Genetic Expression Profiling and Genetic Testing for Familial Cutaneous Malignant Melanoma AHS – M2037

Description of Procedure or Service

Skin cancer is the most common form of cancer, with approximately 2-3.5 million cases identified annually. Skin cancer can be divided into melanoma (also called cutaneous melanoma and malignant melanoma) and non-melanoma types (for example, basal cell and squamous cell skin cancer). Although cutaneous melanoma (CM) is much less prevalent than non-melanoma skin cancer and accounts for only 1% of skin cancer, it causes a large majority of skin cancer deaths. Although it is estimated that 8 to 12 percent of patients with melanoma have a family history of the disease, not all of these individuals have hereditary melanoma.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

Genetic expression profiling and genetic testing for familial cutaneous malignant melanoma is considered investigational. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When Genetic Expression Profiling and Genetic Testing for Familial Cutaneous Malignant Melanoma is covered

N/A

When Genetic Expression Profiling and Genetic Testing for Familial Cutaneous Malignant Melanoma is not covered

1. Genetic testing for inherited forms of melanoma is considered investigational. This includes, but is not limited to, testing of the CDKN2A and CDK4 genes.
2. Genetic expression profiling testing for cutaneous melanoma is considered investigational. 
3. Panel testing codes are considered investigational.

Policy Guidelines

Background

Cutaneous melanomas can develop anywhere on the skin, particularly in areas exposed to the sun. In men, the most common site is the chest or back, while in women, the legs are affected most frequently. Melanomas are also commonly found on the neck or face.

The American Cancer Society’s estimates for melanoma in the United States for 2016 are:

• About 76,380 new melanomas will be diagnosed (about 46,870 in men and 29,510 in women). 
• About 10,130 people are expected to die of melanoma (about 6,750 men and 3,380 women). 

Melanoma is more than 20 times more common in whites than in African Americans. The risk of melanoma increases as people age, and the average age of diagnosis is 63. Melanoma is one of the most common cancers in young adults, especially young women. The rates of melanoma have been rising for the last 30 years (American Cancer Society, 2016).

CM is more common in men than in women, and in 2014 the ACS estimates that 58% of the new cases and 69% of the melanoma-related deaths will be in men. The major risk factor for CM is exposure to ultraviolet radiation. Additionally, people with a large number of moles are at higher risk, as are those with fair skin, light hair, and light eyes. CM has a high cure rate if detected and treated early, but it is more likely to metastasize than non-melanoma skin cancer. When melanoma is localized, the 5-year survival rate is 98%. However, metastatic melanoma has a much lower survival rate. A second melanoma occurs in approximately 5% of initial CM cases.

Natural History

Approximately 10% of CM is considered to be hereditary, and follows an autosomal dominant inheritance pattern. Significant progress has been made toward understanding the genes that contribute to inherited susceptibility for melanoma in some patients. Uncommon, but high-risk, alleles contribute to the hereditary cancer phenotype that includes multiple cases of the associated cancer or cancers on one side of the family, multiple primary cancers in a given individual, and early age of onset for a given cancer (UpToDate, 2017). Cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4) are the most commonly identified gene mutations in familial forms of melanoma. There are no apparent differences in the phenotype (eg, age at diagnosis, number of melanomas) of families carrying either CDKN2A or CDK4 mutations (UpToDate, 2017).

There is a variable rate of CDKN2A mutations in patients with hereditary melanoma. The most extensive analysis of melanoma families found that the major features associated with an increased frequency of CDKN2A mutations were multiple cases of melanoma in a family, early age at diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer. Mutations in the CDKN2A gene have been found in 20 – 40% of CM cases associated with family histories that include at least three family members with CM. Germline CDKN2A mutations in melanoma families are usually missense or nonsense changes that impair the function of the p16 protein, although rare mutations in the p14ARF protein have also been reported (UpToDate, 2017).

CDK4 is also associated with hereditary CM, but mutations in that gene are rare, accounting for only 1% of hereditary CM. In these cases, the mutations were on arginine 24 of CDK4, resulting in a CDK4 protein that is insensitive to inhibition by the p16 protein. The penetrance of CM risk associated with CDKN2A mutations is not complete, which has led to speculation that there are other factors that also impact CM development even when a CDKN2A mutation is present.

It is estimated that about 8% of people with melanoma have a first-degree relative with melanoma and that 1% to 2% of people with melanoma have two or more close relatives with melanoma (American Society of Clinical Oncology, 2015). Studies of families with mutations in CDKN2A from Europe, North America, and Australia have shown that the risk of melanoma varies by geographic area. There is also growing evidence that variations in another gene, MC1R, alter the risk of melanoma, both in individuals with CDKN2A mutations and in individuals without CDKN2A mutations. MC1R is important in regulating pigment; variations have been associated with freckling and red hair (ASCO, 2015).

According to ASCO, other inherited genes are associated with an increased risk of melanoma. For instance, xeroderma pigmentosum (XP) is a rare disorder in which patients have a mutation in a gene needed for repair of ultraviolet radiation (sunlight) induced DNA damage. Patients with XP have an extremely high rate of skin cancer, including melanoma. A hereditary breast cancer gene called BRCA2 is also associated with a risk of melanoma. Scientists believe that there are other genes not yet identified that also increase the risk of melanoma (ASCO, 2015).

The recent landmark study from The Cancer Genome Atlas (TCGA) consortium describing the genomic architecture of 333 cutaneous melanomas provided the largest and broadest analysis to date on the somatic aberrations underlying melanoma genesis (Zhang et al., 2016). The largecohort sequencing efforts have consistently reported key drivers and SMGs in melanoma, including both known (BRAF, NRAS, TP53, CDKN2A, and PTEN) and newly identified genes (NF1, RAC1, PPP6C, IDH1, and ARID2) (Hodis et al., 2012; Krauthammer et al., 2015; Watson et al., 2015).

A high mutation rate in melanoma was replicated by TCGA, with a mean of 16.8 mutations/Mb (Watson et al., 2015). In that study, 76% of primary (44 of 85) and 84% (221 of 262) of metastatic melanomas exhibited a signature consistent with UVR exposure. However, it should be noted that the mutation rate in melanoma varies substantially by body site, such that sun-shielded cutaneous melanomas have markedly lower mutation burdens than those melanomas arising on chronically sun-exposed body sites (Krauthammer et al., 2012). Further exploration of data linking clinical presentation, genetic sequencing, therapeutic regimen, and overall response in retrospective and prospective studies will be useful in identifying new diagnostic and prognostic biomarkers. High somatic mutation burden in melanoma has already been linked to favorable outcomes of immune-based therapeutic approaches using CTLA-4 antibodies (Snyder et al., 2014; Van Allen et al., 2015). Such analyses of genomic correlates and exceptional patient responders will be useful in guiding improved therapeutic options and could lead to new insights into the biological pathways governing melanoma genesis (Zhang et al., 2016).

Genetic Testing

The interpretation of genetic testing for melanoma is difficult, especially in the context of a true negative result. Unaffected individuals from hereditary melanoma families who test negative for the familial CDKN2A mutation are still at increased risk of developing melanoma, despite their negative genetic status. This leads to the concern that a negative test result will result in decreased surveillance and vigilance (UpToDate, 2017).

Genetic testing for CDKN2A mutations could potentially increase the motivation for riskreducing behaviors and frequent surveillance, as well as lowered biopsy threshold for suspicious lesions, which might improve survival if a melanoma occurs (UpToDate, 2017). On the other hand, genetic testing could potentially cause psychological distress, lead to unnecessary biopsies in carriers, and reduce motivation for preventive behaviors in those without CDKN2A mutations (UpToDate, 2017).

Applicable Federal Regulations

N/A

Guidelines and Recommendations

In 2016, Bruno et al concluded that “despite regional differences, Italian patients presenting with only 2 melanomas, even in situ, warrant genetic counseling even in the absence of positive family history”(Bruno et al., 2016).

Based on these findings, in 2017 Leachman et al published updated guideline incorporating a “rule of three” as an indication for genetic testing in multiple melanomas. They state that “Any patient or family that meets the updated rule of threes should be considered a candidate for genetic testing. If melanoma is the only cancer in a pedigree, then to meet the threshold of genetic testing, a pedigree should have three primary melanomas in first- or second-degree relatives in areas with a high melanoma incidence or two primary melanomas in a low-incidence area. This melanoma panel should include BAP1, CDK4, and CDKN2A. Genes for which risk has not been established but for which studies suggest an elevated risk include MITF and POT1 and we recommend including these in the melanoma panel” (Leachman et al., 2017).

The National Comprehensive Cancer Network guidelines state: “Consider referral to a genetic counselor for p16/CDKN2A mutation testing in the presence of 3 or more invasive melanomas, or a mix of invasive melanoma and pancreatic cancer diagnoses in an individual or family. Testing for other genes that can harbor melanoma predisposing mutations (CDK4, TERT, MITF and BAP1) may be warranted” (NCCN, 2017)

Both the Melanoma Genetics Consortium and the American Society of Clinical Oncology have recommended that genetic testing for CDKN2A mutations should be carried out in a research setting rather than a clinical setting. The interpretation of such a test result is difficult, especially in the context of a true negative result. Importantly, unaffected individuals from hereditary melanoma families who test negative for the familial CDKN2A mutation are still at increased risk of developing melanoma, despite their negative genetic status. This leads to the concern that a negative test result will result in decreased surveillance and vigilance. 

The Melanoma Genetics Consortium notes that, “Given current gaps in knowledge about the expression of melanoma susceptibility genes in the population, DNA testing cannot be used as a guide to the clinical practice of prevention and surveillance. Also, “given the current paucity of knowledge about the penetrance of CDKN2A mutations, the failure as yet to identify mutations in over 60% of hereditary melanoma kindreds, and the limited data on the efficacy of prevention and surveillance strategies” all individuals in high risk families should undergo the same increased surveillance.

The American Society of Clinical Oncologists (ASCO) recommend that “genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials.” In general, ASCO only recommends genetic testing that “can be adequately interpreted and the test results have accepted clinical utility.” ASCO states that “genetic tests results for CDKN2A gene are unlikely to change screening recommendations or clinical care for people who have had melanoma or people who have a strong family history of melanoma. Most families with familial melanoma will not even have a genetic mutation identified”(ASCO 2015).

The National Cancer Institute notes, “At this time, identification of a CDKN2A mutation does not affect the clinical management of the affected patient or family members.” Referral for cancer genetic consultation is recommended by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors for individuals with a personal or family history indicative of a hereditary form of cancer.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page. 

Scientific Background and Reference Sources

American Cancer Society. (2016). Key Statistics for Melanoma Skin Cancer, Accessed online on January 27, 2017

American Cancer Society. (2017). Key statistics for melanoma skin cancer. Retrieved October, 2014

American Society of Clinical Oncology (2016). Familial malignant melanoma. Retrieved September 27, 2016

Bruno, W., Pastorino, L., Ghiorzo, P., Andreotti, V., Martinuzzi, C., Menin, C., Bianchi-Scarra, G. (2016). Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup. J Am Acad Dermatol, 74(2), 325-332. doi:10.1016/j.jaad.2015.09.053

Cancer Treatment Center of America. (2016). Melanoma information. Retrieved September 27, 2016

Hodis, E., Watson, I.R., Kryukov, G.V. et al. (2012). A landscape of driver mutations in melanoma. Cell 150, 251–263.

Krauthammer, M., Kong, Y., Bacchiocchi, A. et al. (2015). Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas. Nat. Genet. 47, 996–1002.

Krauthammer, M., Kong, Y., Ha, B.H. et al. (2012). Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat. Genet. 44, 1006–1014.

Leachman, S. A., Lucero, O. M., Sampson, J. E., Cassidy, P., Bruno, W., Queirolo, P., & Ghiorzo, P. (2017). Identification, genetic testing, and management of hereditary melanoma. Cancer Metastasis Rev, 36(1), 77-90. doi:10.1007/s10555-017-9661-5

National Cancer Institute (2017). Genetics of skin cancer. Retrieved January, 2017

NCCN. (2017). NCCN Clinical Practice Guidelines in Oncology for Melanoma Version 1.2018. from NCCN 

Snyder, A., Makarov, V., Merghoub, T. et al. (2014). Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199.

Van Allen, E.M., Miao, D., Schilling, S.A. et al. (2015). Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211.

Watson, I.R., Gershenwald, J.E., Chin, L. et al. (2015). Genomic classification of cutaneous melanoma. Cell 161, 1681–1696.

Zhang, T., Dutton-Regester, K., Brown, K. M. and Hayward, N. K. (2016). The genomic landscape of cutaneous melanoma. Pigment Cell Melanoma Res., 29: 266–283. doi:10.1111/pcmr.12459

Policy Implementation/Update Information

1/1/2019 BCBSNC will not provide coverage for genetic expression profiling and genetic testing for familial cutaneous malignant melanoma because it is considered investigational. BCBSNC does not provide coverage for investigational services or procedures. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (jd)