| Coverage Policy Manual | |
| Policy #: | 2018015 |
| Category: | Laboratory |
| Initiated: | May 2018 |
| Last Review: | June 2023 |
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| Genetic Test: Gene Expression Profiling for Cutaneous Melanoma | |
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| Description: |
Cutaneous melanoma accounts for more than 90% of cases of melanoma (Chang, 1998). For many decades, melanoma incidence was rapidly increasing in the United States. However, recent estimates have suggested the rise may be slowing. In 2018, more than 90,000 new cases of melanoma are expected to be diagnosed and more than 9000 people are expected to die of melanoma Siegel, 2018).
Exposure to solar ultraviolet radiation is a major risk factor for melanoma. Most melanomas occur on sun-exposed skin, particularly those areas most susceptible to sunburn. Likewise, features that are associated with an individual’s sensitivity to sunlight, such as light skin pigmentation, red or blond hair, blue or green eyes, freckling tendency, and poor tanning ability are well-known risk factors for melanoma (Gilchrest, 1999; Gandini, 2005). There is also a strong association between high total body nevus counts and melanoma (Caini, 2009).
Several genes appear to contribute to melanoma predisposition such as tumor suppressor gene CDKN2A, melanocortin-1 receptor (MC1R) gene, and BAP1 variants (Goldstein, 2007; Wendt, 2016; Wiesner, 2011). Individuals with either familial or sporadic melanoma have a 2 to 3 times increased risk of developing a subsequent primary melanoma (Chen, 2015). Several occupational exposures and lifestyle factors, such as body mass index and smoking, have been evaluated as possible risk factors for melanoma (Jiang, 2015).
Primary care physicians evaluate suspicious pigmented lesions to determine who should be referred to dermatology. Factors considered include both a patient’s risk for melanoma as well as visual examination of the lesion. The visual examination assesses whether the lesion has features suggestive of melanoma.
Criteria for features suggestive of melanoma have been developed. One checklist is the ABCDE checklist (Abbasi, 2004):
• Asymmetry;
• Border irregularities;
• Color variegation;
• Diameter ≥6 mm;
• Evolution.
Another criteria commonly used is the “ugly duckling” sign (Grob, 1998). An ugly duckling is a nevus that is obviously different from others in a given patient. Primary care physicians generally have a low threshold for referral to dermatology.
Melanoma is difficult to diagnose based on visual examination and the criterion standard for diagnosis is histopathology. There is a low threshold for excisional biopsy of suspicious lesions for histopathologic examination due to the procedure’s ease and low risk as well as the high probability of missing melanoma. However, the yield of biopsy is fairly low. The number of biopsies performed to yield one melanoma diagnosis has been estimated to be about 15 for U.S. dermatologists (Wilson, 2012). Therefore a test that could accurately identify those lesions not needing biopsy (ie, a rule-out test for biopsy) could be clinically useful.
Many treatment and surveillance decisions are determined by a patient’s prognostic stage group based the American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging system (Gershenwald, 2017). The prognostic groups are as follows: stage I, T1a through T2a primary melanomas without evidence of regional or distant metastases; stage II, T2b through T4b primary melanomas without evidence of lymphatic disease or distant metastases; stage III: pathologically documented involvement of regional lymph nodes or in transit or satellite metastases (N1 to N3); stage IV: distant metastases.
Patients may also undergo sentinel lymph node biopsy (SLNB) to gain more definitive information about the status of the regional nodes.
Wide local excision is the definite surgical treatment of melanoma. Following surgery, patients with AJCC stage I or II (node-negative) melanoma do not generally receive adjuvant therapy. Patients with higher risk melanoma receive adjuvant immunotherapy or targeted therapy. Ipilimumab has been shown to prolong recurrence-free survival by approximately 25% compared with placebo at a median of 5.3 years in patients with resected, stage III disease (Eggemont, 2016). Nivolumab has been shown to further prolong survival compared with ipilimumab by approximately 35% at 18 months (Weber, 2017). For patients who are BRAF V600 variant-positive with stage III melanoma, the combination of dabrafenib plus trametinib has been estimated to prolong relapse-free survival by approximately 50% over 3 years (Long, 2017).
Patients with stage I and II disease should undergo an annual routine physical and dermatologic examination. However, follow-up strategies and intervals have not been standardized or tested, and there is no consensus. These patients typically do not receive surveillance imaging. Patients with stage III melanoma may be managed with more frequent follow-up and imaging surveillance following therapy.
REGULATORY STATUS
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The Pigmented Lesion Assay, myPath Melanoma, and DecisionDx-Melanoma tests are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Coding
There are currently no specific codes for these tests. Providers will most likely bill one of the following miscellaneous codes for these types of tests:
81479: Unlisted molecular pathology procedure
81599: Unlisted multianalyte assay with algorithmic analysis
84999: Unlisted chemistry procedure
There was no specific code for this testing prior to 1/1/2021. CPT code 81529 [Oncology (cutaneous melanoma), mRNA, gene expression profiling by real time RT PCR of 31 genes (28 content and 3 housekeeping), utilizing formalin fixed paraffin embedded tissue, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis] was added effective 1/1/2021.
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Policy/ Coverage: |
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Gene expression testing in the evaluation of patients with suspicious pigmented lesions does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, gene expression testing in the evaluation of patients with suspicious pigmented lesions is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Gene expression testing in the evaluation of patients with melanocytic lesions with indeterminate histopathologic features does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, gene expression testing in the evaluation of patients with melanocytic lesions with indeterminate histopathologic features is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Gene expression testing in the evaluation of patients with cutaneous melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, gene expression testing in the evaluation of patients with cutaneous melanoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Gene expression testing using the myPath Melanoma or the DecisionDx-Melanoma in any other circumstances does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, gene expression testing using the myPath Melanoma or the DecisionDx-Melanoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Gene Expression Profiling To Guide Initial Biopsy Decisions
Clinical Context and Test Purpose
The purpose of gene expression profiling in patients who have suspicious pigmented lesions being considered for biopsy is to inform a decision about whether to biopsy.
The question addressed in this section of the evidence review is: Does gene expression profiling (GEP) improve the net health outcome in individuals with suspicious pigmented lesions?
The following PICOTS were used to select literature to inform review.
Patients
The relevant population of interest is patients with suspicious pigmented lesions being considered for referral for biopsy, specifically those lesions meeting one or more ABCDE criteria.
Interventions
The test being considered is the DermTech Pigmented Lesion Assay (PLA). The PLA test measures expression of 6 genes (PRAME, LINC00518, CMIP, B2M, ACTB, PPIA). The PRAME (PReferentially expressed Antigen in MElanoma) gene encodes an antigen that is preferentially expressed in human melanomas and that is not expressed in normal tissues (except testis) (NCBI, 2018). LINC00518 (Long Intergenic Non-protein Coding RNA518) is a regulatory RNA molecule. The other 4 genes provide normalization values (DermTech, 2015).The feasibility of a test like PLA was first described in Wachsman et al and Gerami et al (Wachsman, 2011; Gerami, 2014). and development of the specific PLA test was described in Gerami et al (Gerami,2017).
The test is performed on skin samples of lesions at least 5 mm in diameter obtained via noninvasive, proprietary adhesive patch biopsies of a stratum corneum specimen. The test does not work on the palms of hands, soles of feet, nails, or mucous membranes, and it should not be used on bleeding or ulcerated lesions (DermTech, 2015).
The PLA test report includes 2 results. The first result is called the PLA MAGE (Melanoma Associated Gene Expression), which indicates low risk (neither PRAME nor LINC00518 expression was detected), moderate risk (expression of either PRAME or LINC00518 was detected), or high risk (expression of both PRAME and LINC00518 was detected). The second result is as an algorithmic PLA score that ranges from 0 to 100, with higher scores indicating higher suspicion of malignant disease (DermTech, 2015). It is not clear whether the PLA test is meant to be used as a replacement, triage, or add-on test with respect to dermoscopy. The PLA sample report states that for low-risk lesions, physicians should “consider surveillance”, while for moderate- and high-risk lesions, physicians should “recommend biopsy”. It does not state whether lesions with negative results should be further evaluated with dermoscopy or other techniques to confirm the lesion should not be biopsied. Therefore, this evidence review evaluates the test as a replacement for dermoscopy. As mentioned previously, there is a low threshold for biopsy of suspicious lesions. As such, tests that can rule-out need for biopsy could be useful and thus sensitivity and negative predictive value are the performance characteristics of most interest.
Comparators
After referral from primary care to dermatology settings, dermatologists use visual examination as well as tools such as dermoscopy to make decisions regarding biopsy of suspicious lesions. A meta-analysis of 9 studies (8487 lesions with 375 melanomas) compared dermoscopy with visual examination alone for the diagnosis of melanoma; it reported that, for clinicians with training in dermoscopy, adding dermoscopy to visual examination increased the sensitivity from 71% to 90%. The specificity numerically increased from 80% to 90% but the difference was not statistically significant (Vestergaard, 2008). Although dermoscopy is noninvasive and may aid in decision making regarding biopsy, it is only used by approximately 50% to 80% of dermatologists in the United States due to lack of training, interest, or time required for the examination (Murzaku, 2014; Engasser, 2010).
The reference standard for diagnosis of melanoma is histopathology.
Outcomes
The beneficial outcomes of a true positive test result are appropriate biopsy and diagnosis of melanoma. The beneficial outcome of a true negative test result is potentially avoiding unnecessary biopsy.
The harmful outcome of a false-positive result is having an unnecessary biopsy. The harmful outcome of a false-negative result is potential delay in diagnosis and treatment.
Timing
The timeframe of interest for calculating performance characteristics is time to biopsy result. Patients who forgo biopsy based on test results could miss or delay diagnosis of cancer. Longer follow-up would be necessary to determine the effects on overall survival.
Setting
Initial identification of potentially cancerous lesions frequently occurs in primary care but may also occur in dermatology. Patients with lesions thought to be suspicious in primary care are frequently referred to dermatology when feasible and decisions regarding biopsy are usually made by dermatologists.
Simplifying Test Terms
There are 3 core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:
• Technically reliable
• Clinically valid
• Clinically useful.
Because different specialties may use different terms for the same concept, we are highlighting the core characteristics. The core characteristics also apply to different uses of tests, such as diagnosis, prognosis, and monitoring treatment.
Diagnostic tests detect presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.
Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or to predicting a response to therapy.
Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.
Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Determining whether a test can guide biopsy decisions is not based only on its sensitivity and specificity, but also on how the accuracy of the existing pathway for making biopsy decisions is changed by test. Therefore, the appropriate design for evaluating performance characteristics depends on the role of the new test in the pathway for making biopsy decision. New tests may be used as replacements for existing tests, to triage who proceeds for existing tests or for add-on tests after existing tests. For replacement tests, the diagnostic accuracy of both tests should be concurrently compared, preferably in a paired design (ie, patients receive both tests), and all patients receive the reference standard. For a triage test, a paired design is also needed, with the reference standard being performed preferably on all patients but at least for all discordant results. For an add-on test, the included patients can be limited to those who were negative after existing tests with verification of the reference standard in patients who are positive on the new test (Bossuyt, 2006).
Study Selection Criteria
For the evaluation of clinical validity of the PLA test, studies that meet the following eligibility criteria were considered:
• Reported on a validation cohort that was independent of the development cohort;
• Reported on the accuracy of the marketed version of the technology;
• Included a suitable reference standard (histopathology);
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described.
Studies were excluded from the evaluation of the clinical validity of the PLA test because they reported results of the development cohort,21 they did not use the marketed version of the test (Gerami, 2014; Gerami, 2017), did not adequately describe the patient characteristics,27 or did not adequately describe patient selection criteria (Ferris, 2017).
The validation cohort from the Gerami et al publication was included (Gerami, 2017). The report stated that included lesions were selected by dermatologists experienced in pigmented lesion management from 28 sites in the United States, Europe, and Australia; therefore, the samples were likely not consecutive or random. Information regarding previous testing was not provided. The flow of potential and included samples was not clear and whether the samples were all independent or multiple samples from the same patient was not described. Diagnosis of melanoma was based on consensus among a primary reader and 3 expert dermatopathologists. The report did not state whether the histopathologic diagnosis was blinded to the results of the PLA test, but did state the diagnosis was “routinely” assessed. Interpretation of the PLA result does not depend on a reader so it is blinded to histopathologic results. In 11% of cases originally selected, a consensus diagnosis was not reached, and these samples were not included in the training or validation cohorts. Dates of data collection were not reported. Sex and anatomic location of biopsy were reported but other clinical characteristics (eg, risk factors for melanoma, presenting symptoms) were not. The study training cohort included 157 samples with 80 melanomas and 77 non-melanomas. The study validation cohort included 398 samples with 87 melanomas and 311 non-melanomas.
PLA Clinical Validity
Multiple high-quality studies are needed to establish the clinical validity of a test. The PLA test has one clinical validity study with many methodologic and reporting limitations. Therefore, performance characteristics are not well characterized. In addition, the test has not been compared with dermoscopy, another tool frequently used to make biopsy decisions.
Clinically Useful
A test is clinically useful if the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.
No direct evidence of clinical utility was identified.
Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility through a chain of evidence.
A decision-impact study by Ferris et al assessed the potential impact of PLA on physicians’ biopsy decisions in patients (Ferris, 2017). Forty-five dermatologists evaluated 60 clinical and dermoscopic images of atypical pigmented lesions (8 melanoma, 52 nonmelanoma). In the first round, dermatologists did not have PLA test results and, in the second round, dermatologists had access to PLA test results with the order of cases being scrambled. The dermatologists were asked whether the lesions should be biopsied after each round. Therefore, the corresponding number of biopsy decisions should be 45×60×2=5400. Data were collected in 2014 and 2015. Results were reported for 4680 decisions with no description of the disposition of the remaining decisions. Of the 4680 reported decisions, 750 correct biopsy decisions were made without PLA results while 1331 were made with PLA results and 1590 incorrect biopsy decisions were made without PLA results while 1009 incorrect biopsy decisions were made with PLA results.
Clinically Useful
There is no direct evidence of clinical utility. A chain of evidence for clinical utility cannot be constructed due to lack of robust evidence of clinical validity.
GEP For Diagnosing Melanoma With Indeterminate Histopathology
Clinical Context and Test Purpose
The purpose of GEP in patients whose melanocytic lesion is indeterminate after histopathology is to aid in diagnosis of melanoma and decisions regarding treatment and surveillance.
The question addressed in this section of the evidence review is: Does GEP improve the net health outcome in individuals with indeterminate melanocytic lesions?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant population of interest is patients whose melanocytic lesion is indeterminate based on clinical and histopathologic features.
Interventions
The test being considered is the Myriad myPath Melanoma test. The myPath test measures expression of 23 genes using quantitative reverse-transcription polymerase chain reaction. Fourteen genes are involved in melanoma pathogenesis and are grouped into 3 components related to cell differentiation, cell signaling, and the immune response, and 9 housekeeper genes are also included. The test is performed on 5 standard tissue sections from an existing formalin-fixed, paraffin-embedded biopsy specimen
The myPath test report includes an algorithmic myPath score ranging from -16.7 to 11.1, with higher, positive scores indicating higher suspicion of malignant disease (Myriad, 2018). The myPath report also classifies these scores: -16.7 to -2.1 are “benign”; -2.0 to -0.1 are “indeterminate”; and 0.0 to +11.1 are “malignant”. Development of the test has been described by Clarke et al (Clarke, 2015).
The myPath test is meant as an add-on test to standard histopathology. No recommendations for treatment or surveillance are given on the report.
Comparators
The reference standard for diagnosis of melanoma is histopathology. However, in cases of indeterminate histopathology, long-term follow-up is needed to determine the final clinical diagnosis.
Fluorescence in situ hybridization (FISH) has been evaluated as a tool to aid in the diagnosis of lesions that are indeterminate following histopathology in 2 studies that included histologically ambiguous lesions and a clinical long-term follow-up to establish diagnosis. One study reported by Gaiser et al included 22 melanocytic lesions (12 indeterminate) followed for a mean of 65 months (range, 10-156 months) and reported a FISH sensitivity of 60% and a specificity of 50% for development of metastases during follow-up (Gaiser, 2010). A second study, reported by Vergier et al, included 90 indeterminate melanocytic lesions of which 69 had no recurrence for at least 5 years of follow-up (mean, 9 years; range, 5-19 years) and 21 lesions that exhibited metastases. The sensitivity and specificity rates of the histopathologic review combined with FISH for the clinical outcome were 76% and 90%, respectively (Vergier, 2011).
Outcomes
The beneficial outcomes of a true positive test result are a diagnosis of melanoma and corresponding appropriate treatment and surveillance. The beneficial outcome of a true negative test result is avoiding unnecessary surgery.
The harmful outcome of a false-positive result is having an unnecessary surgery and surveillance. The harmful outcome of a false-negative result is delay in diagnosis and treatment.
Timing
Recurrence and metastases can occur may years after treatment of melanoma. In the 2 studies evaluating long-term outcomes of FISH (described above), the mean follow-up was approximately 5.5 and 9 years.30,31 In Vergier et al, metastases in the FISH-negative group occurred by 5 years (Vergier, 2011). For this section of the review, at least 5 years of event-free follow-up is required to confirm negative tests.
Setting
Follow-up of melanocytic lesions that are indeterminate after histopathology is generally done in dermatology.
Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.
Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).
Study Selection Criteria
For the evaluation of clinical validity of the myPath test, studies that meet the following eligibility criteria were considered:
• Reported on a validation cohort that was independent of the development cohort;
• Reported on the accuracy of the marketed version of the technology;
• Included a suitable reference standard (final clinical diagnosis with at least 5 years of follow-up for
negatives);
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described.
Studies were excluded from the evaluation of the clinical validity of the myPath test because authors did not use an appropriate reference standard (Clarke, 2015; Gaiser, 2010), or did not adequately describe patient characteristics (Clarke, 2015).
In the clinical validity study by Ko et al, archived melanocytic neoplasms were submitted for myPath testing from university clinics in the United States and United Kingdom with additional samples acquired from Avaden BioSciences (Ko, 2017). Stage I, II, and III primary cutaneous melanomas that produced distant metastases subsequent to the diagnosis and benign lesions with clinical follow-up and no evidence of recurrence of metastases were included. For benign samples, a disease-free time of at least 5 years was recommended. Information on previous testing was not provided. It is not clear if any of the samples originally had indeterminate histopathology results. Dates of data collection were not reported. Sex, age, Breslow depth, and anatomic location were described; presenting symptoms were not reported. A total of 293 samples were submitted; of these 53 did not meet inclusion criteria and 58 (24% of those tested) failed to produce a valid test score. An additional 7 samples with indeterminate results were excluded from the calculations of performance characteristics.
Clinically Valid
Multiple high-quality studies are needed to establish the clinical validity of a test. The myPath test has 1 clinical validity study including long-term follow-up to establish the clinical diagnosis as the reference standard. However, it is not clear whether the study population included lesions that were indeterminate following histopathology and the study had other methodologic and reporting limitations. Therefore, performance characteristics are not well characterized. In addition, the test has not been compared with comparative genomic hybridization and FISH, other tools frequently used along with histopathology to confirm diagnosis in challenging cases.
Clinically Useful
A test is clinically useful if the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.
No direct evidence of clinical utility was identified.
Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
Two decision-impact studies assessed the potential impact of myPath on physicians’ treatment decisions in patients with diagnostically challenging lesions.34,35 Given the lack of established clinical validity and no reported long-term outcomes, it is not known whether any treatment changes were clinically appropriate.
Clinically Useful
There is no direct evidence of clinical utility. A chain of evidence for clinical utility cannot be constructed due to lack of robust evidence of clinical validity.
GEP To Guide Decisions Regarding Sentinel Lymph Node Biopsy In Melanoma
Clinical Context and Test Purpose
The purpose of GEP in patients with melanoma is to identify high-risk patients classified as stage I or II according to the AJCC criteria. Current guidelines do not recommend adjuvant therapy or imaging surveillance for AJCC stage I or II patients following surgery. Patients initially staged as I or II who have positive lymph nodes following sentinel lymph node biopsy (SLNB) are then treated with adjuvant therapy as stage III patients (NCCN,2018).
The management decision to be made based on this test is not clear. The manufacturer’s website indicates that physicians can use DecisionDx-Melanoma information to “consider upstaging” patients for “active systemic surveillance or referral to medical oncology for consideration of systemic drug therapy or clinical trials (Castle Biosciences, 2018).” Similarly, in 1 clinical validity study (described below), the authors stated that “high-risk patients with stage I and II disease may benefit from adjuvant therapy and/or enhanced imaging protocols to allow for early detection of metastasis (Gerami, 2015).” In another clinical validity study, the authors concluded that the test’s “role in consideration of patients for adjuvant therapy should be examined prospectively (Zager, 2018).” However, the manufacturer has also suggested that the test can be used to select patients at low risk of being lymph node positive who can avoid a SLNB (ie, a triage test for SLNB).
The question addressed in this section of the evidence review is: Does GEP improve the net health outcome in individuals with AJCC stage I or II melanoma?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant population of interest is patients with AJCC stage I or II cutaneous melanoma who are being considered for sentinel lymph node biopsy.
Interventions
The test being considered is the Castle Biosciences DecisionDx-Melanoma test. The DecisionDx test measures expression of 31 genes using quantitative reverse-transcription polymerase chain reaction. The test includes 28 prognostic gene targets and 3 endogenous control genes. The test is performed on standard tissue sections from an existing formalin-fixed, paraffin-embedded biopsy or wide local excision specimen.
Development of the test was described in Gerami et al (Gerami, 2015). To develop the DecisionDx-Melanoma gene panel, Gerami et al conducted a meta-analysis of published studies that identified differential gene expression in metastatic vs nonmetastatic primary cutaneous melanoma. Of 54 identified genes, investigators selected 20 for further polymerase chain reaction analysis based on chromosomal location. Five genes from Castle Biosciences’ DecisionDx-UM gene panel were added based on analysis of metastatic and nonmetastatic primary cutaneous melanoma, and 2 probes of the BRCA1-associated protein 1 gene, BAP1, which has been associated with the metastatic potential of uveal melanoma, also were added. Finally, 4 genes with minimal variation in expression level between metastatic and nonmetastatic primary cutaneous melanoma were added as controls. Patients had a minimum follow-up of 5 years unless there was a well-documented metastatic event, including positive SLNB. Information about treatments received was not provided.
The DecisionDx test report provides 2 results: a class and a probability score. The class stratifies tumors as low risk (class 1) or high risk (class 2), with subclassifications within each class (A or B) based on how close the probability score is to the threshold between class 1 and class 2. The probability score ranges from 0 to 1 and appears to be the risk of recurrence within 5 years.
DecisionDx is meant to be used as a triage test with respect to SLNB. However, the sample report makes no recommendations for SLNB, treatment, or surveillance based on test results.
Comparators
Treatment and surveillance recommendations are based on AJCC staging. SLNB may be used to get more definitive information about the status of the regional nodes compared with physical examination. The American Society of Clinical Oncology (Wong, 2012) and National Comprehensive Cancer Network36 have similar but not identical recommendations on which patients should undergo SLNB (patients with thickness more than approximately 1 mm or thin melanomas with other high risk features). SLNB has a low rate of complications; in the Sunbelt Melanoma Trial, a prospective multi-institutional study of SLNB for melanoma reported by Wrightson et al, less than 5% of the 2120 patients developed major or minor complications associated with SLNB (Wrightson, 2003).
Online tools are available to predict prognosis based on the AJCC guidelines. The original AJCC tool was developed by Soong et al (n.d.) (Soong, 2018). Callender et al (2012) incorporated SLNB results into a revised tool (http://www.melanomacalculator.com/) (Callender, 2012).
Outcomes
For patients meeting guideline recommended criteria for SLNB, a positive DecisionDx (class 2) test result would not change outcomes. The patients would proceed to SLNB, as they would have without the DecisionDx test, and treatment and imaging decisions would depend on SLNB results. A negative DecisionDx (class 1) test result would indicate that a patient could avoid a SLNB. Therefore, the potential
beneficial outcomes of a negative result are avoidance of a SLNB. The potential harmful outcomes of a negative result are reduced time to recurrence due to not identifying node-positive patients that would be eligible for beneficial adjuvant treatment.
Timing
The risk of recurrence decreases over time but does not reach zero. In a study of 1568 patients with stage I melanoma, Dicker et al (1999) found that 80% of the recurrences occurred within the first 3 years (Dicker, 1999). A prospective study by Garbe et al (2003) reported that, for stage I and II patients, the risk of recurrence was low after 4.4 years (Garbe, 2003). Among 4731 patients treated for more than 10 years at 1 institution, Faries et al found the majority of recurrences occurred in the first 5 years (Faries, 2013). However, 7% of patients experienced recurrence after 10 years (median, 16 years). Even among stage I/II patients, recurrence after 10 years occurred in 2% of patients.
Five-year recurrence-free survival (RFS) is the outcome and time-point of interest.
Setting
Follow-up of patients with stage I and II melanoma is generally done in secondary care.
Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.
Clinically Valid
Study Selection Criteria
For the evaluation of clinical validity of the DecisionDx test, studies that meet the following eligibility criteria were considered:
• Reported on a validation cohort that was independent of the development cohort;
• Reported on the accuracy of the marketed version of the technology;
• Included a suitable reference standard (5-year RFS);
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described.
Hsueh et al was excluded from the evaluation of the clinical validity of the DecisionDx test because it did not report 5-year outcomes (median follow-up, 1.5 years) (Hsueh, 2017). Samples used in Gerami et al and Ferris et al appear to overlap with the samples from Gerami et al and each other and will not be considered independent validation studies (Ferris, 2017; Gerami, 2015).
Two independent clinical validity studies meeting eligibility criteria have been conducted. Characteristics and results are summarized briefly in the paragraphs that follow.
The validation cohort in Gerami et al (2015) included patients with stage 0, I, II, III, or IV disease from 6 U.S. centers (N=104) (Gerami, 2015). A complete disposition of samples received from the institutions and those included in analysis was not provided. For 78 patients in the validation cohort with AJCC stage I or II cutaneous melanoma who had either a metastatic event or had more than 5 years of follow-up without metastasis, 5-year disease-free survival was 98% (CIs not reported) for class I patients and 37% for class II patients; PPV and NPV were 67% and 94%, respectively.
Zager et al reported results of a second clinical validity study including AJCC stage I, II, or III primary melanoma tumors from 16 U.S. sites (Zager, 2018). The samples were independent of the other validation studies. Of the 601 cases submitted from the institutions, 523 were included in analysis (357 stage I/II). The excluded samples did not meet pre- and postanalytic quality control thresholds. SLN status was untested in 36% of the patients, negative in 34%, and positive in 30%. The report did not describe any adjuvant therapy that the patients received. Overall, 42 (13%) recurrence events occurred in DecisionDx class 1 patients and 100 (48%) recurrence events occurred in DecisionDx class 2 patients. The 5-year RFS estimated by Kaplan-Meier was 88% (95% CI, 85% to 92%) in class 1 and 52% (95% CI, 46% to 60%) in class 2. The reported sensitivity and specificity were 70% (95% CI, 62% to 78%) and 71% (95% CI, 67% to 76%), respectively, with a positive predictive value (PPV) of 48% (95% CI, 41% to 55%) and a negative predictive value (NPV) of 87% (95% CI, 82% to 90%). For comparison, the performance characteristics for 5-year RFS for sentinel lymph node status among those with SLNB were: sensitivity, 66% (95% CI, 57% to 74%); specificity, 65% (95% CI, 58% to 71%); PPV, 52% (95% CI, 44% to 60%); and NPV, 76% (95% CI, 69% to 82%). If DecisionDx were used as a triage test such that only class 2 received SLNB, then 159 class 1 patients would not have undergone SLNB. Of the 159 patients in class 1, 56 were SLNB positive and were therefore eligible for adjuvant therapy. It is not clear if the SLNB-positive patients in this study received adjuvant therapy. Of the 56 patients who were DecisionDx class 1 and SLNB-positive, 22 recurrence events occurred by 5 years.
In a subsequent analysis of patients with melanoma who had undergone SLNB, Gerami et al compared prognostic classification by DecisionDx-Melanoma with biopsy results (Gerami, 2015). A total of 217 patients comprised a convenience sample from a database of 406 patients previously tested with DecisionDx-Melanoma. Patients who had undergone SLNB appear to overlap with patients in Gerami et al (Gerami, 2015) discussed previously. Most (73%) patients had a negative SLNB, and 27% had a positive SLNB. DecisionDx-Melanoma classified 76 (35%) tumors as low risk (class I) and 141 (65%) tumors as high risk (class II). Within the group of SLNB-negative patients, the 5-year overall survival rate was 91% in class I patients and 55% in class II patients. Within the group of SLNB-positive patients, the 5-year overall survival rate was 77% in class I patients and 57% in class II patients.
Ferris et al compared the accuracy of DecisionDx-Melanoma with the web-based AJCC Individualized Melanoma Patient Outcome Prediction Tool (Ferris, 2017). The study included 205 patients who appear to overlap with the patients in the second Gerami et al study described above. AJCC-predicted 5-year survival for each patient was categorized into low and high risk based on both a 68% predicted 5-year survival and a 79% predicted 5-year survival. The 68% and 79% cutpoints were reported to correspond to 5-year survival in patients with stage IIA and IIB, respectively, although it is unclear whether those cutpoints were prespecified, whether they were based on internal or external estimates of risk, or whether they are commonly used in practice. The prognostic sensitivity and specificity for death (median follow-up, 7 years) of the Decision-Dx Melanoma were 78% and 69%, respectively (CIs not reported). The sensitivity and specificity for the AJCC calculator with the 79% cutpoint were 60% and 74%, respectively. The combination of the DecisionDx-Melanoma and AJCC tools had a sensitivity of 82% and specificity of 62%.
Clinically Valid
To use prognostic information for decision-making, performance characteristics should be consistent and precise. Two independent studies, using archived tumor specimens, have reported 5-year RFS in AJCC stage I or II patients. Gerami et al reported RFS rates of 98% in DecisionDx class 1 (low risk) without CIs in AJCC stage I or II patients (Gerami, 2015). Zager et al reported RFS rates of 96% (95% CI, 94% to 99%) for DecisionDx class 1 in patients with AJCC stage I disease and RFS rates of 74% (95% CI, 60% to 91%) for DecisionDx class 1 n patients with AJCC stage II disease (Zager, 2018). Although confidence intervals were not available for the first study, RFS does not appear to be well-characterized in the DecisionDx low-risk group as evidenced by the variation in estimates across studies. Zager et al also reported that 56 of 159 (35%) patients who were DecisionDx class 1 (low risk) were SLNB-positive and in those patients 22 recurrences (39%) occurred over 5 years (Zager, 2018). If the DecisionDx test were used as a triage for SLNB, these patients would not undergo SLNB and would likely not receive adjuvant therapy, which has shown to be effective at prolonging time to recurrence in node positive patients.
Clinical Useful
A test is clinically useful if the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.
Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.
No direct evidence of clinical utility was identified.
Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.
Four decision-impact studies have been published reporting on the impact of DecisionDx on physicians’ management decisions ( Berger, 2016; Farberg, 2017; Schuitevoerder, 2018; Dillon, 2018). Given the lack of established clinical validity and no reported long-term outcomes, it is not known whether any management changes were clinically appropriate.
Clinically Useful
There is no direct evidence of clinical utility. A chain of evidence for clinical utility cannot be created due to lack of robust evidence of clinical validity and lack of evidence-based management pathway.
SUMMARY OF EVIDENCE
For individuals with suspicious pigmented lesions (based on ABCDE and/or ugly duckling criteria) being considered for biopsy who receive gene expression profiling with the DermTech Pigmented Lesion Assay to determine which lesions should proceed to biopsy, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and resource utilization. The Pigmented Lesion Assay has 1 clinical validity study with many methodologic and reporting limitations. Therefore, performance characteristics are not well characterized. In addition, the test has not been compared with dermoscopy, another tool frequently used to make biopsy decisions. No direct evidence of clinical utility was identified. Given that the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility through a chain of evidence. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have melanocytic lesions with indeterminate histopathologic features who receive gene expression profiling with the myPath Melanoma test added to histopathology to aid in diagnosis of melanoma, the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, change in disease status, treatment-related morbidity. The myPath test has 1 clinical validity study, which includes long-term follow-up to establish the clinical diagnosis as the reference standard. However, it is not clear if the study population included lesions that were indeterminate following histopathology and the study had other methodologic and reporting limitations. Therefore, performance characteristics are not well characterized. No direct evidence of clinical utility was identified. Given that the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility through a chain of evidence. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals with American Joint Committee on Cancer (AJCC) stage I or II cutaneous melanoma who receive gene expression profiling with the DecisionDx-Melanoma test to determine whether to perform sentinel lymph node biopsy (SLNB), the evidence includes observational studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, change in disease status, resource utilization and treatment-related morbidity. The DecisionDx-Melanoma test has 2 independent clinical validity studies that have reported 5-year recurrence-free survival (RFS) in AJCC stage I or II patients. Gerami et al reported RFS rates of 98% in DecisionDx class 1 (low risk) without confidence intervals (CIs), in AJCC stage I or II patients. Zager et al reported RFS rates of 96% (95% CI, 94% to 99%) for DecisionDx class 1 in patients with AJCC stage I disease; they also reported RFS rates of 74% (95% CI, 60% to 91%) for DecisionDx class 1 in patients with AJCC stage II disease. Although CIs were not available for the first study, RFS does not appear to be well-characterized as evidenced by the
variation in estimates across studies. Zager et al also reported that, in 56 patients who were DecisionDx class 1 (low risk) but SLNB-positive, 22 recurrences (39%) occurred over 5 years. If the DecisionDx test were used as a triage for SLNB, these patients would not undergo SLNB and would likely not receive adjuvant therapy, which has shown to be effective at prolonging time to recurrence in node-positive patients. No direct evidence of clinical utility was identified. Given that the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility through a chain of evidence. There is also not a clearly explicated, evidence-based management pathway for use of the test. The evidence is insufficient to determine the effects of the technology on health outcomes.
PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) guidelines (v.2.2018) for melanoma made the following statements on use of gene expression profiling (NCCN, 2018). “While there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate primary cutaneous melanomas (before or following sentinel lymph node biopsy) is not recommended outside of a clinical study (trial).”
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below.
NCT02355574a An Ongoing, 5-year Post Market Study to Track Clinical Application of DecisionDx-Melanoma Gene
Expression Profile (GEP) Assay Results and the Impact on Patient Outcomes and Health Economics
Planned Enrollment: 1672
Expected Completion Date: Jun 2024
NCT02355587a An Open, 5-year Registry Study to Track Clinical Application of DecisionDx-Melanoma Gene
Expression Profile Assay Results and Associated Patient Outcomes
Planned Enrollment: 5000
Expected Completion Date: Feb 2024
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
GEP to Guide Management Decisions
Greenhaw et al reported results of an independent study of the DecisionDx test using their institution’s melanoma registry and including patients who had been treated for cutaneous melanoma within the last 5 years and undergone DecisionDx testing (Greenhaw, 2018). Two-hundred fifty-six patients were tested; 84% were categorized as DecisionDx class 1 (low risk) and 16% were DecisionDx class 2 (high risk). 219 (86%) of tumors were AJCC stage I and 37 (14%) were AJCC stage II. None of the 18 stage I/class 2 tumors metastasized but 1 (0.5%) of 201 stage I/class 1 tumors metastasized. Ten (42%) of the stage II/class 2 tumors metastasized and 2 (15%) of the 13 stage II/class 1 tumors metastasized.
Practice Guidelines and Position Statements
National Comprehensive Cancer Network
The National Comprehensive Cancer Network guidelines (v.2.2019) for melanoma made the following statements on use of gene expression profiling (NCCN, 2019), “While there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate primary cutaneous melanomas at low versus high risk for metastasis, routine (baseline) prognostic genetic testing of primary cutaneous melanoma (before or following sentinel lymph node biopsy) is not recommended outside of a clinical study (trial).”
The guidelines state the following regarding diagnostic testing for indeterminate melanocytic neoplasms following histopathology: "They may be used on a case-by-case basis in ambiguous melanocytic tumors; however, their utility is still under evaluation, and more data are needed before they can be routinely recommended." Specifically regarding the GEP test, the guidelines state that '... long-term follow-up is required to validate the prognostic significance of this test'.
The guidelines state the following regarding prognostic testing: "Commercially available GEP tests are marketed as being able to classify cutaneous melanoma into separate categories based on metastasis. However, it remains unclear whether these tests provide clinically actionable prognostic information when used in addition to or in comparison with known clinicopathologic factors or multivariable nomgrams that incorporate patient sex, age, tumor location and thickness, ulceration, mitotic rate, lymphovascular invasion, microsatellites, and SLNB status. Furthermore, the impact of these tests on treatment outcomes or follow-up schedules has not been established.
American Academy of Dermatology
The American Academy of Dermatology (AAD) published guidelines of care for the management of primary cutaneous melanoma in 2019 (AAD, 2019). The guidelines state the following regarding GEP tests:
"Going forward, GEP assays should be tested against all known histopathologic prognostic factors and contemporary eighth edition of AJCC CM staging to assess their additive value in prognostication."
2020 Update
A literature search was conducted through May 2020. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
American Academy of Dermatology
In 2019, the American Academy of Dermatology published guidelines of care for the management of primary cutaneous melanoma (AAD, 2019). The guidelines state the following regarding GEP tests:
National Society for Cutaneous Medicine
In 2019, the National Society for Cutaneous Medicine published appropriate use criteria for the integration of diagnostic and prognostic gene expression profile assays for management of cutaneous melanoma (NSCM, 2019). The criteria were developed with "unrestricted educational grants from related companies involved with these technologies". The majority of the panel members were consultants or advisors for Castle BioSciences or Myriad. The criteria were consensus-based using a modified Delphi approach. Numerous recommendations were made for each of the tests reviewed here. Some of the recommendations are as follows:
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Five decision-impact studies have been published reporting on the impact of DecisionDx on physicians’ management decisions (Berger, 2016; Farberg, 2017; Schuitevoerder, 2018; Dillon, 2018; Hyams, 2021). Given the lack of established clinical validity and no reported long-term outcomes of the test used to select patients for active surveillance, it is not known whether any management changes were clinically appropriate.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In a retrospective study using archived samples from a previous validation study, Clarke et al evaluated the performance of myPath in a population of diagnostically uncertain melanocytic neoplasms as compared with clinical outcomes (Clarke, 2020). Diagnostic uncertainty was defined as at least 1 dermatopathologist: selecting indeterminate as the diagnosis; selecting a diagnosis that was discordant with other dermatopathologists; indicating a need for additional diagnostic workup, or indicating a preference for peer consultation before rendering a final diagnosis. Participating institutions were encouraged to submit lesions with at least 5 years of metastasis-free follow-up, but the length of follow-up was not an inclusion criterion. The median follow-up time for benign lesions was 74.9 months (interquartile range [IQR]: 57.9 to 114.7) and 69% (57/83) of cases had a follow-up of at least 5 years. The median time to metastasis for the malignant cases was 17 months (IQR:10.3 to 37.6).
Six decision-impact studies have been published reporting on the impact of DecisionDx on physicians’ management decisions (Berger, 2016; Farberg, 2017; Schuitevoerder, 2018; Dillon, 2018; Hyams, 2021; Dillon, 2022). Given the lack of established clinical validity and no reported long-term outcomes of the test used to select patients for active surveillance, it is not known whether any management changes were clinically appropriate.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.
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