Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer ...

National Medical Policy Subject:

Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Lynch Syndrome)

Policy Number:

NMP137

Effective Date*:

April 2004

Updated:

March 2017

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

X

Source National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other

Reference/Website Link

None

Use Health Net Policy

MLM. Colorectal Cancer: Preventable, Treatable, and Beatable: Medicare Coverage and Billing for Colorectal Cancer Screening. October 1, 2012: http://www.cms.gov/Outreach-andEducation/Medicare-Learning-NetworkMLN/MLNMattersArticles/downloads/SE0613.pdf

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

Genetic Testing HNPCC Mar 17

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 

determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located 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 (Please refer to HN NMP on Colonoscopy) Health Net, Inc. considers genetic testing [mismatch repair genes (MMR) i.e., MLH1, MSH2, MSH6, PMS2, (EPCAM)] sequence analysis and large rearrangement analysis), for Hereditary Nonpolyposis Colorectal Cancer (HNPCC), now referred to as Lynch syndrome, medically necessary for individuals who meet any of the following criteria: 1.

Individuals meeting either the revised Bethesda guidelines or Amsterdam Criteria (see table below); or

2.

Individuals diagnosed with endometrial cancer under age 50. (Endometrial cancer < 50 y is not included in the revised Bethesda guidelines, however, per the NCCN, recent evidence suggest these individuals should be evaluated for Lynch syndrome); or

3.

Known Lynch syndrome in the family (Per the NCCN, an at-risk member can be defined as a first-degree relative of an affected individual and/or proband. If a first degree-relative is unavailable or unwilling to be tested, more distant relatives should be offered testing for the known mutation in the family); or

4.

Consider testing individuals with >5% risk of lynch syndrome on any one of the following mutation prediction models (i.e. MMRpro, PREMM or MMRpredict). These models may be particularly useful when there is no tumor or insufficient tumor available for IHC or MSI testing, Testing affected individuals in the family with an LS-related cancer is preferred.

Revised Amsterdam II Criteria for clinical definition of Lynch Syndrome

Revised Bethesda Guidelines for testing CRC for Lynch Syndrome by IHC or MSI

At least three relatives must have a cancer associated with Lynch syndrome or HNPCC (colorectal, cancer of endometrial, small bowel, ureter and renal pelvis); and ALL of the following criteria should be present:

Individual must meet ONE of the following criteria:  Colorectal cancer diagnosed under the age of 50 years of age; or  Presence of synchronous or metachronous Lynch syndrome (LS) associated tumors **regardless of age; or  Colorectal cancer with the MSI-H histology (presence of tumor infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern) diagnosed in a patient who is less than 60 years of age; or  Colorectal cancer diagnosed with one or more

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One must be a first-degree relative of the other two At least two successive generations must be affected At least one of the relatives with cancer associated with lynch syndrome/ hereditary nonpolyposis colorectal cancer


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should be diagnosed before the age 50 years Familial adenomatous polyposis (FAP) should be excluded in the colorectal case(s) (if any) Tumors should be verified whenever possible

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first-degree relatives with an LS- related cancer**, with one of the cancers being diagnosed under age 50 years; or Colorectal cancer diagnosed in two or more first or second degree relatives with LS-related tumor, regardless of age.

*Per NCCN:  The decision to test all 4 MMR genes (eg. MLH1, MSH2, MSH6, PMS2) and EPCAM concurrently versus sequentially is left to the discretion of the clinician.

Microsatellite instability (MSI) testing /Immunohistochemical (IHC) analysis Health Net Inc. considers microsatellite instability (MSI) testing and/or immunohistochemical (IHC) analysis (with or without BRAF mutation testing) of the tumor tissue in an effort to identify those individuals who should proceed with HNPCC mutation analysis medically necessary in any of the following, as a preliminary testing strategy in individuals with colorectal cancer in either of the following scenarios: 

Individuals at time of colorectal cancer diagnosis (i.e., universal or reflex testing); or

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Individuals with colorectal cancer diagnosed at 70 who meet the Bethesda guidelines (selective approach).

According to the NCCN, testing the BRAF gene for mutation is indicated when MLH1 expression is absent in the tumor by IHC analysis. The presence of the BRAF mutation indicates that MHL1 expression is down-regulated through somatic methylation of the promoter region of the gene and not by germline mutation. **Lynch Syndrome tumors/cancer include colorectal, endometrial, gastric, ovarian, pancreas, ureter and renal pelvis, biliary tract, brain (usually glioblastoma as seen in Turcot Syndrome) and small intestinal cancers, as well as sebaceous gland adenomas and keratoacanthomas in Muir-Torre syndrome. Note: In general, genetic testing for HNPCC is not recommended for at-risk individuals younger than age 18 years. Guidelines established jointly by the American College of Medical Genetics and the American Society of Human Genetics state that predictive genetic testing should only be performed in individuals younger than age 18 years when it will affect their medical management.

Definitions LS HNPCC MMR MSI

Lynch Syndrome Hereditary Nonpolyposis Colorectal Cancer Mismatch repair genes Microsatellite instability

Codes Related to This Policy NOTE:


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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 153 154.0 197.5 211.3 211.4 230.3 230.4 235.2 239 V10.05 V10.06 V16.0 V76.41

Malignant neoplasm of the colon Malignant neoplasm of the rectosigmoid junction Secondary malignant neoplasm of the large intestine and rectum Benign neoplasm of the colon Benign neoplasm of the rectum and anal canal Carcinoma in situ of the colon Carcinoma in situ to the rectosigmoid junction Neoplasm of uncertain behavior of digestive system; intestine and rectum Neoplasm of unspecified nature; digestive system Personal history of malignant neoplasm; large intestine Personal history of malignant neoplasm; rectosigmoid junction Family history of malignant neoplasm; gastrointestinal tract Special screening for malignant neoplasm; rectum

ICD-10 Codes C18.0-C18.9 C19 C78.5 D01.0-D01.3 D12.0-D12.9 D37.2 D37.4 D37.5 D49.0 Z80.0 Z85.030-Z85.038 Z85.040-Z85.048 Z12.10-Z12.13

Malignant neoplasm of colon Malignant neoplasm of rectosigmoid junction Secondary malignant neoplasm of large intestine and rectum Carcinoma in situ of other and unspecified digestive organs Benign neoplasm of colon, rectum, anus and anal canal Neoplasm of uncertain behavior of small intestine Neoplasm of uncertain behavior of colon Neoplasm of uncertain behavior of rectum Neoplasm of unspecified behavior of digestive system Family history of malignant neoplasm of digestive organs Personal history of other malignant neoplasm of large intestine Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus Encounter for screening for malignant neoplasm of intestinal tract

CPT Codes 81210 81288 81292

BRAF (v-raf murine sarcoma viral oncogene homolog B1) (eg, colon cancer), gene analysis, V6000E variant MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis MLH1 (mutL homolog, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis


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81293 81294 81295 81296 81297 81298 81299 81300 81301

81317 81318 81319 81403 88341 88342 88344

MLH1 (mutL homolog, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MLH1 (mutL homolog, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome); known familial variants MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome); duplication/deletion variants MSH6 [mutS homolog 6 (E.coli)] (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH6 [mutS homolog 6 (E.coli)] (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants MSH6 [mutS homolog 6 (E.coli)] (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants Microsatellite instability analysis (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair of deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed PMS2 [postmeiotic segregation increased 2(S. cerevisiae)] (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis PMS2 [postmeiotic segregation increased 2(S. cerevisiae)] (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants PMS2 [postmeiotic segregation increased 2(S. cerevisiae)] (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants Molecular Pathology Procedure Level 4 Immunohistochemistry or immunocytochemistry, per specimen; each additional single antibody stain procedure (List separately in addition to code for primary procedure) Immunohistochemistry or immunocytochemistry, per specimen; initial single antibody stain procedure Immunohistochemistry or immunocytochemistry, per specimen; each multiplex antibody stain procedure

HCPCS Codes N/A

Scientific Rationale – Update March 2017 According to NCCN guidelines, Genetic/Familial High-Risk Assessment: Colorectal 2.2017, “The traditional approach to identifying an individual at risk for Lynch Syndrome has generally employed a 2-step screening process. First, patients


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meeting clinical criteria based on family history, personal history of cancer, and/or pathologic characteristics are identified, followed by additional application of screening with a molecular test. Commonly employed clinical criteria include Amsterdam II criteria, Bethesda Guidelines, and risk prediction models” NCCN guidelines state further, “As of 2016, the panel recommends universal screening of all CRC’s, in order to maximize sensitivity for Lynch syndrome detection, and simplify care processes. However, evidence suggests an alternate strategy would be to limit screening to individuals with CRC diagnosed < 70 years plus those > 70 years meeting Bethesda guidelines.” Per NCCN, “When genetic testing is recommended, the panel recommends consultation with an individual with expertise in genetics, and germline testing to exclude presence of Lynch-associated mutations. The approach to mutation testing is evolving. Previously, an approach in which 1 or 2 genes were sequenced guided by either disease prevalence or IHC results, followed by additional testing of other genes was followed. Recognition of scenarios in which IHC results were not available also allowed for syndrome specific testing of the panel of genes that cause Lynch syndrome (MHL1, MSH2, MSH^, PMS2, and EPCAM) simultaneously. Reductions in cost of sequencing, and recognition that some patients meeting Lynch syndrome testing criteria may have germline mutations not associated with Lynch syndrome have led to the growing use of so called “multigene” panels in clinical practice. These panels test not only for Lynch syndromeassociated genes, but also for additional mutations. As of 2016. the panel recommends that any of these 3 approaches may be employed as follow-up, and has provided new guidance on the potential role, strengths, and limitations of multi-gene panels in the evaluation of Lynch syndrome, as well as other hereditary cancers.”

Scientific Rationale – Update March 2016 According to NCCN guidelines, Genetic/Familial High-Risk Assessment: Colorectal (2.2015), “Some newer models have been developed to assess the likelihood that a patient carries a mutation in the MMR gene. These computer programs give probabilities of mutations and/or of the development of future cancers based on family and personal history (i.e., PREMM[1,2,6], MMR predict model, MMRpro). These models may be particularly useful when there is no tumor or insufficient tumor available for IHC or MSI testing, and the panel recommends that definitive testing may be considered for individuals with a >5% risk of LS on MMRpro, PREMM[1,2,6}, or MMRpredict.” Kastrinos et al (2015) compared the predictive performance and clinical usefulness of Lynch Syndrome prediction (i.e., MMRPredict, MMRPro, and PREMM [1,2,6] to identify mutation carriers. Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM [1,2,6]. The authors examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided. Mutations were detected in 539 of 2304 (23%) individuals from the clinic-based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and populationbased cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM[1,2,6]. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and


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0.36) but were more satisfactory for PREMM[1,2,6] (1.0 and 0.70). MMRPro or PREMM[1,2,6] predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%. The authors concluded MMRPro and PREMM [1,2,6] can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, the authors suggest considering additional genetic etiologies for the cause of cancer in the family. Goodfellow et al (2015) reported the best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. They sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. ECs from GOG210: (An NRG Oncology and Gynecologic Oncology Group Study) patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. The authors concluded combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease. Dineen et al (2015) reported in the setting of patients with young-onset colorectal cancer (CRC), appropriate genetic workup and testing for potential underlying inherited CRC syndromes is fundamental to patient-centered care. LS is the most common of these inherited syndromes, and current recommendations from the NCCN and other professional societies advocate universal screening for LS among young patients with CRC. The authors conducted a prospective quality improvement intervention trial to optimize universal screening for LS in young (age 5% risk of lynch syndrome on one of the following mutation prediction models: MMRpro, PREMM, or MMRpredict. Testing affected individuals in the family with a lynch syndrome cancer is preferred. The decision to test all 4 MMR genes (eg. MLH1, MSH2, MSH6, PMS2) and EPCAM concurrently versus sequentially is left to the discretion of the clinician. Prior to germline genetic testing, proper pre-test counseling should be done by an individual with expertise in genetics. For individuals found to have a deleterious lynch syndrome mutation, see lynch syndrome surveillance, NCCN recommendations (LS-3 and LS-4). The following statement was removed by NCCN: In addition, individuals with loss of PMS2 or MSH2 and/or MSH6 protein expression via immunohistochemistry, regardless of germline mutation status, should be followed as though they have lynch syndrome.

The Multi-Society Task Force (2014), in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome. The   

following prediction models for lynch syndrome (LS) have been developed: MMRpredict MMRpro PREMM

These prediction models for LS have been validated in several studies and have performed well in identifying LS patients among colorectal cancer cases. However, prediction models have not been evaluated among endometrial cancer cases. Mercado et al. (2013) completed a study done to evaluate the performance of the PREMM, MMRpredict and MMRpro models in detecting Lynch syndrome among unselected, population-based and high-risk, clinic-based endometrial cancer cases. There were 563 population-based, unselected endometrial cancer (EC) cases from Ohio State University and 129 clinic-based, high-risk EC cases from the Colon Cancer Family Registry. PREMM, MMRpredict and MMRpro risk scores were calculated. Discriminative ability of each model was assessed using the area under the receiver operating curve (AUC). Sensitivity and specificity were calculated at 5% cut-off for PREMM and MMRpro, and at 0.5% cut-off for MMRpredict [EC replaced a proximal colorectal cancer (CRC) diagnosis. Pathogenic MMR gene mutations were detected in 14/563 (2.5%) population-based and 80/129 (62%) clinic-based subjects. Pathogenic MMR gene mutations were detected in 14/563 (2.5%) population-based and 80/129 (62%) clinic-based subjects. In contrast to CRC, prediction models for LS have limited clinical utility in determining which patients with EC should undergo clinical genetic testing for LS since these models tend to select too many people for germline testing and miss mutation carriers. Universal tumor testing with MSI and /or IHC may be the best first-line screening strategy if the goal is to identify all mutation carriers. If the goal is to provide a quantitative risk estimate of having LS, development of new prediction models specific for endometrial cancer cases may be necessary.

Scientific Rationale – Update March 2014


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Both the Amsterdam criteria and the Bethesda guidelines attempt to enrich the population of patients with colorectal cancer in whom a genetic cause can be identified and thus avoid the expense and implications of testing patients (and their families) with colorectal cancer in whom there is a low likelihood of uncovering a relevant mutation. Concerns that this approach may miss a substantial proportion of patients with Lynch syndrome has led some investigators to test alternative approaches such as screening all colorectal cancer for evidence of microsatellite instability or loss of mismatch repair (MMR) genes products by immunohistochemistry (IHC). IHC and microsatellite instability (MSI) analyses are screening tests (either by themselves or in conjunction) that are typically done on colon cancer tissues to identify individuals for Lynch Syndrome. Per the National Comprehensive Care Network (NCCN) guidelines on Colorectal Cancer Screening (2.2013), “Many NCCN member institutions and other comprehensive cancer centers now perform IHC and sometimes MSI testing on all colorectal and endometrial cancers regardless of family history to determine which patients should have genetic testing for Lynch syndrome. This approach, referred to as “universal or reflex testing” has been endorsed by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group at the Centers for Disease Control and Prevention (CDC). An alternative approach is to test all patients with colorectal cancer diagnosed prior to the age of 70 years plus patients diagnosed at older ages who meet the Besthesda guidelines (selective approach)” NCCN endorses both the selective approach as well as the universal approach. The National Comprehensive Care Network (NCCN) guidelines on Colon Cancer (2.2014) recommend MMR protein testing be performed for all patients younger than 50 years with colon cancer, based on an increased likelihood of Lynch syndrome in this population. MMR testing should also be considered for all patients with stage II disease, because stage II MSI-H patients may have a good prognosis and do not benefit from 5FU adjuvant therapy. Egoavil et al (2013) aimed to study the prevalence of Lynch Syndrome (LS) among endometrial cancer (EC) patients. Universal screening for LS was applied for a consecutive series EC. Tumor testing using microsatellite instability (MSI), immunohistochemistry (IHC) for mismatch-repair (MMR) protein expression and MLH1-methylation analysis, when required, was used to select LS-suspicious cases. Sequencing of corresponding MMR genes was performed. One hundred and seventythree EC (average age, 63 years) were screened. Sixty-one patients (35%) had abnormal IHC or MSI results. After MLH1 methylation analysis, 27 cases were considered suspicious of LS. From these, 22 were contacted and referred for genetic counseling. Nineteen pursued genetic testing and eight were diagnosed of LS. Mutations were more frequent in younger patients (