Genetic Testing for Familial Cutaneous Malignant Melanoma


» Summary» Procedure Codes
» Description» Selected References
» Prior Approval» Policy History
» Policy
 

Medical Policy: 02.04.41 
Original Effective Date: July 2012 
Reviewed: February 2016 
Revised: April 2014 


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

Description:

Some cases of cutaneous malignant melanoma (CMM) are familial.  Potential genetic markers for this disease are being evaluated in affected individuals with a family history of disease and in unaffected individuals in a high-risk family.

 

A genetic predisposition to cutaneous malignant melanoma (CMM) 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) in the case of 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 CMM susceptibility have now been identified.  Cyclin-dependent kinase inhibitor 2A (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,  cyclin-dependent kinase 4 (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. 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. Mutation detection rates in the CDKN2A gene are generally estimated as 20-25% in hereditary CMM but can vary between 2% and 50%, depending on the family history and population studied.

 

Familial CMM has been described as a family in which either 2 first-degree relatives are diagnosed with melanoma or a family with 3 melanoma patients, irrespective of the degree of relationship. 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.

 

Other malignancies associated with familial CMM, specifically those associated with CDKN2A mutations, have been described. The most pronounced associated malignancy is pancreatic cancer, followed by 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 mutations have been described in families with melanoma and breast cancer, gastrointestinal cancer, pancreatic cancer, or prostate cancer.

 

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 noncarriers of the CDKN2A familial mutation. Thus, the nevus phenotype cannot be used to distinguish carriers from noncarriers of CMM susceptibility in these families.

 

Some common allele(s) are associated with increased susceptibility to CMM 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 CMM. This gene is associated with fair complexion, freckles, and red hair; all risk factors for CMM. Variants in MC1R also modify the CMM risk in families with CDKN2A mutations.

 

Commercially Available Test

Melaris® (Myriad Genetics. Salt Lake City, UT) is commercially available genetic test of the CDKN2A.

 
Summary
The evidence to date is insufficient to permit conclusions concerning the effect of genetic testing for melanoma on health outcomes. Although research continues in this area, none of the articles identified demonstrate how the presence or absence of the gene mutation would impact clinical care, either for those with melanoma or for those at risk due to family history. Changes in patient management that result from finding a mutation in a patient at risk is unknown. In addition, not finding a mutation does not exclude the presence of familial cutaneous malignant melanoma. Therefore, genetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.   
 

Practice Guidelines and Position Statements

 

American Society of Clinical Oncology (ASCO)

In 2010 ASCO updated its policy statement on genetic and genomic testing for canced suspceptibility.  ASCO recommends that "genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials."

 

Melanoma Genetics Consortium

The Melanoma Genetics Consortium, compromising of familial melanoma researchers from North America, Europe and Australia, indicated that genetic testing for melanoma susceptibility should not be offered outside the research setting. There is difficulty in interpreting test results and there is potentially limited impact of the results on clinical management.

 

National Comprehensive Cancer Network (NCCN)

Melanoma Version 2.2016: Current National Comprehensive Cancer Network (NCCN) clinical practice guidelines for melanoma include no specific recommendation for genetic testing for melanoma.

 

Regulatory Status

 

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Melaris® and other CDKN2A tests are laboratory-developed tests (LDTs) and available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require any regulatory review of this test.


Prior Approval:

 

Not applicable


Policy:

Genetic molecular testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.

 

The evidence to date is insufficient to permit conclusions concerning the effect of genetic testing for melanoma on health outcomes. Although research continues in this area, none of the articles identified demonstrate how the presence or absence of the gene mutation would impact clinical care, either for those with melanoma or for those at risk due to family history. Changes in patient management that result from finding a mutation in a patient at risk is unknown. In addition, not finding a mutation does not exclude the presence of familial cutaneous malignant melanoma. Therefore, genetic testing for mutations associated with familial cutaneous malignant melanoma or associated with susceptibility to cutaneous malignant melanoma is considered investigational.  





Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 81404 Molecular pathology procedure, Level 5 (eg analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dyanamic mutation disorder/triplet repeat by Southern blot analysis)-Component within this panel CDKN2A (cyclin dependent kinase inhibitor 2A) (eg CDKN2A related cutaneous malignant melanoma familial atypical mole malignant melanoma syndrome), full gene sequence

Selected References:

Wellmark's policy is based on:

  • National Cancer Institute. Genetics of Skin Cancer (PDQ®) Health professional Version. June 29, 2012. Accessed 7/24/12. Available at: http://www.cancer.gov/cancertopics/pdq/genetics/skin/healthprofessional/allpages/print.
  • American Cancer Society, Inc (ACS). Detailed Guide: Skin Cancer – Melanoma. Can melanoma be found early? Skin Cancer-Melanoma. Last Revised 01/11/2012. Accessed July 20, 2012. Available at: http://www.cancer.org/Cancer/SkinCancer-Melanoma/DetailedGuide/index
  • Leachman SA, Carucci J, Kohlmann W, et al. Selection criteria for genetic assessment of patients with familial melanoma. J Am Acad Dermatol. 2009 October; 61(4): 677.
  • van der Rhee JI, de Snoo FA, Vasen HF, et al. Effectiveness and causes for failure of surveillance of CDLM2A-mutated melanoma families. J Am Acad Dermatol 2011; 65(2):289-96.
  • NCCN Guidelines Version 2.2013 Melanoma www.nccn.org
  • American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility, Journal of Clinical Oncology, Published online before print April 11, 2003, doi: 10.1200/JCO.2003.03.189, JCO June 15, 2003 vol. 21 no. 12 2397-2406
  • NCCN (National Comprehensive Cancer Network) Guidelines Version 2.2016 Melanoma www.nccn.org
  • UpToDate. Inherited Susceptibility to Melanoma. Hensin Tsao, M.D., PhD, Linda Rodgers MGC, CGC, Devanshi Patel MS, CGC. Topic last updated January 20, 2016. www.uptodate.com
  • UpToDate. Screening and Early Detection of Melanoma. Alan C. Geller, R.N., MPH, Susan Swetter, M.D. Topic last updated August 21, 2015. www.uptodate.com
  • American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility, Journal of Clinical Oncology, Volume 28, Number 5, February 10, 2010
  • Durga Udayakumar, PhD et al. Genetic Determinants of Cutaneous Melanoma Predisposition. Seminars in Cutaneous Medicine and Surgery 29:190-195 2010 Elsevier Inc.
  • Cancer.Net. Familial Malignant Melanoma. November 2013. www.cancer.net
  • National Cancer Institute. Genetics of Skin cancer PDQ, Health Professional Version. Last modified February 2014. www.cancer.gov/cancertopics  
  • Christopher K. Bichakjian,M.D. et al. Guidelines for Care for the Management of Primary Cutaneous Melanoma. Journal American Academy Dermatology Volume 65, Number 5. November 2011
  • Marzuka-Alcala A, Gabree MJ, Tsao H. Melanoma susceptibility genes and risk assessment. Methods Mol Biol. 2014;1102:381-393. PMID 24258989
  • Pho L, Grossman D, Leachman SA. Melanoma genetics: a review of genetic factors and clinical phenotypes in familial melanoma. Curr Opin Oncol. Mar 2006;18(2):173-179
  • Chatzinasiou F, Lill CM, Kypreou K, et. al. Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. J Natl Cancer Inst. Aug 17 2011;103(16):1227-1235. PMID 21693730
  • Ward KA, Lazovich D, Hordinsky MK. Germline melanoma susceptibility and prognostic genes: A review of the literature. J Am Acad Dermatol. May 12 2012. PMID 22583682
  • Liang X, Pfeiffer R, Wheeler W, et. al. Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in the melanoma-prone families with/without CDKN2A mutations. Int J Cancer 2012 May 1;130(9):2062-2066
  • Kanetsky PA, Panossian S, Elder DE, et. al. Does MC1R genotype convey information about melanoma risk beyond risk phenotypes? Cancer. May 15 2010;116(10):2416-2428
  • Cust AE, Goumas C, Holland EA, et. al. MC1R genotypes and risk of melanoma before age 40 years: a population based case-control family study. Int J Cancer Aug 1 2012;131(3):e269-281. PMID 22095472
  • Psaty EL. Scope A, Halpern AC, et. al. Defining the patient at high risk for melanoma. Int J Dermatol. Apr 2010;49(4):362-376. PMID 20465687
  • Puntervoll HE, Yang XR, Vetti HH, et. al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. Apr 2013;50(4):264-270. PMID 23384855
  • Aspinwall LG, Taber JM, Leaf SL, et. al. Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome. Psychooncology. Feb 2013;22(2):276-289
  • Aspinwall LG, Taber JM, Leaf SL, et. al. Melanoma genetic counseling and test reporting improve screening adherence among unaffected carriers 2 years later. Cancer Epidemiol Biomarkers Prev. Oct 2013;22(10):1687-1697
  • van der Rhee JI, Boonk SE, Putter H, et. al. Surveillance of second degree relatives from melanoma families with a CDKN2A germline mutation. Cancer Epidemol Biomarkers Prev. Oct 2013;22(10):1771-1777. PMID 23897584
  • van der Rhee JI, de Snoo FA, Vasen HF, et. al. Effectiveness and causes of failure of surveillance of CDKN2A mutated melanoma families. J AM Acad Derm. Aug 2011;65(2):289-296. PMID 21570154  
  • Branstrom R, Kasparian NA, Affleck P, et. al. Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma. Eur J Cancer. Jun 20 2012. PMID 22726816
  • Melaris (Myriad Genetics) www.myriad.com/products-services/hereditary-cancers/melaris
  • Kefford RF, Newton Bishop JA, Bergman W, et. al. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: a consensus statement of the Melanoma Genetics Consortium. J Clin Oncol. Oct 1999;17(10):3245-3251. PMID 10506626
  • Robson M, Bradbury A, Banu A, et. al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. Journal of Clinical Oncology November 1, 2015 Vol 33. No 31 3660-3667 

Policy History:

Date                                      Reason                                Action
July 2012                                Interim review                       Policy revised
February 2013                         Interim review                       Policy revised
April 2013                               Interim review                       Policy revised
June 2013                               Annual review                       Policy revised

April 2014                               Annual review                       Policy revised

March 2015                            Annual review                       Policy renewed
February 2016                        Annual review                       Policy renewed 


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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.