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Protein Biomarkers for Diagnosis and Risk Assessment of Prostate Cancer

Policy Number: MP-707

Latest Review Date: March 2021

Category: Laboratory

Policy Grade: B

POLICY:

The screening for, detection of, and/or diagnosis and management of prostate cancer using protein biomarkers including, but not limited to, the following tests is considered investigational:

  • Kallikrein markers (e.g., 4Kscore™ Test);
  • Autoantibodies ARF 6, NKX3-1, 5’-UTR-BMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1, and CSNK2A2 (e.g. Apifiny)

DESCRIPTION OF PROCEDURE OR SERVICE:

Various protein biomarkers are associated with prostate cancer. These tests have the potential to improve the accuracy of differentiating which men should undergo prostate biopsy or rebiopsy after a prior negative biopsy. This policy will address these types of tests for cancer risk assessment. Magnetic resonance imaging-targeted biopsy of suspicious lesions is not addressed in this policy.

A biomarker is a chemical in the body. Certain biomarkers can show when something unusual is going on with certain bodily processes. One of the most commonly known and tested biomarkers is prostate specific antigen (PSA). Higher levels of PSA in the blood indicate a problem with the prostate. The difficulty is that the PSA test doesn’t tell us what kind of problem is affecting the prostate—whether it is simply an enlarged prostate or cancer. If the PSA is high, the usual next step is biopsy. A biopsy is taking small bits of tissue to if cancer is present. Other biomarker tests have been developed in recent years with the hope of telling doctors which patients should have a biopsy and who can skip it. Published medical studies about these newer prostate biomarker tests are contradictory. That means some studies show the tests detect what they are supposed to and other studies do not. At this time, there is not enough medical evidence to show that prostate cancer biomarker tests are effective.

Prostate Cancer

Prostate cancer is the most common cancer, and the second most common cause of cancer death in men. Prostate cancer is a complex, heterogeneous disease, ranging from microscopic tumors that are unlikely to be life threatening to aggressive tumors which can metastasize, lead to morbidity or death. Early disease that is localized can usually be treated with surgery and radiotherapy although active surveillance may be adopted in men whose cancer is unlikely to cause major health problems during their lifespan or for whom the treatment might be dangerous. In patients with inoperable or metastatic disease, treatment consists of hormonal therapy and possibly chemotherapy. The lifetime risk of being diagnosed with prostate cancer for men in the United States is approximately 16%, while the risk of dying of prostate cancer is 3%. African-American men have the highest prostate cancer risk in the United States; the incidence of prostate cancer is about 60% higher and the mortality rate is more than two to three times greater than that of white men. Autopsy results have suggested that about 30% of men ages 55 and 60% of men ages 80 who die of other causes have incidental prostate cancer, indicating that many cases of cancer are unlikely to pose a threat during a man’s life expectancy.

Grading

The most widely used grading scheme for prostate cancer is the Gleason system. It is an architectural grading system ranging from one (well differentiated) to five (poorly differentiated); the score is the sum of the primary and secondary patterns. A Gleason score of six or less is low-grade prostate cancer that usually grows slowly; seven is an intermediate grade; eight to ten is high-grade cancer that grows more quickly. A revised prostate cancer grading system has been adopted by the National Cancer Institute and the World Health Organization. A cross-walk of these grading systems is shown in the table below.

Table. Prostate Cancer Grading Systems

Grade Group

Gleason Score (Primary and Secondary Pattern)

Cells

1

6 or less

Well differentiated (low grade)

2

7 (3+ 4)

Moderately differentiated (moderate grade)

3

7 (4 + 3)

Poorly differentiated (high grade)

4

8

Undifferentiated (high grade)

5

9-10

Undifferentiated (high grade)

KEY POINTS:

The most recent literature update was performed through February 19, 2021.

Summary of Evidence

For individuals who are being considered for an initial prostate biopsy who receive testing for protein biomarkers of prostate cancer, the evidence includes systematic reviews, meta-analyses, and primarily observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, resource utilization, and quality of life. The evidence supporting clinical utility varies by test but has not been directly shown for any biomarker test. Absent direct evidence of clinical utility, a chain of evidence might be constructed. However, the performance of biomarker testing for directing biopsy referrals is uncertain. While some studies have shown a reduction or delay in biopsy based on testing, a chain of evidence for clinical utility cannot be constructed due to limitations in clinical validity. Test validation populations have included men with a positive digital rectal exam, a PSA level outside of the gray zone (between three or four ng/mL and 10 ng/mL), or older men for whom the information from test results are less likely to be informative. Many biomarker tests do not have standardized cutoffs to recommend a biopsy. In addition, comparative studies of the many biomarkers are lacking. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are being considered for repeat biopsy who receive testing for protein biomarkers of prostate cancer, the evidence includes systematic reviews and meta-analyses and primarily observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, resource utilization, and quality of life. The performance of biomarker testing for guiding rebiopsy decisions is lacking. The tests are associated with a diagnosis of prostate cancer and aggressive prostate cancer, but studies on clinical validity are limited and did not compare performance characteristics with standard risk prediction models. Direct evidence supporting clinical utility has not been shown. No data are currently available on physician decisions on rebiopsy or on the longer term clinical outcomes of men who did not have biopsy based on test results. The evidence is insufficient that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

American Urological Association et al

The American Urological Association (2013; confirmed 2018) published guidelines on the early detection of prostate cancer. The association concluded that:

“the literature supporting the efficacy of digital rectal exam (DRE), PSA [prostate-specific antigen] derivatives and isoforms (e.g. free PSA, -2proPSA, prostate health index, hK2, PSA velocity or PSA doubling time) and novel urinary markers and biomarkers (e.g. PCA3) for screening with the goal of reducing prostate cancer mortality provide limited evidence to draw conclusions. While some data suggest use of these secondary screening tools may reduce unnecessary biopsies (i.e. reduce harms) while maintaining the ability to detect aggressive prostate cancer (i.e. maintain the benefits of PSA screening), more research is needed to confirm this.”

The American Urological Association and the Society of Abdominal Radiology

The American Urological Association and the Society of Abdominal Radiology (2016) published joint guidelines on prostate magnetic resonance imaging and magnetic resonance imaging-targeted biopsy. The associations recommended:

“In patients with negative or low suspicion magnetic resonance imaging (PI-RADS [Prostate Imaging Reporting and Data System] assessment category of one or two, respectively), other ancillary markers (i.e. PSA [prostate-specific antigen], PSAD [PSA density], PSAV [PSA velocity], PCA3, PHI, 4K) may be of value in identifying patients warranting repeat systematic biopsy, although further data are needed on this topic.”

Guidelines published by the American Cancer Society and the American Urological Association have endorsed consideration of PSA screening based on age, other risk factors, and estimated life expectancy.

National Comprehensive Cancer Network

The NCCN guidelines (v.2.2021) recommend that any man with a PSA level greater than 3 ng/mL undergo workup for benign disease, repeat PSA, and digital rectal examination.

The guidelines recommend as part of the workup for benign disease, consideration of biomarkers that improve the specificity of screening that includes percent free PSA, with consideration of 4Kscore in patients with a PSA level greater than 3 ng/mL who have not yet had a biopsy. 4Kscore, might be considered in men who had a negative biopsy but are thought to be at higher risk (category 2A evidence). The NCCN noted that this test may be especially useful in men with PSA levels between 3 ng/mL and 10 ng/mL. NCCN also noted that it is not yet known how these tests could be applied in optimal combination with MRI.

For men who had a negative biopsy but are thought to be at higher risk, NCCN recommends to consider biomarkers that improve the specificity of screening (category 2A evidence). Tests that should be considered in the post-biopsy setting include 4KScore.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force (2018) updated recommendations for prostate cancer screening. Protein biomarkers that are addressed in this evidence review were not mentioned.

The U.S. Preventive Services Task Force advises individualized decision making about screening for prostate cancer after discussion with a clinician for men ages 55 to 69 (C recommendation) and recommends against PSA-based screening in men 70 and older (D recommendation).

KEY WORDS:

4Kscore test, 4Kscore, Kallikrein markers, ARF6, NKX3-1, 5’-UTR-BMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK22, Apinifi, protein biomarkers, prostate cancer, biomarkers, Apifiny

APPROVED BY GOVERNING BODIES:

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. The following laboratories are certified under the Clinical Laboratory Improvement Amendments: BioReference Laboratories and GenPath Diagnostics (subsidiaries of OPKO Health; 4Kscore®). To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of these tests.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

81539

Oncology (High-Grade Prostate Cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA and human kallikrein 2 [hK2]) plus patient age, digital rectal examination status, and no history of positive prostate biopsy, utilizing plasma, prognostic algorithm reported as a probability score

0021U

Oncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3-1, 5’-UTR-BMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score

REFERENCES:

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POLICY HISTORY:

Medical Policy Group, October 2019 (9): Removed all aspects of protein biomarker testing from medical policy #534 and created this individual policy #707.

Medical Policy Panel, November 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Key Points, Description, References. No change to policy statement.

Medical Policy Panel, November 2020

Medical Policy Group, January 2021 (9): 2020 Updates to Key Points, Description, References. Added key word: Apifiny. Corrected misspelling of Apifini to Apifiny in policy statement. No change to policy statement intent.

Medical Policy Panel, March 2021

Medical Policy Group, March 2021 (9): 2021 Updates to Key Points, Description, References. Policy statement updated to remove “not medically necessary,” no change to policy intent.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.