LCD L37798: 4Kscore Test Algorithm

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:

• When all of the components of the algorithm are present.

• 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 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 not considered reasonable and necessary:

• Any test that does not contain all of the following components:

• 4 Kallikreins proteins (Total PSA [tPSA], Free PSA [fPSA], Intact PSA [iPSA] and human Kallikrein-2 [hK2])

• Clinical information including age

• DRE

• Prior biopsy history

• Tests performed without evidence of shared decision making between the ordering provider and the beneficiary.

As published in the CMS IOM Publication 100-08, Medicare Program Integrity Manual , Chapter 13, Section 13.5.4, an item or service may be covered by a contractor LCD if it is reasonable and necessary under the Social Security Act Section 1862 (a)(1)(A). Contractors shall determine and describe the circumstances under which the item or service is considered reasonable and necessary.

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 2 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) 3 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.