**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 5-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:

  1. 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
  2. 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 al2 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.

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.3

The NCCN updated guidelines4 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 desires 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." 3,4 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.3

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 LCD.