs in the blood can serve as a biomarker for therapeutic response to anti-cancer treatment.³⁰ CTCs may be useful for predicting treatment response and survival with hormonal and cytotoxic therapies. One potential challenge is that approximately 50% of patients do not have detectable CTC levels by current detection methods. More sensitive CTC detection techniques are needed, and their utilization for therapeutic guidance is under further evaluation. CTC detection can be invoiced through CMS.

Conclusion

PC biomarkers possess the possibility for assisting clinicians and patients in decision-making concerning choices regarding when to biopsy, when to avoid a repeat biopsy, and when to consider interventional and adjuvant therapies. The newly improved and unique array of biomarkers should allow for a reduction in the number of unnecessary biopsies while allowing more selective and more informed decisions regarding whom to repeat biopsy and whom to consider for active surveillance strategies. In summary, these biomarkers will enable healthcare professionals to improve decision-making in addition to known historical clinical and serum parameters (Table 2).

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