4Kscore Test Algorithm

This LCD supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for the 4Kscore test algorithm. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for 4Kscore test algorithm and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant CMS manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site:

IOM Citations:

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual, Chapter 15 Covered Medical and Other Health Services, Section 80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests
• CMS IOM Publication 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1,
• Part 3, Section 190.31 Prostate Specific Antigen 
• Part 4, Section 210.1 Prostate Cancer Screening Tests
• CMS IOM Publication 100-04, Medicare Claims Processing Manual, Chapter 16 Laboratory Services
• CMS IOM Publication 100-08, Medicare Program Integrity Manual, Chapter 13 Local Coverage Determinations, Section 13.5.4 Reasonable and Necessary Provisions in LCDs

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim.
• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.

Federal Register References:

• Code of Federal Regulations (CFR), Title 42, Chapter IV, Subchapter B, Part 410, Subpart B, Section 410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

Compliance with the provisions in this policy may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

The 4Kscore test measures blood levels of four Kallikreins protein biomarkers (total prostate-specific antigen [tPSA], free PSA [fPSA], intact PSA [iPSA], and human Kallikrein-related peptidase 2 [hK2]) in addition to other clinical information, including age, digital rectal examination (DRE) and prior biopsy history. All of these components are placed into a proprietary algorithm to provide a percent risk for a high-grade Gleason score greater than or equal to 7 cancer on biopsy.¹ The 4Kscore test algorithm's goal is to refine patient selection for biopsies to reduce unnecessary biopsies in men being considered for biopsy of the prostate for potential cancer. The clinical features of this group of men are poorly defined.

NOTE: If any of the above components and protein elements are not present in the test, the test is not a true 4Kscore test and will not be considered for payment.

Covered Indications

The 4Kscore test will be considered medically reasonable and necessary when all the following are met:

1. When all of the components of the algorithm are present.
2. Testing of men 45 years of age and older, prior to an initial biopsy or following a negative biopsy, who have a confirmed* moderately elevated PSA (greater than 3 and less than 10 ng/mL; greater than or equal to 4 and less than 10 ng/mL in men greater than 75 years of age) when BOTH of the following are present:
• No other relative indication** for prostate biopsy including ANY of the following: (this may not be an all inclusive list)
  • DRE suspicious for cancer should be encouraged to undergo biopsy
  • Persistent and significant increase in PSA should be encouraged to undergo biopsy
  • Positive multiparametric magnetic resonance imaging (MRI) (if done)
  • Other major risk factor for prostate cancer including: (this may not be an all inclusive list)
    • Ethnicity at higher risk for prostate cancer
    • First-degree relative with prostate cancer
    • High-penetrance prostate cancer risk gene(s) per the National Comprehensive Cancer Network (NCCN) (if known)
• No other relative contraindication** for prostate biopsy including ANY of the following:
  • Less than a 10 year life expectancy
  • Benign disease not ruled out.

*PSA elevation should be verified after a few weeks under standardized conditions (e.g. no ejaculation, manipulations, and urinary tract infections, no medications such as 5α-reductase) in the same laboratory or other Clinical Laboratory Improvement Amendments (CLIA) approved laboratory before considering a biopsy.

**The relative indications and contraindications are not absolute. When it is determined that the 4Kscore test is medically reasonable and necessary in a beneficiary with one of the relative indications or contraindications for prostate biopsy the medical record must support the medical necessity for the test and there must be documented evidence of shared decision making between the patient and provider. This supporting documentation must be provided to the laboratory at the time of ordering the test.

    3.  Presence of shared decision making between the ordering provider and the beneficiary concerning the 4Kscore testing.

Limitations

The following are considered to be not medically reasonable and necessary:

1. Any test that does not contain all of the following components:
   • 4 Kallikreins proteins (tPSA, fPSA, iPSA and hK2)
   • Clinical information including age
   • DRE
   • Prior biopsy history
2. Tests performed without evidence of shared decision making between the ordering provider and the beneficiary.

In response to 4Kscore data being criticized suggesting that patients were not part of the intended population or that the results of a specific PSA range were not cited, Vickers et al ⁴² reanalyzed data from a recent meta-analysis using a Gleason grade group (GGG) of greater than or equal to 2. The base model that was used consisted of age, total PSA and DRE (if available). Initially, 1,792 different analyses reflecting the most common age, PSA and DRE were performed. The results of these analyses did not vary substantially. An analysis across all possible subgroups of age, PSA, DRE and cohorts was then performed. Out of 180,224 analyses 159,847 had meaningful data. Clinical validity was assessed by calculating the net benefit for the panel and base model at threshold probabilities of 6%, 9%, 12% and 15%. While sometimes at low threshold probabilities, if the PSA or age range was restricted or unusual, the authors were unable to find any reasonable combination of age or PSA in contemporary cohorts for which the decision curve did not support clinical utility of the panel.

Limitations of this analysis include no validation of this format being noted and no clinical outcomes noted. Several terms and definitions such as “results did not vary importantly” and “net benefit” were not defined.

In their guidelines, the American Urological Association (AUA) ²⁴ recognizes that the decision to undergo PSA screening in men ages 55 to 69 involves weighing the benefits of reducing the rate of metastatic prostate cancer and prevention of prostate cancer death against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision-making for men 55 to 69 years of age that are considering PSA screening, and proceeding based on a man's values and preferences.

The Panel does not recommend routine PSA screening in men 70 years of age or older or for any man with less than a 10 to 15 year life expectancy.

It is important to note that the guideline statements listed in this document target men at average risk, defined as a man without risk factors, such as a family history of prostate cancer in multiple generations and/or family history of early onset below age 55, or African American race.

The greatest benefit of screening appears to be in men 55 to 69 years of age. Multiple approaches subsequent to a PSA test (e.g., urinary and serum biomarkers, imaging, risk calculators) are available for identifying men more likely to harbor a prostate cancer and/or one with an aggressive phenotype. The use of such tools can be considered in men with a suspicious PSA level to inform prostate biopsy decisions.²⁴

The NCCN updated guidelines ⁴³ states that the 4Kscore test may be considered prior to biopsy for those with prior negative biopsy who are thought to be at risk for clinically significant prostate cancer. The NCCN notes that it is important for patients and their urologists to understand that no optimal cutoff threshold has been established for the 4Kscore test. The panel recommends that the 4Kscore test may be considered before biopsy in men with serum PSA levels greater than 3ng/ml who desire more specificity.

With a recommendation for specific clinical scenarios, coupled with documented shared decision making the AUA and NCCN organizations both state that biomarkers specifically 4Kscore “can be considered in men with a suspicious PSA level to inform prostate biopsy decisions.” ^{24, 43} Shared decision making is given evidence strength of Grade A for the use of this tool by AUA. The quality of evidence is graded a B by the same organization.²⁴

NCCN grades this tool for testing to improve specificity a 2A recommendation.

Taking into consideration the AUA guidelines and the 2019 NCCN guidelines, limited coverage will be considered medically reasonable and necessary when performed within the covered indications and limitations of this policy.

Please refer to Local Coverage Article: Billing and Coding: 4Kscore Test Algorithm, A56653 for all coding information and for the documentation requirements

Contractor is not responsible for the continued viability of websites listed.

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2. Vickers AJ, Cronin AM, Roobol M, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol. 2010 May 20;28(15):2493-8. doi: 10.1200/JCO.2009.24.
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41. Palmetto GBA Local Coverage Determination (LCD) L36763 MolDX: 4Kscore Assay
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