There are two applications of molecular biomarkers to risk-stratify patients
at increased risk for prostate cancer:  


  1. A non-invasive or minimally invasive test, the results of which are obtained to inform the decision to perform an initial biopsy (pre-biopsy).
  2. A test performed to further refine risk when a biopsy has been performed but does not clearly indicate malignancy on histopathologic examination (post-biopsy). Such a test can potentially obviate the need for a repeat biopsy.

This contractor provides limited coverage for molecular Deoxyribonucleic
acid/ribonucleic acid (DNA/RNA) biomarker tests for the diagnosis of prostate
cancer that help differentiate men who may or may not benefit from a prostate
biopsy when ALL of the following conditions are met:

1\. The patient must not have an established diagnosis of prostate cancer.

2\. The beneficiary is a candidate for prostate biopsy or repeat prostate
biopsy, according to a consensus guideline [(i.e., National Comprehensive
Cancer Network (NCCN), American Society of Clinical Oncology(ASCO), American
Urological Association (AUA)].

  1.     1. For men  75 years of age - Prostate Specific Antigen (PSA) (or adjusted PSA in special populations, i.e., patients taking 5alpha-reductase inhibitors) OR repeat PSA are >3 and <10ng/mL AND/OR Digital Rectal Exam (DRE) findings are very suspicious for cancer.
    2. For men > 75 years of age - PSA (or adjusted PSA in special populations, i.e., patients taking 5-alpha-reductase inhibitors) OR repeat PSA are 4 and <10ng/mL AND/OR DRE findings are very suspicious for cancer.

EXCEPTION: a molecular biomarker test may be performed in men with PSA levels
>10 ng/mL who are being considered for repeat biopsy IF appropriate according
to consensus guidelines AND according to the following: the specific biomarker
test has been validated in men with PSA levels>10 ng/mL AND a Multiparametric
MRI (mpMRI) is negative, _if performed._

3\. The beneficiary has not had a prostate biopsy OR has had a previous
negative or non-malignant but abnormal histopathology finding (i.e., atypical
small acinar proliferation (ASAP) or high-grade prostatic intraepithelial
neoplasia (HGPIN) on prostate biopsy).

 Patients under consideration for a repeat biopsy have first undergone repeat
PSA and/or DRE testing as recommended by consensus guidelines

4\. The beneficiary would benefit from treatment of prostate cancer and
patient management will be impacted by use of a biomarker in a manner already
demonstrated in the peer-reviewed published literature to improve patient
outcomes.

5\. The medical record supports the medical necessity for the biomarker test.

6\. Testing is performed according to the intended use of the test in the
intended patient population for which the test was developed and validated.

7\. Testing must be performed according to Clinical Laboratory Improvement
Amendments (CLIA) and/or Food and Drug Administration (FDA) regulations in an
accredited laboratory.

8\. For a given clinical indication (pre-OR post-biopsy), only one molecular
biomarker may be performed UNLESS a second test, meeting all the criteria
established herein, is reasonable and necessary as an adjunct to the first
test, according to criteria established in this policy.

9\. If the test relies on an algorithm which may range in complexity from a
threshold determination of a single numeric value to a complex mathematical or
computational function, the algorithm must be validated in a cohort that is
not a development cohort for the algorithm.

10\. The analytes measured have demonstrated clinical validity and clinical
utility (i.e., improved detection or discrimination of cancer or high-grade
cancer or reduction in the need for biopsy) in the peer-reviewed published
literature, establishing a clear and significant biological/molecular basis
for stratifying patients and subsequently selecting (either positively or
negatively) their clinical management decision within a clearly defined
population.

11\. The test is ordered by a physician specialist in the management of
prostate cancer, such as a urologist or oncologist. An exception may be made
in geographic locations where the specialist(s) cannot be reasonably reached
by the beneficiary and the ordering provider is located closer to the
beneficiary's place of residence than the nearest specialist. We would
generally expect that beneficiaries for whom the test is ordered under this
exception to be living in rural locations, islands, or some other location
where access to care is limited.

NOTE: If the patient is considered higher risk (due to relevant family or
personal cancer history, relevant high-risk genetic mutations, African
ancestry, or other clinical parameters highly suspicious for cancer including
a persistent and significant increase in PSA), a biopsy may still be
warranted. These relative indications for biopsy should be taken into
consideration as part of a shared decision-making process regarding whether to
proceed with a biopsy.

Analytical validity, clinical validity (of novel analytes), and clinical
utility will be assessed as part of a thorough and comprehensive technical
assessment (TA) by the Molecular Diagnostic Services Program (MolDX).

Prostate cancer is the second leading cause of cancer deaths in American men.
Estimates for 2020 have shown that over 191,000 men will be diagnosed in the
United States.1,2 Prostate cancer can be an indolent, non-aggressive disease
or a fast-growing, aggressive disease with significant morbidity and
mortality. Prostate cancer guidelines, therefore, aim to limit unnecessary
detection and invasive procedures for indolent disease while maximizing the
detection and treatment of aggressive cancer.

Prostate cancer screening with the PSA level has been an accepted approach to
screening men for prostate cancer, and it is a statutorily covered Medicare
benefit. The PSA level correlates with the risk of prostate cancer and the
higher above the median PSA (for a given age group), the higher the risk for
prostate cancer and aggressive prostate cancer. Approximately 30% of men with
serum PSA levels between 4 and 10 ng/mL will be found to have prostate cancer,
and total PSA levels >10 ng/mL confer a >67% likelihood of prostate cancer.3,4
As such, NCCN guidelines recommend that patients with a PSA >10 ng/mL should
be encouraged to undergo biopsy.4 However, PSA is not a cancer-specific
marker, and it is widely known that PSA values can be elevated and fluctuate
for a variety of reasons other than cancer including inflammation, infection,
and benign prostate hyperplasia.5,6 While the test is sensitive, its negative
predictive value (NPV) is relatively low and there are numerous false
positives.7,8 A cohort study of 1268 patients found that repeating the PSA
resulted in normal (<4 ng/mL) values for nearly 25% of patients with initial
PSA levels between 4 and 10 ng/mL.6 Moreover, compared with men who had an
abnormal repeat PSA result, men with normal repeat PSA results were less
likely to undergo biopsy and were approximately 80% less likely to have a
diagnosis of prostate cancer and Gleason score of 7 or higher.6 False negative
PSA results also occur. In the Prostate Cancer Prevention Trial, 15% of men
with PSA levels 4.0 ng/mL (and normal DREs) were diagnosed with prostate
cancer; of these, 14.9% had a Gleason score of 7 or higher.9 Therefore, there
is not one particular value or cut-off with sufficiently high sensitivity and
specificity for assessing prostate cancer risk.

Given the suboptimal ability of the PSA to accurately assess prostate cancer
risk, there is ambiguity regarding its clinical value at various levels when
reviewing associated outcomes subsequent to screening.8 A large multi-center
randomized controlled study, the Prostate, Lung, Colorectal, and Ovarian
(PLCO) Cancer Screening Trial, was conducted involving over 76,000 men from 55
to 74 years of age who received either annual PSA measurements and digital
rectal examinations or their usual care.10 After 7 to 13 years of follow-up,
the mortality rates were low in both groups and not significantly
different.10,11 However, the study's control arm included opportunistic
screening for prostate cancer and therefore greatly confounded the results.
Another large trial involving 8 European countries, the European Randomized
study of Screening for Prostate Cancer (ERSPC), randomized 182,160 men between
the ages of 50 and 74 to receive either screening for prostate cancer
including PSA measurements or a 'truer' control arm (in which only a
relatively small number of men had previously taken a PSA test).12 Patients
received a prostate biopsy if there was a concern for cancer based on the
screening data. This study subsequently followed patients for 16 years and
found that the screening group had a significant relative reduction in
prostate-cancer related mortality of 21% (reported at 13 years of follow-up)
and an even larger absolute benefit and reduction in excess incidence with the
longer follow-up time of 16 years.13,14

Although PSA screening has been associated with a significant reduction in
prostate-cancer related mortality, it has also led to the increased incidence
of prostate cancer, resulting in the overdiagnosis and overtreatment of
indolent tumors, considered to be clinically insignificant.12,15-18 Autopsy
studies have shown that among 70-79 year old men, more than one-third to one-
half have indolent prostate cancer that would not have caused harm if
undiagnosed and untreated.18 The performance of prostate biopsies, an invasive
intervention, is currently the next step in diagnosis and management, and can
involve significant complications, including hospitalization in approximately
1% of patients.19 Moreover, prostate biopsy is also prone to challenges such
as sampling error, which may further lead to both over- and under-treatment,20
with the false-positive and complication rates from biopsy being higher in
older men.7

The management of patients with prostate cancer may include active
surveillance versus definitive therapy. From 1994 through 2002, a large study
of men with localized prostate cancer diagnosed shortly after PSA screening
randomized 731 subjects to radical prostatectomy vs observation. There was no
significant difference in either prostate-cancer specific mortality or all-
cause mortality through at least 12 years of follow-up.21 Although with longer
follow-up, the mortality rate was lower in men who underwent prostatectomy,
though this finding was not statistically significant.22 Additionally, urinary
incontinence, erectile dysfunction (ED), and bowel incontinence were
significantly more common among those men who underwent a prostatectomy.22 In
spite of these challenges, prostate cancer deaths have decreased by 50% since
1988, in large part due to enhanced screening measures.2,23,24

As a result of the ambiguous risk-benefit profile associated with prostate
cancer screening and management, guidelines on screening have differed among
national organizations over the years. In 2012, the United States Preventative
Services Task Force (USPSTF) recommended against PSA-based screening for
prostate cancer, in large part as a result of the initial PLCO and ERSPC
reports.25 However, their most recent update recommended that screening for
prostate cancer with a PSA test should be an individualized decision for men
(aged 55 to 69 years) to discuss with their physicians, but cautioned that
there is a significant risk of false positives and overtreatment with the
possibility of significant complications such as ED and incontinence.26 Such
guidance was similarly endorsed by the Choosing Wisely initiative, which also
highlighted the American Urological Association's (AUA) recommendation to
consider a PSA test only after talking with one's doctor about risk
factors.27,28 Guidelines from the NCCN recommend PSA testing to screen for
prostate cancer in men 45-75 years of age in average-risk patients (and 40-75
years of age in higher-risk patients) as a level 2A recommendation; testing
men >75 years of age is only recommended in healthy men with few to no
comorbidities and is a level 2B recommendation, as widespread testing in this
age group would significantly increase rates of overdetection.4 Moreover, NCCN
guidelines recommend repeat testing if an abnormally high PSA is observed,
particularly if the value is close to the threshold value that prompts
evaluation.4 In the case of a prior negative biopsy, the guidelines recommend
repeat PSA and DRE at 6- to 24-month intervals with consideration of repeat
biopsy based on results.4

It is evident that not all prostate cancers are the same, and detection and
treatment should focus specifically on prostate cancers that are more likely
to contribute to morbidity and mortality. It is also evident that there are
challenges with PSA testing, and a PSA-based screening strategy has not been
proven to help differentiate low risk from aggressive prostate cancer. First-
generation PSA derivative assays (e.g., free PSA, complexed PSA) were designed
to increase PSA specificity for prostate cancer, but not necessarily
specificity for clinically significant cancer. Additionally, multiparametric
MRI (mpMRI) significantly increases the detection of clinically significant,
higher-risk disease and is recommended for many patients with elevated PSA
levels being considered for initial and repeat biopsy. However, a negative MRI
does not exclude the possibility of cancer.4,30 As such, there is clinical
utility for diagnostic tests that can better refine the implications of an
elevated PSA test to help distinguish men with potentially life-threatening
cancer from men who have indolent prostate cancer or no prostate cancer.

**_Biomarkers_**

The most current NCCN recommendations reflect the growing body of evidence
supporting the use of prostate biomarkers to further identify, and risk
stratify those patients at risk of high-grade prostate cancer requiring
further management from those with low grade or indolent cancer who might not
benefit from further intervention and who may be spared unnecessary biopsies
and interventions. Such biomarkers are non-invasive (typically blood-or urine-
based) and may contribute to improved sensitivity and specificity of
screening, surpassing the limitations of PSA testing.4,31-33

There are numerous biomarker tests available for biopsy-naive patients that
may improve the detection of prostate cancer or higher-grade prostate cancer.
Some of these are non-molecular (i.e., they do not detect DNA and/or RNA), and
include the percent free PSA (%fPSA), 4Kscore, and Prostate Health Index
(PHI). Free PSA (fPSA) is an unbound form of PSA that is FDA approved for use
in men with normal DRE and PSA levels of 4-10 ng/mL. At a cutoff of 25% in men
with PSA values between 4-10ng/mL, fPSA has been shown to detect the majority
of prostate cancers while avoiding approximately 20% of unnecessary
biopsies.34 The 4Kscore measures kallikrein markers (including PSA and fPSA)
in the blood and considers other clinical parameters such as age and DRE,
which together have been reported to better detect clinically significant
cancer.35-39 Finally, the Prostate Health Index (PHI) is a blood-based
immunoassay that uses PSA, fPSA, and p2PSA (an isoform of fPSA) to calculate a
score that categorizes a patient's risk as low, moderate, or high. Studies
have shown that the PHI improves the sensitivity of prostate cancer
detection,43,44 discriminates high-grade cancer43,45 and can reduce the rate
of prostate biopsies.46

Other pre-biopsy biomarker tests are molecular and measure the expression of
genes or epigenetic changes associated with prostate cancer. Some of these
couple gene expression with other clinical and laboratory parameters in
multimodal models, to optimize their clinical performance.47-51 For example,
SelectMDx evaluates messenger ribonucleic acid (mRNA) levels of HOXC6 and
DLX1 relative to Kallikrein-related Peptidase 3 (KLK3). When combined with
additional clinical risk factors in a multimodal approach, prospective
multicenter studies found that the area under the curve (AUC) of the receiver
operating characteristic (ROC) reached 0.90 in predicting detection of high-
grade prostate cancer; importantly, the risk score remained a strong predictor
(AUC 0.78) in men with PSA levels <10 ng/mL.52 A urine exosome gene expression
assay, the ExoDxTM Prostate IntelliScore (EPI), has also been reported to be
statistically more predictive than standard of care (SOC) alone for predicting
Gleason score of 7 (GS 7) prostate cancer from GS 6 and benign disease.50 A
clinical utility study in men scheduled for initial biopsy found that, at a
cutoff of 15.6, the test had a NPV of 89% and would reduce total biopsies by
20%; however, the test would miss 7% of high grade cancers.49 In men with a
prior negative biopsy, a prospective clinical validation study found that the
EPI test had a NPV of 92% and would have avoided 26% of unnecessary biopsies
while missing 2% of high-grade cancers.53 Importantly, these results were
independent of SOC and other clinical features.

In the post-biopsy setting, there are biomarkers that improve specificity in
patients who have had at least 1 prior negative biopsy. Some of these are
liquid biomarkers that overlap with those already discussed for use in biopsy-
naive patients, while others are tissue-based and should only be performed on
a biopsy specimen. Some utilize gene expression data while others evaluate
epigenetic markers such as hypermethylation in select genes thought to be
associated with aggressive disease.54-57 Progensa PCA3 is an mRNA expression
assay that can be tested from post-DRE urine. In the post-biopsy setting, it
has been shown to improve the specificity of prostate cancer detection and
determine which patients should undergo a repeat biopsy. One multi-center
study evaluating men with at least 1 prior negative prostate biopsy reported
that those with a score of <25 were more than 4 times as likely to have a
negative repeat biopsy as men with a score of 25.58 ConfirmMDx is a multi-
gene test that uses prostate biopsy tissue to assess the methylation status of
3 biomarkers (GSTP1, RASSF1, APC) associated with prostate cancer.54,57 The
performance of this assay in large, blinded clinical validation studies
demonstrated a NPV of 90% for all prostate cancer and 96% for high-grade
disease, considerably higher than that afforded by standard histopathology
review.54,56 A field observation study conducted in 138 patients with negative
biopsies found a repeat biopsy rate of 4.3%,59 significantly lower than the
40% repeat biopsy rate reported in the PLCO trial, for patients with an
initial negative biopsy.60

In summary, use of biomarker tests may help overcome the limitations of
screening by PSA as well as the limitations and risks associated with prostate
biopsy. On the whole, use of these biomarker tests can better detect cancer or
high-grade cancer, and can reduce the performance of unnecessary prostate
biopsies and their associated risks. It should be noted that mpMRI is also a
consideration in these same patients and, though data is emerging that
combining biomarkers with mpMRI results in improved diagnostic accuracy, it is
not yet known how biomarker tests can be optimally used in conjunction with
MRI.



Numerous prior Medicare coverage decisions have considered the evidence in the
hierarchical framework of Fryback and Thornbury61 where Level 2 addresses
diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses
on whether the information produces change in the physician's diagnostic
thinking; Level 4 concerns the effect on the patient management plan and Level
5 measures the effect of the diagnostic information on patient outcomes. To
apply this same hierarchical framework to analyze an _in vitro_ diagnostic
test, we utilized the ACCE Model Process for Evaluating Genetic Tests.62 The
practical value of a diagnostic test can only be assessed by taking into
account subsequent health outcomes. When a proven, well-established
association or pathway is available, intermediate health outcomes may also be
considered. For example, if a particular diagnostic test result can be shown
to change patient management and other evidence has demonstrated that those
patient management changes improve health outcomes, then those separate
sources of evidence may be sufficient to demonstrate positive health outcomes
from the diagnostic test.

Screening for prostate cancer using PSA is a statutorily covered benefit.
However, PSA is a screening test, and is not diagnostic of either prostate
cancer or of prostate cancer requiring immediate intervention. The diagnosis
relies on a prostate biopsy, which is associated with a risk of significant
post-operative complications.

NCCN Guidelines recognize the benefits of improving the identification of
significant cancer while avoiding the detection of indolent disease, and
recommend (as a level 2A recommendation) the consideration of a biomarker test
(one that has been validated in peer-reviewed studies) to better define the
probability of higher-grade cancer (Gleason score 3+4, Grade Group 2 or
higher) in patients who meet PSA standards for consideration of prostate
biopsy.4 For patients who have not yet had a biopsy, the guidelines include
the use of %fPSA to improve cancer detection, and PHI, SelectMDx,4Kscore,
and ExoDxTM Prostate (EPI) tests to further define the probability of higher-
grade cancer.4 They also include %fPSA, PHI, 4Kscore, EPI, PCA3 and
ConfirmMDx to improve specificity for patients thought to be at higher risk
despite a prior negative biopsy.4 However, as there is variation in the number
and quality of clinical validity and clinical utility studies published, it is
not always clear which biomarker test may be optimal in a particular
setting.4,63

A systematic review found that prostate biomarker tests, even when combined
with a pre-existing multivariable clinical risk calculator such as the
Prostate Cancer Prevention Trial (PCPT) or the European Randomized Screening
for Prostate Cancer (EPSRC) risk calculator, can still miss 5% to 10% of
clinically significant cancers.64 The authors concluded that "Incorporating
the newer prostate biomarkers and mpMRI into predictive algorithms like the
PCPT and EPSRC risk calculators is likely necessary when deciding whether a
patient can forego prostate biopsy."64 They also caution against using
biomarker tests in a binary fashion and note that urologists will need to
decide how to use these tests to determine probability of cancer within the
context of the pre-existing risk predictors, the patient's ethnicity, life
expectancy and quality-of-life goals, and cost.64 Similarly, the NCCN
guidelines state that no biomarker test can be recommended over any other at
this time and that the optimal order of combining biomarker tests with imaging
is unknown.4 Moreover, questions remain regarding how to interpret results of
multiple tests in individual patients, particularly when results are
contradictory. The guidelines also do not recommend the use of a single
parameter (such as a risk calculator) to determine whether a biopsy is
indicated; rather, they encourage a multi-faceted approach that includes
clinical judgment and patient preferences. They also cite several recent
studies suggesting that biomarker testing performed in parallel with
conditional MRI may be an efficient and effective way to assess those with
persistently elevated PSAs. As such, they caution that biomarker tests can be
complex and should be interpreted carefully, and with referral to a
specialist.4

Finally, as some biomarker tests are not clinically validated in patients with
PSA levels >10 ng/mL, their performance in this population is unknown.4
Moreover, though the patients being considered for repeat biopsy of the
prostate may have a rising PSA above this level, the threshold for repeat
biopsy should also be significantly lower in this group, as "patients with a
persistent and significant increase in PSA should be encouraged to undergo
biopsy."4

In sum, biomarkers can help stratify men who have an elevated PSA into those
more likely versus less likely to have aggressive disease. These non-invasive
biomarker tests have demonstrated that they can (1) reduce the need for
unnecessary biopsies in men unlikely to have prostate cancer or high-grade
prostate cancer and/or (2) better define men at risk for higher-grade prostate
cancer. There is adequate evidence to show that the incremental information
provided by validated molecular biomarker tests for prostate cancer in samples
of patients whose findings can be generalized to the Medicare population,
changes physician management in a way that improves outcomes. Tests that
fulfill all criteria outlined in this policy will similarly be considered for
coverage.

The reference to specific biomarkers in this document does not imply coverage
by MolDX.Further, this policy is restricted in scope to molecular biomarkers
only; therefore, non-molecular biomarkers for the same intended use, though
not covered by this policy, may meet coverage criteria of other local coverage
determinations.

This contractor will continue to evaluate biomarkers and will provide coverage
based on the pertinent literature as well as professional society and
nationally recognized guidelines (i.e., (NCCN).