National Medical Policy
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1 National Medical Policy Subject: Policy Number: Genetic Testing for Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Lynch Syndrome) 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 Source Reference/Website Link National Coverage Determination (NCD) National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* X Other MLM. Colorectal Cancer: Preventable, Treatable, and Beatable: Medicare Coverage and Billing for Colorectal Cancer Screening. October 1, 2012: Education/Medicare-Learning-Network- MLN/MLNMattersArticles/downloads/SE0613.pdf None Use Health Net Policy 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 1
2 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 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: 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 Revised Bethesda Guidelines for testing CRC for Lynch Syndrome by IHC or MSI 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 Genetic Testing HNPCC Mar 17 2
3 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 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 Individuals with colorectal cancer diagnosed at <70 or individuals > 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 Lynch Syndrome HNPCC Hereditary Nonpolyposis Colorectal Cancer MMR Mismatch repair genes MSI Microsatellite instability Codes Related to This Policy NOTE: Genetic Testing HNPCC Mar 17 3
4 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 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 239 Neoplasm of unspecified nature; digestive system V10.05 Personal history of malignant neoplasm; large intestine V10.06 Personal history of malignant neoplasm; rectosigmoid junction V16.0 Family history of malignant neoplasm; gastrointestinal tract V76.41 Special screening for malignant neoplasm; rectum ICD-10 Codes C18.0-C18.9 Malignant neoplasm of colon C19 Malignant neoplasm of rectosigmoid junction C78.5 Secondary malignant neoplasm of large intestine and rectum D01.0-D01.3 Carcinoma in situ of other and unspecified digestive organs D12.0-D12.9 Benign neoplasm of colon, rectum, anus and anal canal D37.2 Neoplasm of uncertain behavior of small intestine D37.4 Neoplasm of uncertain behavior of colon D37.5 Neoplasm of uncertain behavior of rectum D49.0 Neoplasm of unspecified behavior of digestive system Z80.0 Family history of malignant neoplasm of digestive organs Z Z Personal history of other malignant neoplasm of large intestine Z Z Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus Z12.10-Z12.13 Encounter for screening for malignant neoplasm of intestinal tract CPT Codes 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 Genetic Testing HNPCC Mar 17 4
5 81293 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 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 , The traditional approach to identifying an individual at risk for Lynch Syndrome has generally employed a 2-step screening process. First, patients Genetic Testing HNPCC Mar 17 5
6 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 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 Genetic Testing HNPCC Mar 17 6
7 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 <50 years) patients, involving 356 eligible patients during the 12-month preintervention period and 299 patients during the postintervention. Applying the Six Sigma conceptual framework, the authors demonstrated a significant increase in use of tumor-based molecular testing and subsequent confirmatory germline mutation testing for LS. This led to identification of more patients to be managed as having LS and of more first- and second-degree relatives to benefit from the testing results. The authors concluded the study demonstrated the successful application of a quality improvement conceptual framework for the universal adoption of molecular biomarker testing in patients with cancer, and for improving adherence to NCCN Clinical Practice Guidelines in Oncology for CRC Screening. As molecular and genetic testing is becoming increasingly common, we present a prototype study for improving the adoption of molecular studies and the provision of guideline-based patient-centered care. Genetic Testing HNPCC Mar 17 7
8 Scientific Rationale Update March 2015 The NCCN Guidelines Version on Genetic/Familial High-Risk Assessment on Lynch Syndrome notes the following revisions: Consider testing individuals with >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 Genetic Testing HNPCC Mar 17 8
9 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 (<50 yrs). Three cases had either intact IHC or MSS and reinforce the need of implement the EC screening with both techniques. Authors concluded the prevalence of LS among EC patients was 4.6% (8/173); with a predictive frequency of 6.6% in the Spanish population. Universal screening of EC for LS is recommended. Ward et al (2013) aimed to determine whether decisions of patients or clinicians reduced detection of Lynch syndrome in a prospective cohort of 245 consecutive individuals with mismatch repair-deficient CRC recruited from a population-based molecular screening program of all incident patient cases of CRC in a health care Genetic Testing HNPCC Mar 17 9
10 region of 1.2 million inhabitants. All incident CRCs were analyzed for mismatch repair protein loss, supported by BRAF mutation and microsatellite instability testing. Advice regarding referral for germline testing was provided to treating surgeons. The mean age of patients was 72.5 ± standard deviation of 12 years; 64% were women; 65% had BRAF-mutant cancers. Consent for germline testing was received from 194 patients (79%): 120 with low and 74 with high likelihood of Lynch syndrome based on tumor molecular profile. Of patients who consented, 143 provided samples for germline analysis, with 12 of 143 showing a mutation (8.4%; 95% CI, 4.4% to 14.2%). Among the 102 patients who chose not to provide a sample or did not consent, an estimated 5.3 of 102 had germline mutations (5.2%; 95% CI, 2.0% to 17.5%). Investigators concluded a universal screening strategy for Lynch syndrome is potentially effective because the overall estimate of germline mutations was 17.3 of 245 patient cases (7.1%; 95% CI, 2.8% to 18.2%). However, the true value of screening is likely to be greatly limited by the decisions and circumstances of patients in taking up germline testing. Heald et al (2013) reported that in 2009, the Evaluation of Genomic Applications in Practice and Prevention recommended that all colorectal cancers (CRCs) be screened for LS through MSI or IHC. No studies report how this process is implemented on a health system-wide basis. Since 2004, Cleveland Clinic has screened CRC specimens with MSI/IHC. Between January 2004 and July 2007, MSI/IHC results went only to the colorectal surgeon (approach 1). Between August 2007 and June 2008, colorectal surgeons and a genetic counselor received the MSI/IHC results, and the counselor e- mailed the colorectal surgeon regarding appropriate patients for genetic counseling (GC) referral (approach 2). After July 2008, the colorectal surgeon and counselor received MSI/IHC results, but the counselor contacted the patient to facilitate referral (approach 3). In approaches 2 and 3, patients were presumed to have sporadic CRC if the tumor lacked MLH1 expression and was also BRAF mutated or if the patient was diagnosed at age greater than 72 years and had no cancer family history. Abnormal MSI/IHC results occurred in 178 (16%) of 1,108 patients. In approach 1, 21 (55%) of 38 patients with abnormal MSI/IHC were referred for GC, 12 (32%) of 38 underwent GC, and 10 (26%) of 38 underwent genetic testing (GT). In approach 2, nine (82%) of 11 patients were referred for GC, seven (64%) of 11 underwent GC, and five (45%) of 11 underwent GT. In approach 3, 56 (100%) of 56 patients were referred for GC, 40 (71%) of 56 underwent GC, and 37 (66%) of 56 underwent GT. Time from referral to GC was 10-fold quicker in approach 3 than approach 1. Authors concluded implementation of universal MSI/IHC with GC/GT, along with effective multidisciplinary communication and plans of responsibility for patient contact, resulted in increased identification of patients with LS. Moreira et al (2012) reported identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. They sought to establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing Genetic Testing HNPCC Mar 17 10
11 of all CRC patients (universal screening). Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%- 98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P <.001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P <.001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%- 96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P <.001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. Investigators concluded universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest. Scientific Rationale Update March 2013 According to the National Comprehensive Care Network (NCCN), Lynch syndrome is the most common form of genetically determined colon cancer predisposition, accounting for 2% to 4% of all colorectal cancer cases. This hereditary syndrome results from germline mutations in DNA mismatch (MMR) genes (MLH1, MSH2, MSH6 and PMS2), although possible associations with three other genes (MlH3, PMS1 and EXO1) have also been found. Recent evidence has shown that 3 deletions in the EPCAM gene, which leads to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing, are an additional cause of lynch syndrome. EPCAM deletions likely account for % of cases in which MSH2 protein is not detected by IHC but germline MSH2 mutations are not found. MMR mutations are detected in more than half if persons meeting the clinical criteria of lynch syndrome, and the lifetime risk of CRC approaches 80% in individuals carrying a mutation in one of these genes. Microsatellite instability (MSI) occurs in 80% to 90% of resulting CRCs. patients H-ne. Although identifying a germline mutation in an MMR gene through sequencing is definitive for Lynch syndrome, patients usually undergo selection by considering family history and performing an initial test on tumor tissue before sequencing. One of two different initial tests can be performed on colorectal cancer specimens to identify individuals who might have Lynch syndrome; immunohistochemical analysis for MMR protein expression, which is often diminished because of mutation, or analysis for microsatellite instability (MSI), which results from MMR deficiency and is detected as changes in length of repetitive DNA elements in tumor tissue caused by insertion or deletion of repeated units. Testing the BRAF gene for mutation is indicated when immunohistochemical analysis shows that MLH1 protein expression is absent in the tumor. The presence of a BRAF mutation indicates that MLH1 gene expression is down-regulated through somatic methylation of the promoter region of the gene and not through a germline mutation. The panel recommends, 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 patients with stage II tumors. The guidelines note that some centers now perform immunohistochemistry and sometimes MSI testing on all colorectal and endometrial cancers regardless of Genetic Testing HNPCC Mar 17 11
12 family history to determine which patients should have genetic testing for Lynch syndrome. This approach was endorsed by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) working group at the Centers for Disease Control and Prevention (CDC). Per the NCCN, individuals with abnormal IHC or MSI results should be referred for genetic counseling so that appropriate follow-up testing can be offered. If a mutation is not found by sequencing, testing for large rearrangements and deletions of MMR genes may also be performed. According to the NCCN guidelines on Colon Cancer Screening (2.2012): It is important to consider genetic testing for at-risk family members when the family mutation is known. At-risk family member can be defined as a first degree relative (FDR) of an affected individual and/or proband. If an FDR is unavailable or unwilling to be tested, more distant relatives should be offered testing for the known family mutation. Testing for Lynch syndrome is advised for individuals who fit any of the following: Meets revised Bethesda guidelines or Amsterdam criteria; Diagnosed with endometrial cancer under age 50; Known Lynch syndrome in the family. They guidelines note the testing strategy will depend on whether there is a known MMR mutation in the family. If so, the individual should be tested for the familial mutation. In the case where no known familial mutation has been previously identified, efforts should be made to identify the mutation. If a relevant CRC or endometrial tumor is available, consider both IHC and MSI testing on the sample. If no suitable sample is available, genetic testing on the affected relative should be considered with the following priority: MLH1 and MSH2 first, then MSH6, and lastly PMS2. Due to its rarity, testing for PMS2 mutation is only necessary if no mutation is found in the other genes. According to a NCBI gene review on Lynch syndrome: MLH1 and MSH2 germline mutations account for approximately 90% of mutations in families with Lynch syndrome; MSH6 mutations in about 7%-10%; and PMS2 mutations in fewer than 5%. Genetic testing for Lynch syndrome is ideally performed in a stepwise manner: Evaluation of tumor tissue for MSI through molecular MSI testing and/or immunohistochemistry (IHC) of the four MMR proteins. The presence of MSI in the tumor alone is not sufficient to diagnosis Lynch syndrome because 10%-15% of sporadic colorectal cancers exhibit MSI. IHC testing helps identify the MMR gene that most likely harbors a germline mutation. Molecular genetic testing of the tumor for methylation and somatic BRAF mutations to help identify those tumors more likely to be sporadic than hereditary. Molecular genetic testing of the MMR genes to identify a germline mutation when findings are consistent with Lynch syndrome Genetic Testing HNPCC Mar 17 12
13 Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family. Wielandt et al (2012) sought to demonstrate the usefulness of MSI and IHC in the detection of mutations in patients with LS. Material and Methods: From our Familial Colorectal Cancer Registry, families suspected of LS were selected according to Amsterdam or Bethesda clinical criteria. Screening of germline mutations of MLH1, MSH2 and MSH6 genes was performed. In addition, analysis of MSI and IHC were performed in colorectal tumors. Results: A total of 35 families were studied (19 met Amsterdam and 16 met Bethesda criteria). Twenty one families harbored a germline alteration in MLH1, MSH2 or MSH6 (18 Amsterdam and 3 Bethesda). In these families, eighteen different alterations were found, 15 of which were mutations and 3 corresponded to variants of uncertain pathogenicity. On the other hand, 80% of the tumors showed positive microsatellite instability (27 MSI-high and 1 MSI-low), and immunohistochemical testing showed that 77% of tumors had the loss of a protein. Correlation between results of tumor molecular studies and the finding of germline nucleotide change showed that IHC and MSI predicted mutations in 81 and 100% of patients, respectively. Conclusions: MSI and IHC can efficiently select patients with a high probability of carrying a mutation in DNA repair genes. Bonnet et al (2012) investigated in routine conditions a strategy that uses simplified clinical criteria plus detection of MisMatch Repair deficiency in tumors to identify Lynch carriers. Colorectal cancer patients that met at least one of three clinical criteria were included: (1) colorectal cancer before 50 years, (2) personal history of colorectal or endometrial cancer, (3) first-degree relative history of colorectal or endometrial cancer. All tumors underwent an MisMatch Repair test combining microsatellite instability analysis and MisMatch Repair immunohistochemistry. Patients with an MisMatch Repair-deficient tumor were offered germline testing. Of the 307 patients fulfilling the clinical criteria, 46 (15%) had a MisMatch Repairdeficient tumor. Amongst them 27 were identified as Lynch carriers (20 with germline mutation: 12 MLH1, 7 MSH2, 1 MSH6; 7 highly suspected cases despite failure of genetic testing). The simplified clinical criteria selected a population whose MisMatch Repair-deficient status was highly predictive (59%) of Lynch syndrome. Investiators concluded the bio-clinical strategy based on simplified clinical criteria combined with an MisMatch Repair test efficiently detected LS cases and is easy to use in clinical practice, outside expert centres. Pérez-Carbonell et al (2012) sought to compare the present approach with universal MMR study-based strategies to detect Lynch syndrome in a large series of patients with colorectal cancer (CRC) patients with CRC from the EPICOLON I and II cohorts were included. Immunohistochemistry for MMR proteins and/or microsatellite instability (MSI) analysis was performed in tumor tissue. Germline MLH1 and MSH2 mutation analysis was performed in patients whose tumors showed loss of MLH1 or MSH2 staining, respectively. MSH6 genetic testing was done in patients whose tumors showed lack of MSH6 expression or a combined lack of MSH2 and MSH6 expression but did not have MSH2 mutations. PMS2 genetic testing was performed in patients showing isolated loss of PMS2 expression. In patients with MSI tumors and normal or not available MMR protein expression, all four MMR genes were studied. A total of 180 patients (8.6%) showed loss of expression of some of the MMR proteins and/or MSI. Four hundred and eighty-six patients (23.2%) met some of the revised Bethesda criteria. Of the 14 (0.7%) patients who had a MMR gene mutation, 12 fulfilled at least one of the revised Bethesda criteria and two (14.3%) did not. Genetic Testing HNPCC Mar 17 13
14 Investigators concluded routine molecular screening of patients with CRC for Lynch syndrome using immunohistochemistry or MSI has better sensitivity for detecting mutation carriers than the Bethesda guidelines. Scientific Rationale Update September 2012 Lynch syndrome, caused by a germline mutation in a mismatch repair gene and associated with tumors exhibiting microsatellite instability (MSI), is characterized by an increased risk of colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and skin. The diagnosis of Lynch syndrome can be made on the basis of family history in those families meeting the Amsterdam criteria who have tumor microsatellite instability (MSI) OR on the basis of molecular genetic testing in an individual or family with a germline mutation in one of four mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). MLH1 and MSH2 germline mutations account for approximately 90% of mutations in families with Lynch syndrome. Genetic testing for Lynch syndrome is ideally performed in a stepwise manner: Evaluation of tumor tissue for MSI through molecular MSI testing and/or immunohistochemistry (IHC) of the four MMR proteins. The presence of MSI in the tumor alone is not sufficient to diagnosis Lynch syndrome because 10%-15% of sporadic colorectal cancers exhibit MSI. IHC testing helps identify the MMR gene that most likely harbors a germline mutation. Molecular genetic testing of the tumor for methylation and somatic BRAF mutations to help identify those tumors more likely to be sporadic than hereditary. If the findings from these and other tests of tumor tissue are consistent with Lynch syndrome, germline molecular genetic testing can be pursued. Molecular genetic testing of the MMR genes to identify a germline mutation when findings are consistent with Lynch syndrome. BRAF mutations, the most common being Val600Glu (V600E), occur in 15% of colorectal cancers. 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 by somatic methylation of the promoter region of the gene and not by germline mutation. BRAF mutations are thought to be rare in Lynch syndrome-related cancers and, thus, in general the presence of a BRAF mutation rules out the diagnosis of Lynch syndrome. BRAF mutations are not common in sporadic endometrial cancers; thus, BRAF testing is not helpful in distinguishing endometrial cancers that are sporadic from those that are Lynch syndrome-related. Parsons et al (2012) performed a systematic review to assess the value of BRAF V600E mutation and MLH1 promoter methylation tumor markers as negative predictors of germline MMR mutation status. Studies were assessed for tumor features, stratified by tumor MMR status based on immunohistochemistry or MSI where possible. Pooled frequencies and 95% CIs were calculated using a random effects model. BRAF V600E results for 4562 tumors from 35 studies, and MLH1 promoter methylation results for 2975 tumors from 43 studies, were assessed. In Genetic Testing HNPCC Mar 17 14
15 550 MMR mutation carriers, the BRAF V600E mutation frequency was 1.40% (95% CI 0.06% to 3%). In MMR mutation-negative cases, the BRAF V600E mutation frequency was 5.00% (95% CI 4% to 7%) in 1623 microsatellite stable (MSS) cases and 63.50% (95% CI 47% to 79%) in 332 cases demonstrating MLH1 methylation or MLH1 expression loss. MLH1 promoter methylation of the 'A region' was reported more frequently than the 'C region' in MSS CRCs (17% vs 0.06%, p<0.0001) and in MLH1 mutation carriers (42% vs 6%, p<0.0001), but not in MMR mutation-negative MSI-H CRCs (40% vs 47%, p=0.12). Methylation of the 'C region' was a predictor of MMR mutation-negative status in MSI-H CRC cases (47% vs 6% in MLH1 mutation carriers, p<0.0001). The reviewer concluded the tumor BRAF V600E mutation, and MLH1 promoter 'C region' methylation specifically, are strong predictors of negative MMR mutation status. It is important to incorporate these features in multifactorial models aimed at predicting MMR mutation status. Geiersbach and Samowitz (2011) reviewed the literature on microsatellite instability in colorectal cancer and current laboratory diagnostic testing strategies for the detection of Lynch syndrome. This review is based on peer-reviewed literature, published guidelines from professional organizations (Evaluation of Genomic Applications in Practice and Prevention Working Group, National Comprehensive Cancer Network), and information from clinical laboratories performing microsatellite instability testing. Reviews noted that universal screening for Lynch syndrome in all individuals affected with colorectal cancer has been recommended by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Preliminary screening tests can identify individuals unlikely to be affected by Lynch syndrome, thereby reducing the need for full gene analysis. Immunohistochemistry and polymerase chain reaction-based tests for microsatellite instability have similar clinical sensitivity and specificity, and each method has advantages and limitations. BRAF and MLH1 methylation testing are useful reflex tests for those with a defect in MLH1 identified by immunohistochemistry. Emerging technologies, such as highthroughput sequencing, may substantially affect diagnostic algorithms in the future. Tresallet et al (2012) studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor MSI, somatic BRAF mutation, MLH1 promoter methylation and MMR gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and compared to the revised Bethesda guidelines and a molecular strategy based on MSI testing in all patients followed by the exclusion of MSI-positive sporadic cases from mutational testing by screening for BRAF mutation and MLH1 promoter methylation. The sensitivities of the three models, at the lowest thresholds proposed, were identical (75%), with similar numbers of probands eligible for further MSI testing (almost half the patients). In the dataset, the prediction models gave no better discrimination than the revised Bethesda guidelines. Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all patients with Lynch syndrome in this series of consecutive CRC. Investigators concluded the results support systematic screening for MMR deficiency in all new CRC case. Scientific Rationale Update December 2010 Lynch syndrome (LS) also called hereditary nonpolyposis colorectal cancer (HNPCC), is associated with cancer diagnosis at an early age and the development of multiple cancer types, particularly colon and endometrial cancer. According to the American Congress of Obstetricians and Gynecologist practice bulletin on Elective and Risk Genetic Testing HNPCC Mar 17 15
16 Reducing Salpingo oophorectomy (Jan 2008), women with HNPCC have a 40 60% lifetime risk of endometrial cancer and an 8 10% risk of ovarian cancer. Lynch syndrome is an autosomal dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the DNA mismatch repair genes (MMR): MSH2, MLH1, MSH6, PMS2. Mutations in MSH2 or MLH1 are thought to account for about 90 percent of the heterozygous germline mutations that have been identified in patients with Lynch syndrome, MSH6 mutations are thought to account for most of the remainder, and PMS2 mutations have been described in relatively few Lynch families. Microsatellite instability refers to the expansion or contraction of short repetitive DNA sequences (microsatellites) that is due to a loss of DNA mismatch repair. Tumors can be tested for microsatellite instability using polymerase chain reaction to amplify a standard panel of DNA sequences containing nucleotide repeats. If 30 percent or more of the markers show expansion or contraction of the repetitive sequences in the tumor compared to the normal mucosa from the same patient, the tumor is reported to have a high level of microsatellite instability (MSI-H). The presence of MSI-H in tumor tissue suggests that a defect in a DNA mismatch repair gene is present. MSI is highly sensitive for Lynch syndrome; more than 90 percent of tumor tissue from patients with Lynch syndrome show high levels of microsatellite instability (MSI-H). MSI-H status cannot be used alone as a test for Lynch syndrome cancers because the specificity of MSI-H for Lynch syndrome is low, however, MSI can be used as one of the first steps in a protocol for individuals who are at increased risk for Lynch syndrome. 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. The Amsterdam criteria have classically been used as a clinical approach to help identify families that are at high enough risk for Lynch syndrome that gene testing should be considered. The Bethesda guidelines were developed to try to identify a larger proportion of the at-risk individuals. The Bethesda guidelines identify individuals with colorectal or other Lynch-associated cancers who should be tested for microsatellite instability with consideration of MMR gene testing in those with MSI-H tumors. According to the National Comprehensive Care Network (2011), testing for Lynch Syndrome is advised for individuals who fit any of the following: Meets revised Bethesda guidelines or Amsterdam criteria; Diagnosed with endometrial cancer under age 50; Known Lynch syndrome in the family. The NCCN notes further that if a relevant CRC or endometrial tumor sample from an affected family member is available, both IHC and MSI testing on the sample should be considered. If no suitable sample is available, genetic testing on the affected relative should be considered with the following priority: MLH1 and MSH2 first, then MSH6, and lastly PMS2. Due to its rarity, PMS2 mutation is only necessary if no mutation is found in the other genes. Upon identification of a familial mutation, individuals testing positive should undergo surveillance for Lynch syndrome; testing for other at risk family members should be considered. If no familial mutation is identified, surveillance should be tailored based on individual and family risk assessment. Genetic Testing HNPCC Mar 17 16
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