Latest Review Date: December 2024

Category: Laboratory

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 are 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.

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 2 to 3 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 (undifferentiated); 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 Table 1.

Table 1. Prostate Cancer Grading Systems

Numerous genetic alterations associated with the development or progression of prostate cancer have been described, with the potential for the use of these molecular markers to improve the selection process of men who should undergo prostate biopsy or rebiopsy after an initial negative biopsy.

KEY POINTS:

This policy has been updated regularly with the most recent literature update was performed through September 16, 2024.

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 (DRE), a prostate-specific antigen (PSA), level outside of the gray zone (between 3 or 4 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 do not compare performance characteristics with standard risk prediction models. Direct evidence supporting clinical utility has not been shown. No data are currently available on the longer-term clinical outcomes of the use of genetic and protein biomarkers to decide on repeat prostate biopsy. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

IsoPSA™ is similar to two reflex tests currently on the market, 4K Score (protein biomarker test) and Prostate Health Index (genetic test, which is not addressed in the policy), which perform identically in head to head comparison. No head to head comparisons have been performed with IsoPSA™. For both tests, the evidence needed to conclude the test has clinical validity is insufficient. A multicenter prospective validation study of IsoPSA™ was identified as well as an observational study. Well-designed randomized controlled trials proving the clinical validity and utility of this technology are needed. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American Urological Association et al

In 2023, the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) published updated guidelines on the early detection of prostate cancer. Specific guidance related to diagnosis, risk assessment, and utilization of biomarkers are stated in Table 2 below.

Table 2. Relevant AUA/SUO Guideline Statements on Prostate Cancer Screening and Biopsy

DRE: digital rectal exam; PSA: prostate-specific antigen; mpMRI: multi-parametric magnetic resonance imaging

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) guidelines  for prostate cancer early detection (v.2.2024) recommend that any man with a PSA level greater than 3 ng/mL undergo workup for benign disease, repeat PSA, and DRE (category 2A evidence).

The NCCN guidelines state that "biomarkers that improve the specificity of detection are not, as yet, mandated as first-line screening tests in conjunction with serum PSA. However, there may be some patients who meet PSA standards for consideration of prostate biopsy, but for whom the patient and/or the physician wish to further define risk." The guidelines recommend that the probability of high-grade cancer (Gleason score ≥3+4, Grade Group 2 or higher) may be further defined utilizing biomarkers that improve the specificity of screening that includes percent free PSA, with consideration of the 4Kscore, IsoPSA, and other tests. NCCN also noted that the extent of validation of these tests across diverse populations is variable and is not yet known how these tests could be applied in optimal combination with magnetic resonance imaging (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 percent-free PSA, 4Kscore, and other tests.

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). An update of these recommendations is pending.

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, IsoPSA

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.

In 2019, the FDA granted breakthrough designation to IsoPSA™ (Cleveland Diagnostics). This test measures PSA chemical structure and uses ratios to predict cancer, with a goal of reducing the number of prostate biopsies performed. Full FDA approval has not been granted.

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.

CURRENT CODING:

CPT Codes:

REFERENCES:

1. American Urological Association. Early detection of prostate cancer. 2013 (Reviewed and Validity Confirmed 2018);www.auajournals.org/doi/10.1016/j.juro.2013.04.119.
2. Arnsrud Godtman R, Holmberg E, Lilja H, et al. Opportunistic testing versus organized prostate-specific antigen screening: outcome after 18 years in the Goteborg randomized population-based prostate cancer screening trial. Eur Urol. Sep 2015; 68(3):354-360.
3. Aus G, Bergdahl S, Lodding P, et al. Prostate cancer screening decreases the absolute risk of being diagnosed with advanced prostate cancer--results from a prospective, population-based randomized controlled trial. Eur Urol. Mar 2007; 51(3):659-664.
4. Bell KJ, Del Mar C, Wright G, et al. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. Int J Cancer. Oct 1 2015; 137(7):1749-1757.
5. Benidir T, Hofmann M, Lone ZM, Weight C, Klein EA. Pathologic and radiographic outcomes following prostate cancer diagnosis aided by IsoPSA testing. Journal of Clinical Oncology. 2022; 40(6):276.
6. Bhattu AS, Zappala SM, Parekh DJ, et al. A 4Kscore Cut-off of 7.5% for Prostate Biopsy Decisions Provides High Sensitivity and Negative Predictive Value for Significant Prostate Cancer. Urology. Feb 2021; 148: 53-58.
7. Buzzoni C, Auvinen A, Roobol MJ, et al. Metastatic prostate cancer incidence and prostate-specific antigen testing: new insights from the European randomized study of screening for prostate cancer. Eur Urol. Nov 2015; 68(5):885-890.
8. Catalona WJ, Partin AW, Sanda MG, et al. A multicenter study of [-2] pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol. May 2011; 185(5): 1650-5.
9. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. Apr 25 1991; 324(17):1156-1161.
10. Cui Y, Cao W, Li Q, et al. Evaluation of prostate cancer antigen 3 for detecting prostate cancer: a systematic review and meta-analysis. Sci Rep. May 10 2016; 6: 25776.
11. Djavan B, Waldert M, Zlotta A, et al. Safety and morbidity of first and repeat transrectal ultrasound guided prostate needle biopsies: results of a prospective European prostate cancer detection study. J Urol. Sep 2001; 166(3):856-860.
12. Gleason DF. Classification of prostatic carcinomas. Cancer Chemother Rep. Mar 1966; 50(3):125-128.
13. Gosselaar C, Roobol MJ, Roemeling S, et al. The role of the digital rectal examination in subsequent screening visits in the European randomized study of screening for prostate cancer (ERSPC), Rotterdam. Eur Urol. Sep 2008; 54(3):581-588.
14. Hoogendam A, Buntinx F, de Vet HC. The diagnostic value of digital rectal examination in primary care screening for prostate cancer: a meta-analysis. Fam Pract. Dec 1999; 16(6):621-626.
15. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014. Bethesda, MD: National Cancer Institute; 2017.
16. Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Goteborg randomised population-based prostate-cancer screening trial. Lancet Oncol. Aug 2010; 11(8):725-732.
17. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
18. Kawada T, Shim SR, Quhal F, et al. Diagnostic Accuracy of Liquid Biomarkers for Clinically Significant Prostate Cancer Detection: A Systematic Review and Diagnostic Meta-analysis of Multiple Thresholds. Eur Urol Oncol. Aug 2024; 7(4): 649-662. 
19. Konety B, Zappala SM, Parekh DJ, et al. The 4Kscore(R) test reduces prostate biopsy rates in community and academic urology practices. Rev Urol. 2015; 17(4):231-240.
20. Lavallee LT, Binette A, Witiuk K, et al. Reducing the harm of prostate cancer screening: repeated prostate-specific antigen testing. Mayo Clin Proc. Jan 2016; 91(1):17-22.
21. Liss M, Ehdaie B, Loeb S, et al. The Prevention and Treatment of the More Common Complications Related to Prostate Biopsy Update. 2012; updated 2016; www.auanet.org/guidelines/prostate-needle-biopsy-complications.
22. Lujan M, Paez A, Santonja C, et al. Prostate cancer detection and tumor characteristics in men with multiple biopsy sessions. Prostate Cancer Prostatic Dis. 2004; 7(3):238-242.
23. Mackinnon AC, Yan BC, Joseph LJ et al. Molecular biology underlying the clinical heterogeneity of prostate cancer: an update. Arch Pathol Lab Med 2009; 133(7):1033-40.
24. Mi C, Bai L, Yang Y, et al. 4Kscore diagnostic value in patients with high-grade prostate cancer using cutoff values of 7.5% to 10%: A meta-analysis. Urol Oncol. Jun 2021; 39(6): 366.e1-366.e10.
25. National Cancer Institute. SEER Database. https://seer.cancer.gov/seerinquiry/index.php?page=view&id=20170036&type=q.
26. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: prostate cancer early detection V.1.2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate_detection.pdf.
27. Odedina FT, Akinremi TO, Chinegwundoh F, et al. Prostate cancer disparities in Black men of African descent: a comparative literature review of prostate cancer burden among Black men in the United States, Caribbean, United Kingdom, and West Africa. Infect Agent Cancer. 2009; 4 Suppl 1:S2.
28. Parekh DJ, Punnen S, Sjoberg DD, et al. A Multi-institutional Prospective Trial in the USA Confirms that the 4Kscore Accurately Identifies Men with High-grade Prostate Cancer. Eur Urol. Oct 27 2014.
29. Partin AW, Brawer MK, Subong EN, et al. Prospective evaluation of percent free-PSA and complexed-PSA for early detection of prostate cancer. Prostate Cancer Prostatic Dis. Jun 1998; 1(4):197-203.
30. Punnen S, Freedland SJ, Polascik TJ, et al. A Multi-Institutional Prospective Trial Confirms Noninvasive Blood Test Maintains Predictive Value in African American Men. J Urol. Jun 2018; 199(6): 1459-1463.
31. Rosario DJ, Lane JA, Metcalfe C, et al. Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study. BMJ. 2012; 344:d7894.
32. Rosenkrantz AB, Verma S, Choyke P, et al. Prostate Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Patients with a Prior Negative Biopsy: A Consensus Statement of the American Urological Association and the Society of Abdominal Radiology's Prostate Cancer Disease Focused Panel. J Urol. Dec 2016; 196(6):1613-1618.
33. Russo GI, Regis F, Castelli T, et al. A Systematic Review and Meta-analysis of the Diagnostic Accuracy of Prostate Health Index and 4-Kallikrein Panel Score in Predicting Overall and High-grade Prostate Cancer. Clin Genitourin Cancer. Aug 2017; 15(4): 429- 439.e1.
34. Schipper M, Wang G, Giles N, et al. Novel prostate cancer biomarkers derived from autoantibody signatures. Transl Oncol. Apr 2015; 8(2):106-111.
35. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. Mar 26 2009; 360(13):1320-1328.
36. Scovell JM, Hettel D, Abouassaly R, Almassi N, Berglund R, et al. IsoPSA® Reduces Provider Recommendations for Biopsy and Magnetic Resonance Imaging in Men with Total Prostate Specific Antigen ≥4 ng/ml: A Real-World Observational Clinical Utility Study. Urology Practice. 2022 Mar; 9(2): 173-180.
37. Stattin P, Vickers AJ, Sjoberg DD, et al. Improving the specificity of screening for lethal prostate cancer using prostate-specific antigen and a panel of kallikrein markers: a nested case-control study. Eur Urol. Aug 2015; 68(2):207-213.
38. Stovsky M, Klein EA, Chait A, Manickam K, Stephenson AJ, Wagner M, Dineen M, Lotan Y, Partin A, Baniel J, Kestranek A, Gawande P, Zaslavsky B. Clinical Validation of IsoPSA™, a Single Parameter, Structure Based Assay for Improved Detection of High Grade Prostate Cancer. J Urol. 2019 Jun; 201(6):1115-1120.
39. Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst. Apr 19 2006; 98(8):529-534.
40. Thompson IM, Pauler DK, Goodman PJ, et al. Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. N Engl J Med. May 27 2004; 350(22):2239-2246.
41. Tosoian JJ, Sessine MS, Trock BJ, et al. MyProstateScore in men considering repeat biopsy: validation of a simple testing approach. Prostate Cancer Prostatic Dis. Sep 2023; 26(3): 563-567. 
42. U. S. Preventive Services Task Force. Prostate Cancer: Screening. 2018;www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/prostate-cancer-screening1.
43. Van Neste L, Hendriks RJ, Dijkstra S, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol. Nov 2016; 70(5):740-748.
44. Van Neste L, Partin AW, Stewart GD, et al. Risk score predicts high-grade prostate cancer in DNA-methylation positive, histopathologically negative biopsies. Prostate. Sep 2016; 76(12): 1078-87.
45. van Vugt HA, Roobol MJ, Kranse R, et al. Prediction of prostate cancer in unscreened men: external validation of a risk calculator. Eur J Cancer. Apr 2011; 47(6):903-909.
46. Vickers AJ, Gupta A, Savage CJ, et al. A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening. Cancer Epidemiol Biomarkers Prev. Feb 2011; 20(2):255-261.
47. Wei JT, Barocas D, Carlsson S, et al. Early Detection of Prostate Cancer: AUA/SUO Guideline Part II: Considerations for a Prostate Biopsy. J Urol. Jul 2023; 210(1): 54-63.
48. Wei JT, Barocas D, Carlsson S, et al. Early Detection of Prostate Cancer: AUA/SUO Guideline Part I: Prostate Cancer Screening. J Urol. Jul 2023; 210(1): 46-53.
49. Wolf AM, Wender RC, Etzioni RB, et al. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin. Mar-Apr 2010; 60(2):70-98.
50. Wysock JS, Becher E, Persily J, et al. Concordance and Performance of 4Kscore and SelectMDx for Informing Decision to Perform Prostate Biopsy and Detection of Prostate Cancer. Urology. Jul 2020; 141: 119-124.

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.

Medical Policy Panel, November 2021

Medical Policy Group, April 2022 (9): Updated Key Points, Description, Approved By Governing Bodies, References. Added CPT code 81599 to current coding section. Added key word “IsoPSA”. No change to policy intent.

Medical Policy Group, November 2022 (9): Added CPT code 0359U to current coding section due to coding update effective 1/1/23.

Medical Policy Panel, November 2022

Medical Policy Group, November 2022 (9): Annual update to Key Points, Description, References. No change to policy intent.

Medical Policy Panel, November 2023

Medical Policy Group, December 2023 (5): Updates to Description, Key Points; Practice Guidelines and Position Statements, Benefit Application, and References. No change to Policy Statement.

Medical Policy Panel, November 2024

Medical Policy Group, December 2024 (5): Updates to Key Points, USPSTF Recommendations, and References. No change to Policy Statement.

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.