| Coverage Policy Manual | |
| Policy #: | 2004043 |
| Category: | Laboratory |
| Initiated: | July 2004 |
| Last Review: | April 2024 |
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| Genetic Test: Melanoma, Hereditary | |
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| Description: |
A genetic predisposition to cutaneous malignant melanoma is suspected in specific clinical situations: 1) melanoma has been diagnosed in multiple family members; 2) multiple primary melanomas are identified in a single patient; and 3) when there is an early age of onset. A positive family history of melanoma is the most significant risk factor; it is estimated that approximately 10% of melanoma cases report a first- or second-degree relative with melanoma. While some of the familial risk may be related to shared environmental factors, 3 main genes involved in cutaneous malignant melanoma susceptibility have now been identified. CDKN2A, located on chromosome 9p21 encodes proteins that act as tumor suppressors. Mutations at this site can alter the tumor suppressor function. The second gene, CDK4, is an oncogene located on chromosome 12q13, and has been identified in about 6 families worldwide. A third gene, not fully characterized, maps to chromosome 1p22.
The incidence of CDKN2A mutations in the general population is very low. For example, it is estimated that in Queensland, Australia, an area with a high incidence of melanoma, only 0.2% of all patients with melanoma will harbor a CDKN2A mutation. Mutations are also infrequent in those with an early age of onset or those with multiple primary melanomas (Hayward 2003). However, the incidence of CDKN2A mutations increases with a positive family history; CDKN2A mutations will be found in 5% of families with first-degree relatives, rising to 20%–40% in kindreds with 3 or more affected first-degree relatives (Kefford et al, 1999). Mutation detection rates in the CDK2NA gene is generally estimated as 20%–25% in hereditary CMM but can vary between 2% and 50% depending on the family history and population studied. Validated clinical risk prediction tools to assess the probability that an affected individual carries a germline CDKN2A disease-associated variant are available (Niendorf, 2006; Wang, 2010).
Familial cutaneous malignant melanoma (CMM) has been described in families in which either 2 first-degree relatives are diagnosed with melanoma or a family with 3 melanoma patients irrespective of the degree of relationship. (de Snoo et al, 2003). Others have defined familial CMM as having at least 3 (first-, second- or third-degree) affected members, or 2 affected family members in which at least 1 was diagnosed before age 50 years or pancreatic cancer occurred in a first- or second-degree relative, or 1 member had multiple primary melanomas (Casula et al, 2007).
Other malignancies associated with familial CMM, specifically those associated with CDKN2A variants, have been described. The most pronounced associated malignancy is pancreatic cancer. Other associated malignancies include other gastrointestinal malignancies, breast cancer, brain cancer, lymphoproliferative malignancies, and lung cancer. It is also important to recognize that other cancer susceptibility genes may be involved in these families. In particular, germline BRCA2 gene variants have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer, or prostate cancer.
Some common allele(s) are associated with increased susceptibility to cutaneous malignant melanoma but have low-to-moderate penetrance. One gene of moderate penetrance is the melanocortin 1 receptor gene (MC1R). Variants in this gene are relatively common and have low penetrance for cutaneous malignant melanoma. This gene is associated with fair complexion, freckles, and red hair, all risk factors for cutaneous malignant melanoma. Variants in MC1R also modify the cutaneous malignant melanoma risk in families with CDKN2A variants (Pho, 2006).
CMM can occur either with or without a family history of multiple dysplastic nevi. Families with both CMM and multiple dysplastic nevi have been referred to as having familial atypical multiple mole and melanoma syndrome (FAMMM). This syndrome is difficult to define since there is no agreement on a standard phenotype, and dysplastic nevi occur in up to 50% of the general population. Atypical or dysplastic nevi are associated with an increased risk for CMM. Initially, the phenotypes of atypical nevi and CMM were thought to cosegregate in FAMMM families, leading to the assumption that a single genetic factor was responsible. However, it was subsequently shown that in families with CDKN2A mutations, there were family members with multiple atypical nevi who were non-carriers of the CDKN2A familial mutation. Thus, the nevus phenotype cannot be used to distinguish carriers from non-carriers of CMM susceptibility in these families.
In 2012, Ward et al reviewed the literature on germline melanoma susceptibility and concluded that in addition to the 2 rare, high-penetrance variants (CDKN2A and CDK4), there are potentially many single nucleotide polymorphisms which have small effects and low penetrance (Ward, 2012).
No widely accepted guidelines for the management of families with hereditary risk of melanoma exist (Marzuka-Alcala, 2014). In 2012, Badenas et al suggested several parameters to guide genetic testing for melanoma: in countries with a low to medium incidence of melanoma, genetic testing should be offered to families with 2 cases of melanoma or to an individual with 2 primary melanomas (the rule of 2); in countries with a high incidence of melanoma, genetic testing should be offered to families with 3 cases of melanoma, or to an individual with 3 primary melanomas (the rule of 3) (Badenas, 2012). In 2017, Delaunay et al suggested a modification to the recommendations by Badenas et al (2012). In countries with a low to medium incidence of melanoma, Delaunay et al proposed that the rule of 2 should guide genetic testing only if there is an individual with melanoma before the age of 40, otherwise the rule of 3 should apply (Delaunay, 2017).
In general, individuals with increased risk of melanoma are educated on prevention strategies such as reducing sun exposure and on skin examination procedures.
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 (CLIA). Melaris® (Myriad Genetics) and other CDKN2A tests are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA 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
Effective in 2013, there is CPT coding to more specifically report CDKN2A testing. Code 81404 includes:
CDKN2A (cyclin-dependent kinase inhibitor 2A) (e.g., CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence
Prior to 2013, there were no specific CPT codes for genetic testing specifically for susceptibility to malignant melanoma. A series of CPT codes describing the individual steps in the genetic analysis would have been used.
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Policy/ Coverage: |
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for mutations associated with hereditary cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is a screening procedure. Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures).
When the above situations do not apply, genetic testing for mutations associated with hereditary cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant 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, when the above situations do not apply, genetic testing for mutations associated with hereditary cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Validation of the clinical use of any diagnostic test focuses on 3 main principles: 1) analytic validity of the test; i.e., the technical performance of the test; 2) clinical validity, i.e., the diagnostic performance of the test, such as sensitivity, specificity, and positive and negative predictive values in different populations of patients and compared to the gold standard; and 3) clinical utility of the test, i.e., how the results of the diagnostic test will be used to improve patient management.
Analytic Validity
Genetic testing typically consists of sequence analysis of the coding regions and intron/exon splice sites or analysis of a specific mutation. Studies report identifying deleterious mutations in the 5' untranslated region and deep intronic mutations in the CDKN2A gene.
Clinical Validity
The clinical validity is related to the interpretation of the results of the genetic analysis for the individual patient. One issue common to genetic testing for any type of cancer susceptibility is determining the clinical significance of individual mutations. For example, mutations in the CDKN2A gene can occur along its entire length, and some of these mutations represent harmless polymorphisms or noncoding mutations. Interpretation will improve as more data accumulate regarding the clinical significance of individual mutations in families with a known hereditary pattern of melanoma. However, the penetrance of a given mutation will also affect its clinical significance, particularly since the penetrance of CDKN2A mutations may vary with ethnicity and geographic location (Hayward, 2003; Kefford, 1999). For example, exposure to sun and other environmental factors, as well as behavior and ethnicity may contribute to the penetrance. Bishop and colleagues have estimated that the calculated risk of developing melanoma before age 80 years in carriers of CDKN2A mutations ranges from 58% in Europe to 91% in Australia (Bishop, 2002).
Interpretation of a negative test is another issue. CDKN2A mutations are found in less than half of those with strong family history of melanoma. Therefore, additional melanoma predisposition genes are likely to exist, and patients with a strong family history with normal test results must not be falsely reassured that they are not at increased risk (Hayward, 2003). For example, in a 2011 meta-analysis of 145 genome-wide association studies, 8 independent, genetic loci were identified as being associated with a statistically significant risk of cutaneous melanoma, including 6 with strong epidemiological credibility (MC1R, TYR, TYRP1, SLC45A2, ASIP/PIGU/MYH7B, and CDKN2A/MTAP) (Chatzinasiou, 2011). Also, in a 2011 meta-analysis of 20 studies with data from 25 populations, red hair color variants on the MC1R gene were associated with the highest risk of melanoma but non-red hair color variants were also associated with an increased risk of melanoma. (8) In a 2012 review, Ward and colleagues noted the genetics of melanoma are far from being understood, and “it is likely a large number of SNPs (single nucleotide proteins), each with a small effect and low penetrance, in addition to the small number of large effect, high-penetrance SNPs, are responsible for CMM (cutaneous malignant melanoma) risk (Ward, 2012).”
In 2009, Yang and colleagues conducted a study to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations (Yang, 2009). The investigators genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A-positive, 9 CDKN2A-negative) for genes involved in DNA repair, apoptosis, and immune response. Their analyses identified some candidate genes, such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9, and JAK3, that were associated with CMM risk; after correction for multiple comparisons, IL9 remained significant. The effects of some genes were stronger in CDKN2A-positive families (BCL7A and IL9), while some were stronger in CDKN2A-negative families (BCL2L1). The authors concluded that these findings support the hypothesis that common genetic polymorphisms in DNA repair, apoptosis, and immune response pathways may modify the risk of CMM in CMM-prone families, with or without CDKN2A mutations.
In 2010, Kanetsty and colleagues conducted a study to describe associations of MC1R (melanocortin 1 receptor gene) variants and melanoma in a U.S. population and to investigate whether genetic risk is modified by pigmentation characteristics and sun exposure (Kanetsky, 2010). The study population included melanoma patients (n=960) and controls (n=396), with self-reported phenotypic characteristics and sun exposure information. Logistic regression was used to estimate associations of high- and low-risk MC1R variants and melanoma, overall and within phenotypic and sun exposure groups. Carriage of 2 low-risk, or any high risk MC1R variants, was associated with increased risk of melanoma (odds ratio [OR]: 1.7; 95% confidence interval [CI]: 1.0-2.8; and OR: 2.2; 95% CI: 1.5-3.0, respectively). However, risk was noted to be stronger in or limited to individuals with protective phenotypes and limited sun exposure, such as those who tanned well after repeated sun exposure (OR: 2.4), had dark hair (OR: 2.4), or had dark eyes (OR: 3.2). The authors concluded that these findings indicate MC1R genotypes provide information about melanoma risk in those individuals who would not be identified as high-risk based on their phenotypes or exposures alone. However, how this information impacts patient care and clinical outcomes is not known.
A 2010 article on identifying individuals at high risk for melanoma emphasizes the use of the family history (Psaty, 2010).
Clinical Implications
While genetic testing for CDKN2A mutations is recognized as an important research tool, its clinical use will depend on how the results of the genetic analysis can be used to improve patient management. Currently, management of patients considered at high risk for malignant melanoma focuses on reduction of sun exposure, use of sunscreens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions. (See policy No. 2003021 for further discussion of dermatoscopy and related techniques for skin surveillance.) At present, it is unclear how genetic testing for CDKN2A would alter these management recommendations. The following clinical situations can be considered:
1. Affected individual with a positive family history
If an affected individual tests positive for a CDKN2A mutation, he/she may be at increased risk for a second primary melanoma compared to the general population. However, limited and protected sun exposure and increased surveillance would be recommended to any patient with a malignant melanoma, regardless of the presence of a CDKN2A mutation. However, a positive result will establish a mutation, thus permitting targeted testing for the rest of the family. In addition, a positive mutation in an affected family member increases the likelihood of its clinical significance if detected in another family member. As described, a negative test is not interpretable.
2. Unaffected individual in a high-risk family
If the unaffected individual is the first to be tested in the family (i.e., no affected relative has been previously tested to define the target mutation), it is very difficult to interpret the clinical significance of a mutation, as described. The likelihood of clinical significance is increased if the identified mutation is the same as one reported in other families, although the issue of penetrance is a confounding factor. If the unaffected individual has the same mutation as an affected relative, then the patient is at high risk for melanoma. However, again it is unclear how this would affect the management of the patient. Increased sun protection and surveillance are recommended for any patient in a high-risk family.
The published data on genetic testing of the CDKN2A and CDK4 genes focus on the underlying genetics of hereditary melanoma, identification of mutations in families at high risk of melanoma, and risk of melanoma in those harboring these mutations. Other studies have also focused on the association between CDKN2A and pancreatic cancer (Puig, 2005; Rulyak, 2003; Rutter, 2004). One publication added the caution that differences in melanoma risk across geographic regions justify the need for studies in individual countries before counseling should be considered (Goldstein, 2007).
In a 2008 study, Aspinwall et al. found short-term change in behavior among a small group of patients without melanoma who were positive for the CDKN2A mutation (Aspinwall, 2008). In this prospective study of 59 members of a CDKN2A mutation-positive pedigree, behavioral assessments were made at baseline, immediately after CDKN2A test reporting and counseling, and at 1-month follow-up (42 participants). Across multiple measures, test reporting caused CDKN2A mutation carriers without a melanoma history to improve to the level of adherence reported by participants with a melanoma history. CDKN2A-positive participants without a melanoma history reported greater intention to obtain total body skin examinations, increased intentions and adherence to skin self-examination recommendations, and increased number of body sites examined at 1 month.
In a 2011 retrospective case-control study, van der Rhee and colleagues sought to determine whether a surveillance program of families with CDKN2A mutations allowed for earlier identification of melanomas (van der Rhee, 2011). Characteristics of 40 melanomas identified in 35 unscreened patients (before heredity was diagnosed) were compared to 226 melanomas identified in 92 relatives of those 35 unscreened melanoma patients that were found to have the CDKN2A mutation and participated in a surveillance program over a 25-year period. Surveillance consisted of a minimum of an annual total skin evaluation, which became more frequent if melanoma was diagnosed. Melanomas diagnosed during surveillance were found to have a significantly lower Breslow thickness (median thickness 0.50 mm) than the melanomas identified in the unscreened patients (median thickness 0.98 mm), signifying earlier identification with surveillance. However, only 53% of melanomas identified in the surveillance group were detected on regular screening appointments. Additionally, there was no correlation between length of screening intervals (for intervals less than 24 months) and melanoma tumor thickness at time of diagnosis. The authors also noted that despite understanding the importance of surveillance, patient noncompliance was still observed in the surveillance program, and almost half of patients were noncompliant when first diagnosed with melanoma.
Branstrom and colleagues examined a self-reported survey of genetic testing perceptions and preventive behaviors in 312 family members with increased risk of melanoma. Fifty-three percent had been diagnosed with melanoma, and 12% had a positive susceptibility genetic test (Branstrom, 2012). The study indicated that a negative test might be associated with an erroneous perception of lower risk and fewer preventive measures.
Ongoing Clinical Trials
A search of online site ClinicalTrials.gov identified one observational study, sponsored by the National Cancer Institute, to identify genetic and environmental factors related to melanoma risk in individuals and families at high risk for melanoma (NCT00040352). Another study to develop a model for genetic susceptibility for melanoma is active but no longer recruiting patients (NCT00591500).
Summary
Because some cases of cutaneous malignant melanoma (CMM) are familial, potential genetic markers for this disease are being evaluated. Some of these markers are being evaluated in those with a family history of disease; other markers are being evaluated to estimate risk of CMM in those who may not have a family history.
The evidence to date is insufficient to permit conclusions concerning the effect of genetic testing for melanoma on health outcomes. While research continues in this area, none of the articles identified demonstrate how the presence or absence of these genetic mutations would impact clinical care—either for those with melanoma or for those at risk due to a family history. The changes in patient management that result from finding a mutation in a patient at risk are not known. In addition, not finding a mutation does not exclude the presence of familial cutaneous malignant melanoma. The conclusion concerning unknown impact on outcomes applies to both mutations with high penetrance (CDKN2A), as well as those with low penetrance (MC1R), which may increase susceptibility.
Practice Guidelines and Position Statements
The Melanoma Genetics Consortium, comprising familial melanoma researchers from North America, Europe, and Australia, indicated, in 2002, that genetic testing for melanoma susceptibility should not be offered outside of a research setting (Kefford, 2002).
In 2002, in an American Society of Clinical Oncology (ASCO) publication, Kefford noted the sensitivity and specificity of tests for CDKN2A mutations are not fully known (Kefford, 2002). Because interpreting genetic tests is difficult and because test results do not alter patient management, the Kefford publication indicated CDKN2A genetic testing should be performed only in clinical trials for several reasons including: a low likelihood of finding mutations in known melanoma susceptibility genes, uncertainty about the functionality and phenotypic expression of the trait among mutation carriers, and the lack of proven melanoma prevention and surveillance strategies. Additionally, it was noted all patients with risk factors for cutaneous melanoma should follow programs of sun protection and skin surveillance, not just those patients considered to be high risk due to family history.
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search was conducted through August 2017. There was no new published studies identified that would prompt a change in the coverage statement.
In 2016, Di Lorenzo et al published a study on 400 patients with CMM who were observed for a 6-year period at an Italian university (Di Lorenzo, 2016). Forty-eight patients met the criteria of the Italian Society of Human Genetics (SIGU) for the diagnosis of familial melanoma and were screened for CDKN2A and CDK4 variants. Genetic testing revealed that none of the families carried variants in the CDK4 gene and only 1 patient harbored the rare CDKN2A p.R87W variant. The study did not identify a high variant rate of CDKN2A in patients affected by familial melanoma or multiple melanomas. This difference could be attributed to different factors, including the genetic heterogeneity of the Sicilian population. It is likely that, as in the Australian people, the inheritance of familial melanoma in this island of the Mediterranean Sea is due to intermediate-/low-penetrance susceptibility genes, which, together with environmental factors (eg, latitude, sun exposure), could determine the occurrence of melanoma.
2018 Update
A literature search was conducted through August 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Borroni et al evaluated asymptomatic individuals with family members diagnosed with primary cutaneous melanoma (PCM) and a CDKN2A variant who underwent genetic testing and counseling (Borroni, 2017). Of the 19 unrelated patients with PCM and a CDKN2A variant, 40 clinically healthy relatives were tested. Fifteen of the 40 relatives tested positive for the same variant as the relative with PCM. The 15 relatives underwent a complete dermatologic examination with dermoscopy. During a mean follow-up of 37 months (range, 4-53 months), none of the relatives developed PCM.
PRACTICE GUIDELINES AND POSITION STATEMENTS
The American Academy of Dermatology published guidelines on the management of primary cutaneous melanoma (AAD, 2011). The use of genetic testing in patients diagnosed with cutaneous malignant melanoma or asymptomatic patients with family history of the disease was not addressed.
2019 Update
A literature search was conducted through August 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Artomov et al assessed the rate of rare genetic variants including CDKN2A among patients with familial cutaneous melanoma (n=273) in the United States and Greece (Artomov, 2017). A validation set utilizing case-matched European controls against data obtained from The Cancer Genome Atlas melanoma cohort (n=379) confirmed statistically significant association for the CDKN2A variant (p=0.009).
Gironi et al conducted genetic testing in Italian families prone to cutaneous melanoma to elucidate distinctive clinical and histological features of melanomas in CDKN2A mutation carriers (Gironi, 2018). Three hundred patients with cutaneous melanoma were enrolled and interviewed about their personal and family history of cutaneous melanoma and other cancers. Specifically, patients were eligible for genotyping if they had a histologically proven diagnosis of 1 or more cutaneous melanoma and met at least 1 of the following inclusion criteria: 1) cutaneous melanoma diagnosis at ≤ 40 years of age; 2) multiple primary melanoma; 3) family history of cutaneous melanoma; and/or 4) Personal and/or family history of non-cutaneous cancers suggestive of familial cancer syndrome related to germline mutations of CDKN2A, CDK4, MITF, and BAP1 genes. Genotyping revealed 100 patients with wildtype CDKN2A genes and 32 patients with CDKN2A variants that were subsequently analyzed according to histological and clinical features. The wildtype group did not significantly differ from the CDKN2A mutation-positive group with respect to phototype (p=-0.759), number of total common melanocytic nevi (p=0.131). However, a personal history of previously excised dysplastic nevi was more frequent among CDKN2A variant-positive patients compared to wildtype (62.5% vs. 26%; p=<0.001). A positive family history of cutaneous melanoma and/or pancreatic cancer was detected in 90.6% of mutation-positive patients compared to 37% of the wildtype group (p<0.001). This significance was maintained for cutaneous melanoma or pancreatic cancer, individually (78.1% vs. 29%; p<0.001 and 34.4% vs. 10%; p<0.001). There were 54 (41%) patients in this study with at least 1 family member with a history of cutaneous melanoma. Among these patients, 25/54 (46.3%) carried a CDKN2A germline mutation. There were 21 (16%) of the patients with a family history of pancreatic cancer. Among these patients, 11/21 (52.4%) carried a CDKN2A germline mutation. Patients with a CDKN2A germline mutation developed a statistically significant higher number of multiple primary melanomas compared to the wildtype group (mean, 1.88 vs. 1.18; p<0.001). However, while most patients in both genotype groups developed 2 primary melanomas (61% CDKN2A, 87.5% WT), 3 or 4 multiple primary melanomas were observed more frequently in patients with a CDKN2A mutation. All CDKN2A carriers were found to develop superficial spreading melanomas whereas wildtype patients generated mostly nodular melanomas or lentigo maligna and lentigo maligna melanomas (p=0.006). There was no significant difference in CDKN2A status with respect to meeting inclusion criteria for sentinel node biopsy (15.6% CDKN2A, 22% wildtype; p=0.302). Additionally, 0/5 (0%) patients who underwent the procedure with a CDKN2A variant showed metastases compared to 4/22 (18.2%) of wildtype patients.
Stump et al provided genetic test reporting and counseling for melanoma risk in pediatric patients to assess effects on sun-protective behaviors and psychological harms (Stump, 2018). Patients aged 10-15 with a parent with a CDKN2A/p16 mutation, no personal history of melanoma, and no previous genetic testing for melanoma were eligible for the study. Twenty children enrolled and 2 withdrew prior to the 1-month follow-up visit, resulting in 18 participants from 11 families. Measures of protective behavior and distress were collected at baseline, 1 week, 1 month, and 1 year. Participants and their mothers were individually interviewed regarding the psychological and behavioral impact of genetic testing. CDKN2A carriers (n=9) and non-carriers (n=9) both reported significantly fewer sunburns and a greater proportion reported sun protection adherence between baseline and 1 year; results did not vary by mutation status. Anxiety symptoms were low post-disclosure, whereas depressive symptoms and cancer worry decreased.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
De Simone et al (2020) conducted a retrospective review of melanoma predisposition variants (eg, CDKN2A, CDK4) in 888 patients with melanoma from Central Italy (De Simone, 2020). Overall, the study included 309 patients with multiple primary melanomas, 435 patients with familial melanoma, and 144 cases with both multiple primary melanomas and familial melanoma. Of the 888 patients, 98 (11%) had the CDKN2A variant.
Stump et al investigated whether genetic counseling and test reporting for CDKN2A carrier status promoted objective reductions in sun exposure (Stump, 2020). Participants were recruited from 2 types of pedigrees: families with an identified CDKN2A mutation and families with a similar melanoma history but no identified CDKN2A mutation. Subjects from CDKN2A-positive families were derived from 3 kindreds and accounted for 32 carriers and 46 noncarriers. No-test control subjects (n=50) were derived from 9 CDKN2A-negative families. The daily standard erythemal dose (SED; J/m2) of ultraviolet radiation (UVR) exposure was measured with a wrist-worn, battery-powered dosimeter over three 27-day periods. Complete dosimetry data was available for 75.8% of participants, with missing data due to technical issues, device loss, or device damage. The average number of days coded as "not worn" ranged from 7-10 days in each assessment period. Both carriers and no-test controls exhibited a significant decrease in UVR dose at 1 year compared to baseline (p<0.01). No change from baseline was noted for noncarriers at any timepoint. However, these outcomes do not account for the use of sunscreen or sun-protective clothing. Skin pigmentation was assessed via reflectance spectroscopy, yielding a Melanin Index score in which higher scores represent greater melanin content. Measurements from the face and wrist were standardized to measurements obtained from non-exposed sites to account for differences in skin tone. Data from patients using artificial tanning products within a week of testing were excluded. Only carriers exhibited a significant decrease in skin pigmentation at the wrist at 1 year (p<0.001). However, no corresponding changes in facial pigmentation were detected for any group. Both carriers and no-test controls self-reported fewer sunburns than non-carriers (p<0.05). Noncarriers did not demonstrate changes in any measure of UVR exposure; however, daily UVR exposure was higher among noncarriers compared to no-test controls at baseline (p=0.03). Despite the incorporation of propensity score matching in their statistical methods, the authors acknowledge that they cannot exclude yet-to-be identified confounding factors driving between-group differences in their non-equivalent control study design. The study did not assess key health outcomes such as melanoma incidence.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Pissa et al conducted genetic testing for CDKN2A variants among 403 Swedish families between 2015-2020 (Pissa, 2021). Included families had 3 or more cases of melanoma and/or pancreatic cancer, 2 melanomas in first-degree relatives with the youngest case occurring before age 55, or individuals with 3 or more multiple primary melanomas, with the first occurring before age 55. A total of 33 families (8.2%) were found to have CDKN2A pathogenic variants. Frequencies of CDKN2A pathogenic variants ranged from 0.9% in families with only 2 melanomas to 43.2% in families with 3 or more melanoma cases and pancreatic cancer. The frequency of CDKN2A variants ranged from 2.1% to 16.5% in families where the youngest case occurred after age 55 or before age 35 (p=.04). Families with CDKN2A pathogenic variants had a higher rate of melanoma-related mortality (37.6% versus 10.0%; p<.001). The authors concluded that these findings may help inform selection criteria to guide genetic testing for familial melanoma.
Primiero et al published 2 systematic reviews evaluating the impact of genetic testing in familial melanoma on primary and secondary preventative behaviors and psychosocial outcomes and attitudes (Primiero, 2021; Primiero, 2021). Eight studies evaluating sun-protective behaviors were identified. Authors concluded that genetic testing has a modestly positive impact on sun-protective behaviors (e.g., sunscreen use, sun-protective clothing, avoiding sun exposure and tanning) in high-risk individuals. These improvements were observed regardless of mutation carrier status, although higher adherence was observed in carriers. Twelve studies evaluating psychosocial outcomes and behaviors were identified. The authors found that generalized distress does not appear to be impacted by testing outcomes, carrier status, or personal history. However, melanoma-specific distress was associated with carrier status and/or personal history. Genetic risk assessment was not found to impact participants' perceived risk of subsequent melanomas.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2024. No new literature was identified that would prompt a change in the coverage statement.
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| References: |
American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility. J Clin Oncology 2003; 21. Artomov M, Stratigos AJ, Kim I, et al.(2017) Rare Variant, Gene-Based Association Study of Hereditary Melanoma Using Whole-Exome Sequencing. J. Natl. Cancer Inst. 2017 Dec;109(12). PMID 29522175 Aspinwal LG, Leaf SL, Dola ER et al.(2008) CDKN2A/p16 genetic test reporting improves early detection intenetions and practices in high-risk melanoma families. Cancer Epidemiol Biomarkers Prev 2008; 17(6):15110-1519. Badenas C, Aguilera P, Puig-Butille JA, et al.(2012) Genetic counseling in melanoma. Dermatol Ther. Sep-Oct 2012; 25(5): 397-402. PMID 23046018 Bichakjian CK, Halpern AC, Johnson TM, et al.(2011) Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. J Am Acad Dermatol. Nov 2011;65(5):1032-1047. 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