National Medical Policy

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1 National Medical Policy Subject: Policy Number: Melaris Genetic Testing for Malignant Melanoma and Pancreatic Cancer NMP397 Effective Date*: December 2007 Updated: November 2015 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State's Medicaid manual(s), publication(s), citations(s) and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* X Other Palmetto MolDX Approved Gene Testing (M00041): sf/docscat/moldx%20website~moldx~browse %20By%20Topic~Covered%20Tests~9BMLRK6 738?open&navmenu=Browse^By^Topic None Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 1

2 outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Health Net, Inc. considers Melaris genetic testing investigational, for mutations which indicate inherited susceptibility to malignant melanoma and pancreatic cancer. Clinical evaluation of risk remains the gold standard for preventing melanoma. Firstdegree relatives of individuals at high risk should be engaged in the same programs of melanoma prevention and surveillance irrespective of the results of any genetic testing. Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes Malignant Melanoma of skin Neoplasm of other and unspecified digestive organs, including the pancreas Neoplasm of unspecified nature, digestive system V26.3 Genetic counseling and testing; or V26.31 Screening for genetic disease carrier status ICD-10 Codes C25.0-C25.9 Malignant neoplasm of pancreas C43.0-C44 Melanoma and other malignant neoplasm of skin Z13.71 Encounter for nonprocreative screening for genetic disease carrier status Z15.09 Genetic susceptibility to other malignant neoplasm CPT Codes Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterizations of a dynamic mutation disorder/triplet repeat by Southern blot analysis) HCPCS Codes N/A Scientific Rationale Update November 2015 According to NCCN guidelines on melanoma (1.2016), Risk factors for melanoma include a positive family history of melanoma, prior melanoma, multiple clinically atypical moles or dysplastic nevi, and rarely inherited genetic mutations. Genetic Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 2

3 counseling could be considered for individuals with a strong family history. In addition to genetic factors, sun exposure may also contribute to the development of melanoma. A footnote was added to the NCCN guideline, While there is interest in prognostic molecular techniques such as gene expression profiling to differenciate benign and low versus high risk for metastasis, routine (baseline) testing of primary cutaneous melanoma [before or following sentinel lymph node biopsy (SLNB)] is not recommended outside of a clinical study (trial). The current guidelines do not mention the Melaris genetic testing or genetic testing for CDKN2A. Updated NCCN guidelines on pancreatic adenocarcinoma (2.2015) still state, Pancreatic cancer is thought to have a familial component in approximately 10% of cases, and familial excess of pancreatic cancer is associated with high risk. The genetic basis is not known in most cases, however, some familial cancer syndromes are associated with an increased risk for pancreatic cancer. NCCN guidelines note further, Familial Malignant Melanoma syndrome (also known as Melanoma- Pancreatic Cancer Syndrome or Familial Atypical Multiple Mole Melanoma syndrome (FAMMM) is caused by germline mutations of the CDKN2A gene. This syndrome is associated with a 20 fold increase risk for pancreatic cancer than the general population. However, the guidelines do not mention the Melaris genetic test nor does it offer recommendations regarding testing for mutation of the CDKN2A gene. Zhen et al (2015) reported that familial pancreatic cancer kindreds contain at least two affected first-degree relatives. Comprehensive data are needed to assist clinical risk assessment and genetic testing. Germ-line DNA samples from 727 unrelated probands with positive family history (521 met criteria for familial pancreatic cancer) were tested in compliance with the Clinical Laboratory Improvement Amendments for mutations in BRCA1 and BRCA2 (including analysis of deletions and rearrangements), PALB2, and CDKN2A. The authors compared prevalence of deleterious mutations between familial pancreatic cancer probands and nonfamilial pancreatic cancer probands (kindreds containing at least two affected biological relatives, but not first-degree relatives). They also examined the impact of family history on breast and ovarian cancers and melanoma. Prevalence of deleterious mutations (excluding variants of unknown significance) among familial pancreatic cancer probands was: BRCA1, 1.2%; BRCA2, 3.7%; PALB2, 0.6%; and CDKN2A, 2.5%. Four novel deleterious mutations were detected. Familial pancreatic cancer probands carry more mutations in the four genes (8.0%) than nonfamilial pancreatic cancer probands (3.5%) (odds ratio: 2.40; 95% confidence interval: ; P = 0.03). The probability of testing positive for deleterious mutations in any of the four genes ranges up to 10.4%, depending on family history of cancers. BRCA2 and CDKN2A account for the majority of mutations in familial pancreatic cancer. The authors concluded genetic testing of multiple relevant genes in probands with a positive family history is warranted, particularly for familial pancreatic cancer. Wu et al (2015) examined changes in frequency of discussion about melanoma preventive behaviors among adults who received melanoma genetic test reporting and counseling and their children and grandchildren, correspondence of frequency of discussion with intentions, and content of discussions. Participants received CDKN2A/p16 testing and counseling (N=24, 46 % p16-positive). Discussions about preventive behaviors were assessed before testing and 1 and 6 months post-testing. Intentions to discuss preventive behaviors and perceived preparedness to discuss risk were assessed post-testing. Open-ended questions assessed content of reported discussions. Discussion of preventive behaviors declined following test reporting, with more rapid decline reported by noncarriers. There was a large gap between the percentage of participants who intended to discuss preventive behaviors and who then reported discussions 1 and 6 months after counseling. Participants felt prepared to discuss melanoma risk but also suggested resources to facilitate discussions. Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 3

4 Genetic test reporting and counseling alone did not sustain discussions about preventive behaviors for a hereditary cancer with children and grandchildren. The gap between intentions to have discussions and reported discussions has implications for augmentation of counseling to support at-risk families' discussions about preventive behaviors. Sargen et al (2015) sought to identify associations between histology of melanomas and CDKN2A genotype. This was a case-control study design comparing 28 histopathologic tumor features among individuals with sporadic melanomas (N = 81) and cases from melanoma families with (N = 123) and without (N = 120) CDKN2A germline mutations. Compared with CDKN2A(-) cases, mutation carriers tended to have histologic features of superficial spreading melanoma subtype including higher pigmentation (Ptrend =.02) and increased pagetoid scatter (Ptrend =.07) after adjusting for age at diagnosis, sex, and American Joint Committee on Cancer thickness category. Similar associations were observed when comparing mutation carriers with a combined group of CDKN2A(-) (wild type) and sporadic melanomas. The presence of spindle cell morphology in the vertical growth phase was also an important predictor of genotype. Of the 15 cases with this phenotype, none were observed to harbor a CDKN2A mutation. The authors noted the study examined rare mutations and may have been underpowered to detect small, but biologically significant associations between histology and genotype. The authors concluded familial melanomas with CDKN2A mutations preferentially express a histologic phenotype of dense pigmentation, high pagetoid scatter, and a non-spindle cell morphology in the vertical growth phase. Scientific Rationale Update November 2014 According to NCCN guidelines on melanoma (1.2015). Risk factors for melanoma include a positive family history of melanoma, prior melanoma, multiple clinically atypical moles or dysplastic nevi, and rarely inherited genetic mutations. Genetic counseling could be considered for individuals with a strong family history. The current guidelines do not mention the Melaris genetic testing or genetic testing for CDKN2A. According to NCCN guidelines on pancreatic adenocarcinoma (2.2014), Pancreatic cancer is thought to have a familial component in approximately 10% of cases, and familial excess of pancreatic cancer is associated with high risk. The genetic basis is not known in most cases, however, some familial cancer syndromes are associated with an increased risk for pancreatic cancer. NCCN guidelines note further, Familial Malignant Melanoma syndrome (also known as Melanoma-Pancreatic Cancer Syndrome or Familial Atypical Multiple Mole Melanoma syndrome (FAMMM) is caused by germline mutations of the CDKN2A gene. This syndrome is associated with a 20 fold increase risk for pancreatic cancer than the general population. In an unselected series of 225 patients with pancreatic cancer in Italy, 5.7 had mutations in CDKN2A. The guideline also addresses the genetics of patients with Lynch Syndrome who have an estimated 9-11 fold elevated risk for pancreatic cancer, as well as those families with hereditary Breast-Ovarian-Cancer syndrome harboring BRCA1 and BRCA2 mutations. The NCCN guideline notes that as many as 80% of patients with a family history of pancreatic cancer have no known genetic cause. The panel emphasizes the importance of taking a thorough family history when seeing a new patient with pancreatic cancer. In particular, a family history of pancreatitis, melanoma, and cancers of the pancreas, colorectum, breast and ovaries should be noted. A free online pancreatic cancer risk prediction tool, called PancPro, is available and may help determine risk. If a cancer syndrome is identified, at risk relatives should be offered genetic counseling. With or without a known syndrome, individuals with a suspicious family history should be advised on risk-reducing strategies including smoke cessation and weight loss. In addition, the possibility of Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 4

5 screening for pancreatic and other cancers should be discussed. The guidelines do not mention the Melaris genetic test nor does it offer recommendations regarding testing for mutation of the CDKN2A gene. Aspinwall et al (2014) reported that reducing ultraviolet radiation exposure may decrease melanoma risk in the hereditary melanoma setting. It is unknown whether genetic counseling and test reporting of CDKN2A/p16 mutation status promote longterm compliance with photoprotection recommendations, especially in unaffected mutation carriers. The authors evaluated changes 2 years following melanoma genetic testing in self-reported practice of sun protection (sunscreen, photoprotective clothing, and ultraviolet radiation avoidance) among 37 members of two CDKN2A/p16 kindreds (10 unaffected carriers, 11 affected carriers, and 16 unaffected noncarriers; response rate = 64.9% of eligible participants). Multivariate profile analysis indicated that all three participant groups reported increased daily routine practice of sun protection 2 years following melanoma genetic testing (P < 0.02), with 96.9% reporting that at least one sun protection behavior was part of their daily routine, up from 78.1% at baseline (P < 0.015). Unaffected carriers (P < 0.024) and unaffected noncarriers (P < 0.027) reported significantly more frequent use of photoprotective clothing. Affected carriers maintained adherence to all sun protection behaviors. Reported sunburns in the past 6 months decreased significantly (P < 0.018).The investigators concluded members of high-risk families reported increased daily routine sun protection and decreased sunburns 2 years following melanoma genetic testing, with no net decline in sun protection following negative test results. Thus, genetic testing and counseling may motivate sustained improvements in prevention behaviors. Aspinwall et al (2014) sought to determine how risk perceptions change following genetic testing and whether information is recalled accurately over time. In the United States, a CDKN2A/p16 mutation confers 76% lifetime risk of melanoma. Following genetic counseling and test reporting, subjective risk estimates and recall of counselor-provided risk estimates were assessed 5 times over the next 2 years among 60 adult members of 2 extended CDKN2A/p16 kindreds. No sustained changes from baseline in risk perceptions were reported. Unaffected carriers (n=15) consistently reported significantly lower subjective risk estimates (46%) than they were actually given (76%, p<0.001) or recalled having been given (60%, p<0.001). Noncarriers' (n=27) risk estimates decreased following results disclosure, but rebounded, with both subjective and recalled estimates subsequently exceeding what they were told by the counselor (both ps<0.001). Affected carriers' (n=18) risk estimates for developing a new melanoma corresponded well to counselor-provided information (p=0.362). For all 3 patient groups, results were consistent across multiple risk measures and remained similar when demographic, phenotypic, and baseline behavioral contributors to melanoma risk were statistically controlled. These findings are consistent with other studies of risk perception, but additional studies of more diverse populations are needed to understand the reasons behind both the persistence of initial risk estimates and their divergence from information provided by the counselor during genetic counseling. Additionally, determining whether holding subjective risk perceptions that differ from counselor-provided information ultimately affects adherence to management recommendations will help guide the presentation of risk information in genetic counseling practice. Gabree et al (2014) reported that families that have several relatives with melanoma, multiple primary melanomas in one individual, younger than average ages of melanoma onset, and/or the presence of both pancreatic cancer and melanoma may be suggestive of a hereditary melanoma syndrome and are candidates for genetic counseling and risk assessment. Genetic counseling for hereditary melanoma presents many complexities. Only a minority of hereditary Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 5

6 melanoma cases have been attributed to a single genetic factor, CDKN2A. Both the frequency and the penetrance of CDKN2A mutations has been shown to be dependent on multiple factors. The clinical utility of genetic testing for hereditary melanoma families is debatable because CDKN2A status may not impact medical management in patients with melanoma. No standard medical management guidelines exist for families with CDKN2A mutations; however, family history of melanoma and pancreatic cancer may warrant further discussion. Clinicians should discuss the clinical and psychological implications before genetic testing. Genetic counseling and pretest education regarding melanoma risk factors provides an opportunity to increase knowledge and understanding of melanoma risk, while addressing psychological risks and concerns. Scientific Rationale Update November 2013 Per the NCCN Guidelines on Melanoma (Version 1, 2014) and the NCCN Guidelines on Pancreatic Cancer (Version ) there is no specific mention of Melaris genetic testing nor of CDKN2A Testing. Scientific Rationale Update February 2012 According to the 2013 NCCN guidelines on melanoma, Risk factors for melanoma include positive family history of melanoma, prior melanoma, multiple clinically atypical moles or dysplastic nevi and rarely inherited mutations. Sun exposure may also contribute to the development of melanoma. Autosomal dominantly inherited mutations in melanoma susceptibility genes are responsible for only 5 to 10 percent of cutaneous melanomas. Mutations in two genes, CDKN2A and CDK4, have been identified in melanoma-prone families. Melaris is a commercially available genetic test of the CDKN2A gene, which is altered in approximately 40% of cutaneous malignant melanoma (CMM) patients with a family history of melanoma. The NCCN does not address Melaris genetic testing in their guidelines on malignant melanoma or pancreatic cancer. At the present time, no published studies using the commercially available tests for CDKN2A genetic testing were identified in the peer review literature. The Melanoma Genetics Consortium recommends that DNA testing for mutations in melanoma susceptibility genes be performed only rarely outside of defined research programs. This recommendation is based upon a lack of knowledge regarding the penetrance of CDKN2A mutations, the failure to identify mutations in more than 60 percent of hereditary melanoma kindreds, and limited data on the efficacy of prevention and surveillance strategies Maubec et al (2012) investigated association of 3 clinical features with the presence of a CDKN2A mutation in a family by extent of cutaneous melanoma (CM) family clustering (2 vs 3 patients with CM among first-degree relatives in a family). The investigators included 483 French families that comprised 387 families with 2 patients with CM (F2 families) and 96 families with 3 or more patients with CM (F3+ families). Three clinical factors were examined individually and in a joint analysis: median age at diagnosis younger than 50 years, and 1 or more patient in a family with multiple primary melanoma or with pancreatic cancer. The frequency of CDKN2A mutations was higher in F3+ families (32%) than in F2 families (13%). Although early age at melanoma diagnosis and occurrence of multiple primary melanoma in 1 or more patient were significantly associated with the risk of a CDKN2A mutation in F2 families, early age at melanoma diagnosis and occurrence of pancreatic cancer in a family were significantly associated with CDKN2A mutations in F3+ families. The study was limited as it was not population based. Investigators concluded the study shows that factors associated with CDKN2A mutations differ by Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 6

7 extent of CM family clustering. Per the authors, it indicates that, in France, families with 2 patients with CM are eligible for genetic testing especially when there is an early age at CM diagnosis and/or 1 or more patients with multiple primary melanoma. Harinck et al (2012) reported that CDKN2A-mutation carriers run a high risk of developing melanomas and have an increased risk of developing pancreatic cancer (PC). Familial PC (FPC) patients with a personal history or family history of melanomas are therefore offered CDKN2A-mutation analysis. In contrast, CDKN2A testing in FPC families without a history of melanomas is not generally recommended. The aim of this study was to evaluate the frequency of CDKN2Amutations in FPC families without melanomas. Data were gathered from PC family registers. FPC families were defined as families with clustering of PC without meeting diagnostic criteria of familial cutaneous malignant melanoma (familial CMM) or other inherited cancer syndromes. Blood samples were obtained for DNA isolation from PC patients or first degree relatives and analysed for CDKN2A-mutations. Among 40 FPC families, DNA analyses were carried out in 28 families (70%), leading to identification of CDKN2A-mutations in six families (21%). None of the CDKN2Amutation-positive families fulfilled the diagnostic criteria for familial CMM and in three CDKN2A families no melanomas were observed. Two CDKN2A-mutations were found; the Dutch founder mutation p16-leiden (c.225_243del, p.ala76fs) and the c.19_23dup, p.ser8fs-mutation. After disclosure of the CDKN2A-mutation in one of the families, a curable melanoma was diagnosed at dermatological surveillance in a 17-year-old family member. Investigators concluded CDKN2A-mutation can be found in a considerable proportion of families with FPC. CDKN2A-mutation analysis should therefore be included in genetic testing in FPC families, even in the absence of reported melanomas. This strategy will enhance the recognition of individuals at risk for PC and facilitate the early detection of melanomas Scientific Rationale Update February 2011 Cutaneous malignant melanoma (CMM) is an invasive skin cancer that originates from the melanocytes or the pigment-producing skin cells. CMM is the most lethal form of skin cancer, causing more than 8000 deaths in the United States annually. Risk factors for development of CMM include: exposure to sunlight, particularly sunburns during childhood; family history of melanoma or pancreatic cancer; fair skin and/or red or blonde hair; and a large number of freckles or moles. The first sign of CMM is often a mole that changes color or shape. Approximately 10% of patients diagnosed with CMM report a family history of the disease. Genetic studies have identified a gene known as the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene, which is altered in approximately 40% of CMM patients with a family history of melanoma. The CDKN2A gene is transmitted in an autosomal dominant fashion. Current treatment for CMM includes surgical excision of the lesion, potentially followed by chemotherapy, radiation therapy, and/or immunotherapy. CMM has a good clinical prognosis if detected at an early stage. The Melaris genetic test offers DNA sequence determination of approximately 471 base pairs, comprising the coding region of three exons from the CDKN2A gene, and approximately 95 base pairs of adjacent noncoding sequence. Myriad Genetic Laboratories also offers Single Site Melaris for detection of known CDKN2A sequence variants previously identified in an index case from the family. Genetic testing for sequence variants in the CDKN2A gene is currently available from several laboratories including Boston University Center for Human Genetics (Boston, MA), Emory Genetics Laboratory (Decatur, GA), GeneDx Inc. (Gaithersburg, MD), and Myriad Genetic Laboratories Inc. (Salt Lake City, UT). Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 7

8 The overall prevalence of sequence variants in the CDKN2A gene is estimated to be 40% in melanoma-prone families; however, prevalence estimates vary markedly between geographic regions. Though penetrance estimates also vary by region, the overall estimated penetrance of CDKN2A is 67% by age 80. Assessing the clinical validity of testing for CDKN2A is difficult as, at present, there is incomplete knowledge of the genes contributing to familial CMM, and more than half of all patients with a family history of melanoma will test negative for a genetic variant in CDKN2A. The clinical interpretation of a negative test result is unclear, given the potential role of undiscovered genes, and the risk associated with phenotype and environmental factors. However, preliminary studies have indicated a potential benefit to CDKN2A genetic testing, as measured by cognitive scores and behavioral patterns of skin examination and photoprotection. Follow-up studies are needed to determine whether these positive behavioral changes lead to improved treatment and survival. Future research is likely to identify new genetic variants related to melanoma predisposition, and promising new treatments are also being explored. The variability in the background incidence of melanoma, and the penetrance of CDKN2A in different geographic regions, makes it difficult to create general guidelines for genetic testing that would be applicable worldwide. Leachman et al. (2009) reviewed the published literature and sought to identify individuals who would derive the most benefit from referral to a genetics clinic for possible testing. The authors concluded that, in areas with moderate to high melanoma incidence, patients with three or more primary melanomas among first or second degree blood relatives, and/or families with at least one melanoma and two or more cases of melanoma and/or pancreatic cancer among first or second degree blood relatives, would derive the most benefit from melanoma genetic testing. For low melanoma incidence areas, two melanoma and/or pancreatic cancer cases in a family may be adequate to refer for genetic testing. Regardless of whether or not genetic testing is part of the care for melanoma-prone families, the authors concluded that there is a likely benefit to identifying the highest-risk families and targeting them for education and intense surveillance. CDKN2A gene testing may be considered most beneficial for the following patient groups: Patients with 3 primary invasive melanomas. Patients with at least 1 invasive melanoma, and with 2 melanoma or pancreatic cancer diagnoses among first- or second-degree blood relatives. Asymptomatic blood relatives of genetically confirmed CDKN2A-positive melanoma patients. Clinical alternatives to CDKN2A gene testing involve a full medical work-up, including histopathological confirmation of CMM. Patients with CMM generally present with atypical skin lesions that may have recently changed in appearance. Melanoma skin lesions are characterized by asymmetry, border irregularities, heterogeneous color, large size, and elevation from the skin. The ABCD (Asymmetry, Border, Color, Dimension) criteria, first introduced in 1985, is a commonly used guide for the clinical diagnosis of early CMM. To improve diagnostic accuracy, and to clarify the differential diagnosis of pigmented lesions, dermatoscopy should be used whenever possible. A full family and medical history is also part of the routine clinical work-up, making particular note of any changes to preexisting melanocytic nevus. Confirmation of diagnosis is made by excision biopsy of the lesion, followed by histopathological examination. A complete pathology report should include diagnosis, clinicopathological type, thickness of lesion (known as the Breslow measurement), depth of invasion, growth pattern, margin status, dimensions, and presence or absence of ulceration. Following a pathologically confirmed diagnosis of CMM, Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 8

9 examination and possible biopsy of regional lymph nodes is recommended. Staging of CMM is based on the American Joint Committee on Cancer (AJCC) staging and classification system. Depending on the stage at diagnosis, chest x-ray, magnetic resonance imaging (MRI), computed tomography (CT), or positron emission tomography (PET) scans may be necessary to detect distant metastases. Serum protein S-100 and L-lactate dehydrogenase (LDH) may also be used as markers of metastases and relapse. Radiation therapy, chemotherapy, or immunotherapy may also be recommended for patients with CMM diagnosed at an advanced stage.57 The patient and their family should be counseled in avoidance of sunburn and prolonged unprotected UVR exposure, as well as lifelong regular self-examination of the skin. Clinical follow-up recommendations based on stage at diagnosis vary from two to four times per year for the first 5 years, followed by one to two times per year for years 6 to 10. Currently, the best predictor of prognosis for melanoma patients is the stage at diagnosis. However, there are some patients with early-stage melanoma who develop metastases and may potentially die of the disease. One area of active research is the identification of biomarkers with prognostic significance in melanoma to guide management of patients and potentially lead to new therapeutic interventions. Scientific Rationale Update December 2009 A Medline search fails to reveal any additional randomized controlled studies that offer predictive DNA testing for malignant melanoma and pancreatic cancer outside of defined research protocols. Therefore, the Melaris test used to screen individuals for hereditary melanoma and pancreatic cancer continues to be considered investigational. Scientific Rationale Update December 2008 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. While some of the familial risk may be related to environmental factors, the above noted three main genes involved in cutaneous malignant melanoma susceptibility have now been identified. Other studies have also focused on the association between CDKN2A and pancreatic cancer. However, a literature search did not identify any study that focused on how genetic testing for the identified genes would result in an improvement in patient management. Melaris is a commercially available genetic test of the CDKN2A gene. Aspinwall et al. (2008) completed a small prospective study of 59 individuals 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. However, because the impact of this testing on clinical outcomes is still not known, the policy statement is unchanged; this technique is considered investigational. Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 9

10 Scientific Rationale Initial The sequencing of the human genome has sparked great interest in what many have called genomic medicine. Genetic testing generally refers to the direct testing of an individual s DNA where there is some evidence of disease. This is distinct from genetic screening, which involves testing families or populations where there is no prior evidence of disease. There are a number of different forms of genetic testing: (1) confirmatory diagnosis; (2) carrier testing; (3) prenatal/neonatal screening; and (4) predictive and susceptibility testing. More recently, the sequencing of the human genome has generated large amounts of genetic data and research is now focused on developing a new generation of genetic tests for more common conditions, such as cancer and heart disease. However, progress in utilizing this new knowledge in diagnostics has been much slower than expected. One reason for this is that common disorders are genetically complex and certain genes may also require interaction with particular environmental factors or with other genes in order to produce an effect. These problems with finding robust gene-disease associations raises serious questions about the extent to which it will be possible to develop new genetic tests for anything other than a few well characterized subsets of diseases. In addition to skin type and sun exposure, a very important risk factor for the development of melanoma is the history of a family member with melanoma. Melanoma kindreds have been identified that show germline defects in several genes that relate to cell-cycle regulation. Genetic testing would be a means of identifying individuals who would be at high risk for the development of melanoma to allow rigorous promotion of prevention tactics and close surveillance. The only commercially available test of clinical value is p16 gene (CDKN2A) analysis, the Melaris test by Myriad. CDKN2A, located on chromosome 9p21, encodes proteins that act as tumor suppressors and its gene product inhibits the CDK4 cell-cycle protein kinase, an important enzyme in the regulation of cell growth. This second gene, CDK4, is an oncogene located on chromosome 12q13, and has been identified in only 0.2% of all patients with melanoma. Between 20% and 40% of melanoma families carry abnormalities in this gene, which is also associated with familial pancreatic cancer. An important fact is that 95% of patients with a melanoma will not have the p16 mutation. In addition, there is a high incidence of melanoma in patients without identifiable mutations in melanoma-prone families, as well as a large variation of penetrance. 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. Some believe that, if testing is desired, it should be done only in patients who have already have had a melanoma and who fulfill any of the following criteria: The melanoma patient has 3 or more melanomas in other family members; The melanoma patient has only 1 family member with melanoma, but either the patient or the family member has had multiple melanomas; The melanoma patient has a family member with melanoma and another with pancreatic carcinoma; The melanoma patient has multiple primary melanomas (3 or more); There is an early age of onset Analytical validity refers to how well a test performs in the laboratory, that is, how well the test measures the property or characteristic it is intended to measure. In other words, does the test do what its makers claim it does? If so, it must produce Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 10

11 the same results repeatedly and in different laboratories, given the same set of procedures. Clinical validity refers to the accuracy with which a test predicts the presence or absence of a clinical condition or predisposition. Initially, the test has to be conducted on individuals who are known to have the condition (as well as those who do not) to determine its success rate. 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 non-coding mutations. Interpretation will improve as more data accumulates 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. Exposure to sun and other environmental factors, as well as behavior and ethnicity may contribute to the penetrance. Bishop and colleagues (2002) have estimated that the calculated risk of developing melanoma before 80 years in carriers of CDKN2A mutations ranges from 58% in Europe to 91% in Australia. 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 an increased risk. Clinical utility refers to the usefulness of the test and the value of information to the person being tested. If a test has utility, it means that the results, whether they are positive or negative, provide information that is of value to the person being tested because he or she can use that information to seek an effective treatment or preventive strategy. Even if no interventions are available to treat or prevent disease, there may be benefits associated with knowledge of a result. 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. At the present time, it is unclear how genetic testing for CDKN2A would alter these management recommendations already in place. 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, it is unclear how a positive test result would alter patient management as 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, On the other hand, a positive result will establish a mutation, thus permitting targeted testing for the rest of the family. Additionally, a positive mutation in an affected family member increases the likelihood of its clinical significance if detected in another family member. As described above, a negative test is not interpretable. 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. 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 Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 11

12 unaffected individual has the same mutation as an affected relative, then the patient is at high risk for melanoma. However, as discussed above, it is unclear how this would affect the management of the patient. Once again, increased sun protection and surveillance is recommended for any patient in a high-risk family. The published data on genetic testing of the CDKN2A gene focuses on the underlying genetics of hereditary melanoma, identification of mutations in families at high risk of melanoma, and risk of melanoma in those harboring CDKN2A mutations. Other studies have focused on the association between CDKN2A and pancreatic cancer. However, no studies have focused on how testing for CDKN2A gene mutations would result in improved patient outcomes. Although there is an investigative interest in genetic testing for mutations associated with susceptibility to malignant melanoma, it is not known if this technology leads to improved diagnosis, treatment or healthcare outcomes. Currently, clinical evaluation remains the gold standard for determining melanoma risk. In 1999, The Melanoma Genetics Consortium, comprised of familial melanoma researchers worldwide, published a recommendation that genetic testing for melanoma susceptibility should not be offered outside of a research setting. They stated that: Until further data become available, however, clinical evaluation of risk remains the gold standard for preventing melanoma. Firstdegree relatives of individuals at high risk should be engaged in the same programmes of melanoma prevention and surveillance irrespective of the results of any genetic testing. For these reasons, it is currently premature to offer predictive DNA testing for malignant melanoma and pancreatic cancer outside of defined research protocols. Therefore, the Melaris test used to screen individuals for hereditary melanoma and pancreatic cancer is considered investigational. Review History December 2007 February 2008 December 2008 December 2009 February 2011 November 2011 November 2012 November 2013 November 2014 November 2015 Medical Advisory Council initial approval Coding updates Update. No revisions. Codes reviewed. Update. No revisions. Codes reviewed. Update. Added Medicare Table. No revisions. Update no revisions Update no revisions Update no revisions. Codes updated. Update no revisions Update no revisions This policy is based on the following evidence-based guidelines: 1. American Society of Clinical Oncology: Statement of the American Society of Clinical Oncology: Genetic testing for cancer susceptibility. Update. J Clin Oncol 2003; 21(12): Scottish Intercollegiate Guidelines Network (SIGN). Cutaneous melanoma. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); Available at: Kefford RF, Newton Bishop JA, Bergman W, et al. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 12

13 statement of the Melanoma Genetics Consortium.J Clin Oncol 1999;17(10): Available at: 4. Clinical Practice Guidelines. The Management of cutaneous melanoma Agency for Healthcare, Research and Quality (AHRQ). Technology Assessment. Genetic Tests for Cancer. January 9, Hayes. GTE Report. CDKN2A Testing for Malignant Melanoma. June 15, Updated June Updated June Update June National Comprehensive Cancer Network (NCCN). Guidelines Pancreatic Cancer. Version Update version National Comprehensive Cancer Network (NCCN). Guidelines Melanoma. Version Update Version References Update November Avril MF, Bahadoran P, Cabaret O, et al. Recommendations for genetic testing and management of individuals genetically at-risk of cutaneous melanoma. Ann Dermatol Venereol Jan;142(1): Ghiorzo P. Genetic predisposition to pancreatic cancer. World J Gastroenterol Aug 21;20(31): Glitza IC, Davies MA. Genotyping of cutaneous melanoma. Chin Clin Oncol Sep;3(3): Norris AL, Roberts NJ, Jones S, et al. Familial and sporadic pancreatic cancer share the same molecular pathogenesis. Fam Cancer Mar;14(1): Petersen GM. Familial Pancreatic Adenocarcinoma. Hematol Oncol Clin North Am Aug;29(4): Potrony M, Badenas C, Aguilera P, et al. Update in genetic susceptibility in melanoma Ann Transl Med Sep;3(15): Sargen MR, Kanetsky PA, Newton-Bishop J, et al. Histologic features of melanoma associated with CDKN2A genotype. J Am Acad Dermatol Mar;72(3): e7. 8. Taber JM, Aspinwall LG. Framing recommendations to promote prevention behaviors among people at high risk: A simulation study of responses to melanoma genetic test reporting. J Genet Couns Oct;24(5): Wu YP, Aspinwall LG, Michaelis TC, et al. Discussion of photoprotection, screening, and risk behaviors with children and grandchildren after melanoma genetic testing. J Community Genet Jun Zhen DB, Rabe KG, Gallinger S, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med Jul;17(7): References Update November Aspinwall LG, Taber JM, Kohlmann W, wt al. Unaffected family members report improvements in daily routine sun protection 2 years following melanoma genetic testing. Genet Med Apr Aspinwall LG, Taber JM, Kohlmann W, et al. Perceived risk following melanoma genetic testing: a 2-year prospective study distinguishing subjective estimates from recall. J Genet Couns Jun;23(3): 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;22(10): Aspinwall LG, Taber JM, Leaf SL, et al. Genetic testing for hereditary melanoma and pancreatic cancer: a longitudinal study of psychological outcome. Psychooncology Feb;22(2): Gabree M, Patel D, Rodgers L. Clinical applications of melanoma genetics. Curr Treat Options Oncol Jun;15(2): Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 13

14 6. Kurian AW, Hare EE, Mills MA, et al. Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol Jul 1;32(19): Pollio A, Tomasi A, Pellacani G, et al. Multiple primary melanomas versus single melanoma of the head and neck: a comparison of genetic, diagnostic, and therapeutic implications. Melanoma Res Jun;24(3): Saiki Y, Horii A. Molecular pathology of pancreatic cancer. Pathol Int Jan;64(1):10-9. References Update November Curiel-Lewandrowski C. Risk factors for the development of melanoma. UpToDate. August 26, Ghiorzo P, Bonelli L, Pastorino L, et al. MC1R variation and melanoma risk in relation to host/clinical and environmental factors in CDKN2A positive and negative melanoma patients. Exp Dermatol Sep;21(9): doi: /j x. 3. Tsao H, Gabree MJ. Inherited susceptibility to melanoma. UpToDate. March 23, References Update November Axilbund JE, Wiley EA. Genetic testing by cancer site: pancreas. Cancer J Jul;18(4): Harinck F, Kluijt I, van der Stoep N, et al. Indication for CDKN2A-mutation analysis in familial pancreatic cancer families without melanomas. J Med Genet Jun;49(6): Epub 2012 May Liang XS, Pfeiffer RM, Wheeler W, et al. Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations. Int J Cancer May 1;130(9): Maubec E, Chaudru V, Mohamdi H, et al. Familial melanoma: Clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family. J Am Acad Dermatol Jul 26. References- Update November Buecher B, Gauthier-Villars M, Desjardins L, et al. Contribution of CDKN2A/P16 ( INK4A ), P14 (ARF), CDK4 and BRCA1/2 germline mutations in individuals with suspected genetic predisposition to uveal melanoma. Fam Cancer Dec;9(4): Christensen KD, Roberts JS, Shalowitz DI, et al. Disclosing individual CDKN2A research results to melanoma survivors: interest, impact, and demands on researchers. Cancer Epidemiol Biomarkers Prev Mar;20(3): Liang XS, Pfeiffer RM, Wheeler W, et al. Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations. Int J Cancer Jun 13. doi: /ijc Pedace L, De Simone P, Castori M, et al. Clinical features predicting identification of CDKN2A mutations in Italian patients with familial cutaneous melanoma. Cancer Epidemiol Sep 3 5. Verna EC, Hwang C, Stevens PD, et al. Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics. Clin Cancer Res Oct 15;16(20): References Update February University of Pennsylvania. Genetic Epidemiology of Melanoma Research Portfolio Online Reporting Tool Expenditures and Results (RePORTER). Available at: Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 14

15 Queensland Institute of Medical Research. Pathways from Genotype and Environment to Melanoma Research Portfolio Online Reporting Tool Expenditures and Results (RePORTER). Available at: Leeds Cancer Centre at St. James's University Hospital. Identifying Gene Mutations in Patients With Melanoma and in Families With a History of Hereditary Melanoma. National Library of Medicine (NLM) Identifier: NCT Updated February 11, ClinicalTrials. Available at: 4. Rother J, Jones D. Molecular markers of tumor progression in melanoma. Curr Genomics. 2009;10(4): Larson AR, Konat E, Alani RM. Melanoma biomarkers: current status and vision for the future. Nat Clin Pract Oncol. 2009;6(2): Aspinwall LG, Leaf SL, Dola ER, et al. CDKN2A/p16 genetic test reporting improves early detection intentions and practices in high-risk melanoma families. Cancer Epidemiol Biomarkers Prev. 2008;17(6): References Update December Leachman SA, Carucci J, Kohlmann W, et al. Selection criteria for genetic assessment of patients with familial melanoma. J Am Acad Dermatol Oct; 61(4):677.e Aspinwall LG, Leaf SL, Kohlmann W, et al. Patterns of photoprotection following CDKN2A/p16 genetic test reporting and counseling.j Am Acad Dermatol May; 60(5): Epub 2009 Mar 10. References Update December de Snoo FA, Riedijk SR, van Mil AM, et al. Genetic testing in familial melanoma: uptake and implications. Psychooncology Aug; 17 (8): Hansson J. Familial melanoma. Surg Clin North Am Aug; 88 (4): , viii. 3. Aspinwall LG, Leaf SL, Dola ER et al. CDKN2A/p16 genetic test reporting improves early detection intentions and practices in high-risk melanoma families. Cancer Epidemiol Biomarkers Prev 2008; 17(6): References Initial 1. Bishop JN, Harland M, Randerson-Moor J, Bishop DT. Management of familial melanoma. Lancet Oncol Jan; 8(1): Orlow I, Begg CB, Cotignola J, et al. GEM Study Group. CDKN2A germline mutations in individuals with cutaneous malignant melanoma. J Invest Dermatol May; 127(5): de Snoo FA, Kroon MW, Bergman W, et al. From sporadic atypical nevi to familial melanoma: risk analysis for melanoma in sporadic atypical nevus patients. J Am Acad Dermatol May; 56(5): Lukowsky A, Schäfer-Hesterberg G, Sterry W, and Voit C. Germline CDKN2A/p16 mutations are rare in multiple primary and familial malignant melanoma in German patients. J Dermatol Sci Sep Fargnoli MC, Argenziano G, Zalaudek I, Peris K. High- and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev Anticancer Ther May; 6(5): Bishop JN, Harland M, Bishop DT. The genetics of melanoma. Br J Hosp Med (Lond) Jun; 67(6): Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 15

16 7. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev Aug 15; 20(16): Available at: 8. Goldstein AM, Chan M, Harland M, et al. Melanoma Genetics Consortium (GenoMEL). High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res Oct 15; 66(20): Begg CB, Orlow I, Hummer AJ, et al. Genes Environment and Melanoma Study Group. Lifetime risk of melanoma in CDKN2A mutation carriers in a populationbased sample. J Natl Cancer Inst Oct 19; 97(20): Available at: Pig S, Malvehy J, Badenas C et al. Role of the CDKN2A locus in patients with multiple primary melanomas. J Clin Oncol 2005; 23(13): Begg CB, Orlow I, Hummer AJ, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst 2005; 97: Available at: 7f9b18cbf78cfb752cd4dd Ratter JL, Bromley CM, Goldstein AM et al. Heterogeneity or risk for melanoma and pancreatic and digestive malignancies: a melanoma case-control study. Cancer 2004;101(12): Hansen CB, Wadge LM, Lowstuter K, et al. Clinical germline genetic testing for melanoma. The Lancet Oncology 2004; 5(5): Rulyak SJ, Brentnall TA, Lynch HT, Austin MA. Characterization of the neoplastic phenotype in the familial atypical multiple-mole melanoma-pancreatic carcinoma syndrome. Cancer 2003;98(4): Hayward NK. Genetics of melanoma predisposition. Oncogene 2003;22: Skin Cancer Foundation. (2003). NCI scientists say "no" to screening for inherited risk of melanoma. Bishop DT, Demenais F, Goldstein AM et al. Geographic variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst 2002;94(12): Kefford R, Bishop JN, Tucker M et al. Genetic testing for melanoma. Lancet Oncol 2002;3(11): Olopade OI, Offit K, Garber JE. Genetic Testing for Susceptibility to Cancer. JAMA 1998; 279(20): Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language Melaris Genetic Testing for Malignant Melanoma and Pancreatic CA Nov 15 16

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