Molecular diagnostic tests used to assist in risk stratification of melanoma
patients are covered when ALL of the following are true:

  1. The patient has a personal history of melanoma AND:
    1. Either: 
      1. Has Stage T1b and above OR
      2. Has T1a with documented concern about adequacy of microstaging
    2. Is undergoing workup or being evaluated for treatment, AND
    3. Does not have metastatic disease AND
    4. Presumed risk for a positive Sentinel Lymph Node Biopsy (SLNB) based on clinical, histological, or other information is >5% AND
    5. Has a disease stage, grade, and Breslow thickness (or other qualifying conditions) within the intended use of the test
  2. The TEST has demonstrated, as part of a Technical Assessment:
    1. Clinical validity of analytes tested in predicting metastatic disease (or the absence of metastatic disease) in peer-reviewed scientific literature 
    2. Utility beyond clinical, histological, and radiographical factors in the ability to accurately stratify patients into risk groups to manage patient care, such by precluding unnecessary sentinel lymph node biopsies
    3. Appropriate analytical validity
    4. Performance characteristics equivalent or superior to other covered, similar tests

Cutaneous melanoma (CM) is increasing in incidence in the U.S., with an
estimated 96,480 cases expected to be diagnosed in 2019 with 7,230 deaths.1

In the treatment of CM, the risk that a patient has or will develop metastatic
disease is central to many of the decision management choices in cutaneous
melanoma, with more aggressive management or treatment strategies recommended
for patients who are at a higher risk.2 Per current national guidelines, a
SLNB procedure is considered for all patients with melanoma pathologic Stage
T1b and above, as well as those patients with T1a tumors in whom there is
significant uncertainty about the adequacy of microstaging.2,3 Patients with a
positive SLN are at substantially increased risk for distant metastatic
disease and death;4 however, the procedure only provides prognostic
information, and the MSLT-II study showed no survival benefit associated with
completion lymphadenectomy in SLN positive patients.5 Currently, the
identification of SLN positive patients helps identify Stage III patients who
can potentially benefit from targeted and immunotherapeutic agents in the
adjuvant setting.6-8 The procedure can be associated with complications in a
substantial proportion of patients such as pain, seromas, nerve damage and
edema, and requires a large team of dedicated personnel, including nuclear
medicine physicians, surgeons, and pathologists.9-11 It has been estimated
that the cost of a SLNB can be 10 times that of a wide excision alone, and the
cost per life saved in a patient population with low prevalence of positive
SLN can approach 1 million dollars.12 Overall, the likelihood of a positive
SLN after the SLNB procedure is 16%,4,13 but this is variable for specific
populations.13-16 Elderly patients account for a substantial proportion of CM
patients, and 60% of melanoma-related deaths occur in patients 65 years-old.
While older age is associated with a poor prognosis, fewer elderly patients
are SLN positive,14-18 which indicates that the prognostic value of SLNB is
limited in this population.19,20 In general, a 5% likelihood for a positive
SLN is recommended as a threshold for performing this procedure in a patient
population.13

Molecular diagnostic tests have been proposed to help managing clinicians risk
stratify patients for selecting their most appropriate management based on
their probability of developing metastatic disease; these tests may score
patients' probabilities of resultant metastatic disease by measuring tumor
biomarkers such as relevant gene expression.21-24 One gene expression profile
(GEP) test (DecisionDx Melanoma, Castle Biosciences) was evaluated in a
retrospective cohort (n=782) to evaluate its ability to predict metastasis and
ability to predict SLNB status with tumors with a Breslow thickness <2.0 mm
(American Joint Committee on Cancer [AJCC] T1 T2).25

The ability of the test to identify a low-risk group was initially assessed
and compared to SLNB in 2 contemporary, multi-center, prospective study
cohorts: a 584 patient cohort from 2 published prospective studies (overall
14% SLN positive rate)23,26 and a 837 patient cohort from prospectively tested
patients at 5 large academic institutions (overall 12% SLN positive rate).25
The rate of SLN positivity in both prospective study cohorts aligns with the
SLN positivity rate in the general population of melanoma patients who have
undergone SLNB. The results show that in patients from the Medicare-eligible
population (65 years old and over) who were determined to be low-risk by this
test, the concordance of a negative SLNB was 98.4%. These studies showed
improved performance in other patient groups as well.

SLNB positivity rates for T3 tumors with low-risk score for this test is 8.7%.
Importantly, the 5-year melanoma specific survival (MSS) rate for T1/T2 low-
risk group remains favorable; with 99% MSS, comparable to that observed in T1a
tumors and for which current guidelines do not recommend SLNB.2,27
Furthermore, T1/T2 low-risk patients show 5-year overall survival (OS) of 97%
and distant metastasis free survival (DMFS) of 93%.28 The MSLT-II study
demonstrated that a delay in lymph node dissection does not adversely affect
survival, thus clinical follow up of low-risk patients and lymphadenectomy for
those few who develop clinically detectable nodal disease should achieve
similar outcomes to those who currently undergo a planned SLNB.5 Thus, the
test identifies a patient population with <5% likelihood of a positive SLN and
high survival rates and therefore, has utility in guiding SLNB decisions in
patients 65 years-old and over with T1-T2 CM tumors. In this population, the
test could potentially reduce the rate of SLNB by up to 78% while still
maintaining an MSS survival rate of 99% in those patients with low-risk tumor
biology who can safely avoid the procedure.

Clinical validation of this same test as a prognostic test for CM patients was
performed in 3 multicenter, prospectively designed archival tissue studies
including 782 patients.21,22,24 These studies have shown that the test
accurately predicts risk for local/regional recurrence, distant metastasis,
melanoma-related mortality, and all-cause mortality independent of
clinicopathologic factors used in staging and that the test shows improved
sensitivity and negative predictive value (NPV) for recurrence-free (RFS),
distant metastasis-free (DMFS), melanoma-specific (MSS) and overall survival
(OS) individually or in conjunction with established clinicopathologic
factors. A study focused on patients with melanoma of the head and neck (H&N)
demonstrated that patients with H&N melanoma have poorer outcomes and lower
rates of SLN positivity which makes the prognostic value of the SLNB procedure
limited and thus additional prognostic information provided by this test is
important in this group of patients.28 Four prospective, independent studies
(n=510) and an interim analysis of 2 prospective registries (n=322) have
confirmed the prognostic accuracy of the assay.23,29-32 This suggests that the
test may be useful in stratifying risk and patient treatment decisions.

A retrospective study directly compared the ability of DecisionDX Melanoma
with the ability of AJCC melanoma staging to predict longer term outcomes.33
This study looked at 205 archived formalin-fixed, paraffin-embedded primary
melanoma tissue blocks from 6 centers. This included 109 Stage I and 96 Stage
II cancers, and median time to follow-up was 6.9 years. The median time to
recurrence was 1.7 years, and the median time to distant metastasis was 1.6
years. In general, the test scoring alone had greater sensitivity to
recurrence, distant metastasis, and death than AJCC staging. Alternatively,
AJCC staging had greater specificity for these outcomes. The use of this assay
with AJCC staging had a higher sensitivity to these adverse outcomes than
either prognostic measurement alone. Studies have also suggested that
clinicians value and use this test in their medical decision making regarding
aggressiveness of melanoma management.34-36

Recent publications have provided further evaluation of these types of genetic
risk stratification tests. Some studies and meta-analyses evaluating a host of
clinical studies have cast doubt on the utility of gene expression profiles
(GEPs) for risk stratification.37-38 Grossman et al37 described the findings
of the National Melanoma Prevention Working Group, which evaluated 3
prognostic GEP tests. This included a review of online surveys, journal
articles from 2015-2019, and relevant abstracts. One of the findings from the
group was that it was difficult, due to a lack of clinical trial data
reviewed, to clearly separate known clinical pathological factors that are
associated with risk of recurrence/metastases from the GEP findings, stating
that while some such factors were considered, not all such factors were
considered in clinical studies that support GEP use. Additionally, it was
noted that some of the staging used in the favorable studies were not using
current AJCC8 staging criteria. Additionally, Marchetti et al38 performed a
systematic review and meta-analysis of 7 GEP studies, including 5 that
evaluated DecisionDx-Melanoma and 2 studies evaluating MelaGenix. They
evaluated patients in these studies, who were characterized as high-risk or
low-risk, dependent on staging, with recurrence (primary endpoint) or
metastases (secondary endpoint). They determined that among patients with
recurrence, DecisionDx-Melanoma correctly classified 29% of stage I patients
and 82% of stage II as high-risk. Among patients without recurrence, this test
identified 90% of stage I patients and 44% of stage II correctly as low-risk.
The Melagenix test classified 32% of stage I and 76% of stage 2 patients with
recurrence correctly as high-risk; and 77% of stage I and 43% of stage II
patients without recurrence correctly as low-risk. The data evaluating
metastasis as an endpoint was considered poor and not significantly evaluated.

Other studies, including meta-analyses, maintained and strengthened the
evidence for the use of GEP tests. One example is Greenhaw et al42 that
evaluated three studies that met criteria and analyzed raw data for a
systematic review of 1479 patients. This study demonstrated that the Melanoma
DecisionDX test was an independent predictor of both recurrence and distant
metastasis-free survival based on multivariate analysis (including Breslow
thickness, ulceration, age, and SLNB status; with the GEP having the highest
Hazard Ratio of 2.9). The NPV of the GEP test was 92% (90-94% CI) for
recurrence-free survival and 93% (91-95% CI) for distant metastasis-free
survival, both outperforming SLNB. Although sensitivity for RFS and DMFS were
76%, this was superior to SLNB, although these data were not broken down by
patient stage. Specificity for RFS and DMFS was similar to SLNB. Litchman et
al46 evaluated 6 studies and noted high-risk GEP results correlated with
poorer RFS and DMFS, as well as correlated with OS. A recent prospective study
by Hsueh et al43 evaluated the use of DecisionDX Melanoma in 323 patients in
two prospective trials with three years of follow-up (INTEGRATE and EXPAND
registries), and demonstrated that a GEP high risk result was a significant
predictor of RFS, DMFS, and OS in univariate analysis, and was demonstrated to
be an independent predictor of RFS, DMFS, and OS in multivariate analysis,
including AJCC 8th ed. staging (staging was also an independent predictor).
Other studies had similar findings.47 Combining AJCC staging or other
clinicopathological factors and GEP was also found to improve risk
stratification.44,48-49 Other prospective and retrospective studies have
subsequently been performed for GEP testing and demonstrate similar findings.
Of importance, some studies have shown that the use of GEP has reduced some
unnecessary SLNB, although these data are limited.45. It is understood that
comprehensive data are currently being compiled.

For cutaneous melanoma, a well-established set of clinical pathways is
available for patient management, which are heavily based on risk
stratification of patients with higher risk patients being recommended to have
a more intense diagnostic workup or more intensive treatment. While the
consensus guidelines also give specific clinical, pathologic, and imagining
findings that can help to risk stratify a patient, additional evidence
suggests that molecular diagnostic tests can be used to further improve risk
stratification, thereby improving the accuracy of the risk stratification that
is key to deciding on the optimal patient management plan in these clinical
pathways. This is particularly the case for identifying the patients at a
higher risk of adverse outcomes as a result of the melanoma.

Although some recent publications and evidence has cast doubt in the clinical
utility of these tests, it is important to consider these in light of the
intended use of these tests as covered in this policy.37,38 The negative
studies demonstrate disagreement in expert consensus on test use or question
the predictive ability of the tests to accurately identify RFS in a stage
dependent manner; however, other prospective trials and meta-analyses support
the use of GEP testing and evaluate the evidence in univariate and
multivariant analyses including AJCC 8th ed. staging criteria. Despite this,
it is important to note that from a clinical utility perspective, a major of
these GEP tests as described in this policy is to modify management of
patients who have >5% likelihood of a positive SLN to preclude unnecessary
SLNB. The data reviewed suggest not only that GEP tests can better predict SLN
positivity than staging and clinicopathological criteria alone; they may be
more predictive of DFS and DMFS than SLNB and may be even more effective when
combined with clinicopathological factors. The Marchetti et al38 paper did not
evaluate DMFS or SLB positivity because of limited data, and thus did not
directly address the value this payor sees in these tests as a tool to help
reduce the need for unnecessary SLNB in low-risk patients. Based on the
evidence published and reviewed to date, this payor sees evidence that GEP
testing may be used to better risk stratify and manage melanoma patients as
defined in the coverage section of this policy. Specifically, this test has
shown to be able to predict SLN status better than other methodologies, and
thus likely reduce unnecessary SLNB in a low-risk population who would
otherwise have received a SLNB as well as advocate for SLNB in those patients
who may otherwise forgo the procedure based on staging criteria and clinical
factors alone. Admittedly, the data supporting this test is limited and
imperfect; however, the current alternative tools for assessing patient risk
stratification in this population in accepted practice are even more so; with
this policy we leave it to clinicians to use these services to mitigate a
challenging clinical situation and hope that further evidence is developed to
clearly guide melanoma patient management. We await more comprehensive
published and peer-reviewed prospective data that support or refute changes in
patient management based on the use of these or other similar tests.

Since the clinical utility of testing is dependent upon consensus-based
management recommendations based on risk, this coverage decision is subject to
change pending changes in the consensus recommended use of risk strata for
patient management and the accuracy of alternative risk-stratification tools.
This coverage decision will be periodically re-evaluated.