Clinical Policy Title: COLARIS testing for Lynch syndrome

Transcription

1 Clinical Policy Title: COLARIS testing for Lynch syndrome Clinical Policy Number: Effective Date: October 1, 2014 Initial Review Date: March 19, 2014 Most Recent Review Date: March 6, 2018 Next Review Date: March 2019 Policy contains: COLARIS testing. Colorectal cancer (CRC). Lynch syndrome (LS). Related policies: CP# CP# Familial polyposis gene testing Colorectal cancer screening ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers the use of COLARIS testing, also known as genetic testing for the germline mutations MLH1, MSH2, or MSH6, which causes hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome (LS), to be clinically proven and, therefore, medically necessary in members who meet the following criteria (Barrow, 2013; Boland, 2010; Bonis, 2007; Coates, 2011; EGAPP, 2009; Hampel, 2014; Palomaki, 2009; U.S. Department of Health and Human Services (USDHHS), 2017; U.S. Multi- Service Task Force on Colon Cancer (USMSTFCC), 2014): The initial screening for Lynch syndrome to evaluate tissue tumor must use microsatellite instability (MSI) or immunohistochemistry (IHC) with or without BRAF/MLH1 promoter methylation testing. Those who are candidates for COLARIS testing include: Members with colorectal cancer (CRC) diagnosed in the past. Members with at-risk relatives diagnosed with Lynch syndrome with a known mismatch repair mechanism (MMR) mutation. 1

2 Members with endometrial cancer and one first-degree relative diagnosed with a Lynchassociated cancer, with one of the cancers being diagnosed before age 50 for the diagnosis of Lynch syndrome. Members who have been diagnosed, before age 60, with colorectal cancer or endometrial cancer and a high microsatellite instability in the tumor. Members with a differential diagnosis of attenuated familial adenomatous polyposis (FAP) versus (muty homolog) s (MUTYH-) associated polyposis versus Lynch syndrome. Members without colorectal cancer but with a family history meeting the Amsterdam or revised Bethesda criteria, when no affected family members have been tested for mismatch repair mutations; members referred for genetic testing if family member meets Amsterdam II or revised Bethesda criteria. a. Amsterdam II clinical criteria (all criteria must be fulfilled) for defining families at high risk for Lynch syndrome: Three or more relatives with a histologically verified HNPCC-associated cancer (colorectal cancer or cancer of the endometrium, small intestine, ureter, or renal pelvis), one of whom is a first-degree relative of the other two. HPNCC-associated cancer involving at least two generations.* Cancer in one or more affected relatives diagnosed before age 50. Familial adenomatous polyposis excluded in any cases of colorectal cancer. Tumors should be verified by pathologic examination. (Note: Recognizing the difficulty of obtaining pathology reports of family members, pathology reports should be verified whenever possible.) *Modifications allow for small HNPCC families: Either these families must have two colorectal cancers in first-degree relatives involving at least two generations, with at least one individual diagnosed by age 55, or, in families with two first-degree relatives affected by colorectal cancer, the presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is sufficient. b. Revised Bethesda guidelines: Meeting any of the following is sufficient for consideration of microsatellite instability/immunohistochemistry testing: Colorectal cancer diagnosed before age 50. Presence of synchronous or metachronous colorectal cancer or other Lynchassociated tumor, regardless of age. Colorectal cancer with MSI-H histology diagnosed in an individual who is under age 60. Colorectal cancer diagnosed with one or more first-degree relatives with a Lynchrelated tumor, with one of the cancers diagnosed before age 50. Colorectal cancer diagnosed in two or more first- or second-degree relatives with a Lynch-related tumor, regardless of age. There has been a recommendation for testing made after genetic counseling performed by a specialist or other physician equivalent to that provided by a genetic counselor and also be appropriate for the test being requested. 2

3 *Note: Family history should include information on cancers in first-degree (parents, siblings, children) and second-degree (grandparents, aunts/uncles, nieces/nephews, grandchildren) relatives on maternal and paternal sides, including cancer type and age of person when diagnosed. Limitations: All other uses of COLARIS testing, also known as genetic testing for Lynch syndrome, are not clinically proven and, therefore not medically necessary. Testing must be performed at a participating laboratory facility when available. Alternative covered services: Colonoscopy for colorectal screening. Network provider evaluation and surveillance. Background Colorectal cancer is the second most deadly cancer (behind only lung/bronchus cancer) of men and women in the United States; in 2016, an estimated 134,490 Americans were diagnosed with the disease, and 49,190 died from it (Howlader, 2016). When colorectal cancer is detected early, illness and death can be prevented. The U.S. Department of Health and Human Services is committed to boosting public awareness about the importance of screening and treatment for colorectal cancer. Colorectal cancer poses elevated risk to adults over age 50, and the United States Preventive Services Task Force (USPSTF) recommends that all individuals ages 50 to 75 be screened for colorectal cancer as part of routine preventive health care (USPSTF, 2016). Currently, about one in three adults between the ages of 50 and 75 are not receiving recommended screening (CDC, 2013). Lynch syndrome is an autosomal dominant familial cancer syndrome caused by mutations in multiple susceptibility genes (e.g., MLH1, MSH2, MSH6, PMS2, EPCAM) and is associated with an increased lifetime risk for colorectal cancer and other malignancies within the tumor spectrum including at least endometrial, ovarian, gastric, small bowel, urothelial, hepatobiliary tract, sebaceous, and pancreatic cancers. Lynch syndrome prevalence in colorectal cancer and endometrial cancer is estimated at 1 percent to 3 percent, and annual incidence ranges between 1 of 660 and 1 of 2,000 (de la Chapelle, 2005). In individuals with Lynch syndrome, the lifetime risk of colorectal cancer may be as high as 80 percent (Cancer.Net, 2017). While the incidence of adenomas in individuals with Lynch syndrome is similar to that in the general population, the high rate of colorectal cancer is due to an acceleration of the adenoma to carcinoma sequence. Cancer risks associated with Lynch syndrome are largely derived from family studies. Mutations in MLH1 and MSH2 account for 70 percent to 90 percent of families with Lynch syndrome. The risk of colon and 3

4 endometrial cancer is lower in MSH6 and PMS2 mutation carriers, although the cancer risk may not be lower for MSH6 carriers if data are extended to age 80. While individuals with a single MLH1, MSH2, MSH6, and PMS2 mutation develop cancers in midlife, individuals with biallelic MLH1, MSH2, MSH6, and PMS2 mutations have a distinctive phenotype and tumor spectrum, and often develop cancer as early as the first decade of life. First-degree relatives of mutation carriers have a 50 percent probability of having the same germline mutation. Despite the high penetrance of colorectal cancer and endometrial cancer and recommendations of consideration for screening unaffected first-degree relatives following diagnosis of Lynch syndrome proband, testing of genetic carriers who are unaffected with a Lynch-related cancer is not a Medicare benefit and is statutorily excluded from coverage. COLARIS is a genetic test that assesses a person s risk of developing hereditary colorectal cancer and a woman s risk of developing hereditary uterine cancer. COLARIS PLUS detects disease-causing mutations in the MLH1, MSH2, MSH6, PMS2, EPCAM, and MYH genes that are responsible for the majority of Lynch syndrome and MYH-associated polyposis (MAP) cases. Lynch syndrome, also known as HNPCC, is the most common of the hereditary colon cancer syndromes and is believed to account for 3 percent to 5 percent of all colorectal cancers (NLM, 2017). COLARIS is a test for Lynch syndrome. Knowing the results may help patients and their physicians take steps to prevent cancer before it has a chance to develop. MYH-associated polyposis is caused by mutations in the muty homolog (MYH) gene. Individuals with MYHassociated polyposis have mutations in both of their muty homolog genes one from each parent often referred to as "biallelic muty homolog (MYH) mutations." Patients often have no family history of colorectal cancer or polyps in parents, although siblings may be affected. The muty homolog gene is an important part of the base excision repair (BER) pathway, which allows for repair of DNA mutations caused by oxidative damage to cells. COLARIS is a simple blood test or oral rinse sample used to find out if a patient has MLH1, MSH2, MSH6, PMS2, EPCAM, or muty homolog mutations. Knowing the results may help patients and their physicians act before cancer has a chance to develop. Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality Guideline Clearinghouse and evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). 4

5 We conducted searches on January 19, Search terms were: Colorectal Cancer, Gene testing, and Lynch Syndrome. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings Various professional societies and groups have endorsed universal genetic testing for Lynch syndrome for all persons diagnosed with colorectal cancer. An early analysis conducted for the Agency for Healthcare Research and Quality of 104 studies screening colorectal cancer patients included 40 studies assessed for clinical validity; presence of age <50 years; history of colorectal cancer or endometrial cancer in a firstdegree relative; or multiple colorectal or endometrial cancers. Immunohistochemistry or microsatellite instability testing of tumor tissue were each as effective as more complex tests. In the 61 other studies, no long-term harm of testing was found, while genetic counseling was efficacious (Bonis, 2007). The Evaluation of Genomic Applications in Practice and Prevention Working Group, an independent panel of experts established by the Centers for Disease Control and Prevention (CDC), recommended genetic testing for Lynch syndrome in all newly diagnosed colorectal cancer patients, but failed to find a specific genetic testing strategy (EGAPP, 2009; Palomaki, 2009). A 2010 workshop in Jerusalem recommended that all colorectal cancer patients under age 70 should be screened with immunohistochemistry or microsatellite instability for mismatch repair proteins. Any abnormality means patients should be offered genetic counseling plus genetic testing for Lynch syndrome. Patients with Lynch syndrome should receive an annual colonoscopy (Boland, 2010). The U.S. Multi-Society Task Force on Colorectal Cancer consists of the American Society for Gastroendoscopy, American Gastroenterological Association, American College of Gastroenterology, and the American Society of Colon and Rectal Surgeons. The group recommended universal testing for Lynch syndrome in all newly diagnosed colorectal cancer patients in persons under age 70 and persons over age 70 with a family history of the syndrome. Testing can be done by immunohistochemistry and/or microsatellite instability. In addition, the panel recommends genetic evaluation for Lynch syndrome for persons with a history of a tumor with mismatch repair deficiency; with uterine cancer diagnosed by age 50; with a known family gene mutation; or with fulfillment of the Amsterdam criteria or Bethesda guidelines (USMSTFCC, 2014). 5

6 An article whose primary author was an official from the CDC recommended preliminary screening tests for colorectal cancer patients, including microsatellite instability, immunohistochemistry, and BRAF and/or MLH1 promoter hypermethylation testing for cases with no immunohistochemistry staining for MLH1. This approach will improve efficiency and reduce costs in patients most likely to have mismatch repair mutations (Coates, 2011). The National Comprehensive Care Network (NCCN) updated its recommendations for Lynch syndrome testing in 2014, supporting universal screening for colorectal cancer patients. NCCN also recommended that the preferred method of testing is immunohistochemistry or microsatellite instability alone for those with a personal or family history, and immunohistochemistry and microsatellite instability together for routine testing (Hampel, 2014). The CDC publication Healthy People 2020 includes a goal to increase the proportion of newly diagnosed colorectal cancer patients tested for Lynch syndrome (USDHHS, 2017). A systematic review of 12 studies found that screening the general population for Lynch syndrome reduced colorectal cancer incidence by 68 percent and all-cause mortality by 78 percent. Universal screening beginning at age 20 resulted in the greatest gain, but was also not cost-effective. Authors concluded inadequate evidence exists to compare harms and benefits for such screening (Prince, 2017). Authors of a study of 1,344 colorectal cancer patients under age 60 recommended that microsatellite instability be the initial test for population-based screening of Lynch syndrome in younger colorectal cancer patients (Schofield, 2009). A meta-analysis of 1,114 Lynch syndrome families concluded 1 of 71 males and 1 of 102 females with MLH1 or MSH2 mutations can expect a diagnosis of colorectal cancer in the next five years, and thus the standard for people in their 30s (colonoscopy every one to two years) might not be justifiable for those in their 20s (Jenkins, 2015). A systematic review of five studies of women with HNPCC failed 2to identify an evidence-based means for surveilling members of families with Lynch syndrome mutations (Auranen, 2011). However, the immunohistochemistry and microsatellite instability tests continue to be the standard for Lynch syndrome. A study of 1,566 patients with colorectal cancer found 2.8 percent with Lynch syndrome (each had at least three relatives with Lynch syndrome). It also found immunohistochemistry to be nearly as sensitive to as microsatellite instability. Bethesda criteria failed to identify 28 percent of Lynch syndrome patients (Hampel, 2008). Analyzing BRAF mutations can help in diagnosing Lynch syndrome; in one study of subjects with at least one mismatch repair absent, BRAF mutation was found in 55 percent, or 36 of 65, simplifying genetic testing for Lynch syndrome (Jin, 2013). The Bethesda guidelines are helpful, but not in all cases. One study found 62 of 1,040 colorectal cancer patients had an abnormal immunohistochemistry or microsatellite instability result, but 37 percent (23) of these abnormalities did not meet Bethesda criteria (Canard, 2012). Another review found that tumor mismatch repair testing cases in persons under age 70 with colorectal cancer fulfilling Bethesda guidelines missed 4.9 percent of Lynch syndrome cases, but required 28.6 percent fewer cases undergoing mutational analysis than the universal approach (Moreira, 2012). 6

7 Detected mutations are often good predictors of colorectal cancer risk. One study found that carriers of the EPCAM deletion had a 75 percent risk of colorectal cancer (Kempers, 2011), even though this deletion only accounts for 1.1 to 2.8 percent of confirmed Lynch syndrome families (Kuiper, 2011). Conversely, in some patient categories, testing for Lynch syndrome is not always effective. One study concluded that in colorectal cancer patients under age 50 ( apparently sporadic ), only 21 percent have features of Lynch syndrome (Goel, 2010). While genetic testing patients and family members with colorectal cancer and other cancers is indicated, there has been only one meta-analysis of efficacy, which found that nine of 10 studies described a reduction of colorectal cancer incidence and mortality with registration and screening (Barrow, 2013). Significant differences in the risk of developing cancer by age 70 were found between the mutations MH1, MSH2, and MSH6. The risks of developing colorectal cancer were 41 percent for MLH1, 48 percent for MLH2, and 12 percent for MSH6; for endometrial cancer, risks were 54, 21, and 16; and for ovarian cancer, risks were 20, 24, and 1 percent (Bonadona, 2011). Several cost-effectiveness analyses of testing for Lynch syndrome have been conducted. One study of screening three to four relatives of persons diagnosed with colorectal cancer, using immunohistochemistry and BRAF mutation testing, found a cost per life-year gained of $44,000 for testing up to 70 years, while screening without an upper age limit cost $88,700 per life-year gained (Ladabaum, 2011). Testing women with endometrial cancer who had at least one first-degree relative with a Lynch-associated cancer yielded a favorable incremental cost-effectiveness ratio of $9,126 per life-year gained; testing all relatives of women with endometrial cancer would be more costly, i.e., $648,494 per life-year gained (Kwon, 2011). Policy updates: In 2017, a total of 11 professional guidelines/other and 22 peer-reviewed references were added to this policy. In 2018, a total of one professional guideline and two peer-reviewed references were added to this policy. Summary of clinical evidence: Citation Snowsill (2017) Content, Methods, Recommendations Key points: Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation This systematic review and model-based economic evaluation examined diagnostic test accuracy of two tumor based tests (microsatellite instability and mismatch repair immunohistochemistry) and cost-effectiveness for National Health Service. Ten studies were identified that evaluated the two tests for identifying Lynch syndrome in colorectal cancer patients. For microsatellite instability testing, sensitivity ranged from % and specificity ranged from %. For immunohistochemistry, sensitivity ranged from % and specificity ranged from %. The sensitivity of microsatellite instability testing increased but specificity fell when lesions showing low levels of microsatellite 7

8 Citation Tognetto (2017) Content, Methods, Recommendations instability were treated as a positive result. No end-to-end studies of screening for Lynch syndrome in people with colorectal cancer were identified. Nine economic evaluations were identified, none of which mirrored the research question. Therefore the authors extended a model they developed previously. The base-case results in the economic evaluation suggest that screening for Lynch syndrome in CRC patients using immunohistochemistry (IHC), BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of 20,000 per quality-adjusted life-year, while the incremental cost-effectiveness ratio was 11,008 per quality-adjusted life-year compared with no screening. Screening without tumor tests was not predicted to be cost-effective. Limitations included that most of the studies on diagnostic test accuracy were viewed as having potential bias or the research samples were unrepresentative. No direct evidence was found that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. Key points: A systematic review on the existing screening pathways for Lynch syndrome identification This systematic review examines the existing screening pathways for Lynch syndrome through publications that evaluate a structured and permanent screening pathway for the identification of Lynch syndrome carriers. The pathway effectiveness was analyzed in terms of the detection rate of Lynch syndrome. Five studies were included. All the screening pathways started from cases of colorectal cancer. Three followed a universal screening approach. The pathways used immunohistochemistry and/or microsatellite instability testing. If the response indicated a risk for Lynch syndrome, genetic counseling performed by a geneticist or a genetic counselor was mandatory to undergo DNA testing. The overall Lynch syndrome detection rate ranged from 0 to 5.2%. The authors concluded that although current clinical guidelines suggest testing all colorectal cancer cases, the actual implementation of pathways for LS identification is not complete. Wider screening for Lynch syndrome has the potential to reduce morbidity and mortality from colorectal cancer, but requires a coordination to educate key stakeholders and address public needs. Prince (2017) Key points: Is there evidence that we should screen the general population for Lynch syndrome with genetic testing with genetic testing? Systematic review of 12 studies. No studies address risk/benefit of screening for Lynch syndrome in the general population. Meta-analyses find relative reductions in colorectal cancer incidence and mortality of 68% and 78%. Universal screening beginning at age 20 is most effective, but not cost-effective. Barrow (2013) Key points Systematic review of the impact of registration and screening on colorectal cancer incidence + mortality in familial adenomatous Systematic review of 33 studies on familial adenomatous polyposis and Lynch syndrome. Nine of 10 studies found reduction of colorectal cancer incidence and mortality after registration and screening for Lynch syndrome. Evidence graded a level 2 (Grade B). 8

9 Citation polyposis and Lynch syndrome Bonadona (2011) Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome Ladabaum (2011) Strategies to identify the Lynch syndrome among patients with colorectal cancer: a costeffectiveness analysis Content, Methods, Recommendations Key points: French study ( ) of Lynch syndrome families with segregating mutated genes (248 with MLH1, 256 with MSH2, and 33 with MSH6). Cumulative risk of colorectal cancer by age 70 were 48%, 41%, and 12%. Cumulative risk of endometrial cancer by age 70 were 54%, 21%, and 16%. Cumulative risk of ovarian cancer by age 70 were 20%, 24%, and 1%. Lifetime risks for other tumor types were less than 3% for each gene mutation. Key points: Literature review of persons newly diagnosed with colorectal cancer and their relatives. Current testing, screening, and surgical interventions reduce colorectal cancer deaths 7 42% and endometrial/ovarian cancer deaths 1 6%. Immunohistochemistry testing plus BRAF mutation testing had greatest cost-effectiveness ($36,200 per life-year gained); others have higher cost figure. Screening for Lynch syndrome up to age 70 cost $44,000 per incremental life-year gained, and $88,700 for all ages. References Professional society guidelines/other: Boland CR, Shike M. Report from the Jerusalem workshop on Lynch syndrome hereditary nonpolyposis colorectal cancer. Gastroenterology. 2010;138(7):e Doi: /j.gastro Bonis PA, Trikalinos TA, Chung M, et al. Hereditary nonpolyposis colorectal cancer: diagnostic strategies and their implications. Evid Rep Technol Assess (Full Rep). 2007;(150): PMC Cancer.Net. Lynch Syndrome. May Accessed January 19, Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009;11(1): Doi: /GIM.0b013e31818fa2ff. Giardello FM, Allen JI, Axibund JE, et al. Guideline on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointestinal Endoscopy. 2014;80(2): Doi: /ajg

10 Gulland, A. All patients with colorectal cancer should be tested for genetic condition, NICE advises BMJ 2017; 356 :j998. Doi: /bmj.j998. Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, Bethesda MD: National Cancer Institute Accessed January 19, Rubenstein JH, Enns R, Deidelbaugh J, Barkun A, Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome. Gastroenterology. 2015;149(3): Doi: /j.gastro U.S. Centers for Disease Control and Prevention (CDC). CRC screening rates remain low. Atlanta GA: CDC, November 5, Accessed January 19, U.S. Department of Health and Human Services (USDHHS). Healthy People Washington, D.C.: USDHHS Office of Disease Prevention and Health Promotion. Accessed January 19, U.S. Multi-Society Task Force on Colorectal Cancer (USMSTFCC). Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer. GIE Journal. 2014: Accessed January 19, U.S. National Library of Medicine (NLM). Lynch syndrome. March 7, Accessed January 19, Peer-reviewed references: Auranen A, Joutsiniemi T. A systematic review of gynecological cancer surveillance in women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstet Gynecol Scand. 2011;90(5): Doi: /j x. Barrow P, Khan M, Lalloo F, Evans DG, Hill J. Systematic review of the impact of registration and screening on colorectal cancer incidence and mortality in familial adenomatous polyposis and Lynch syndrome. Br J Surg. 2013;100(13): Doi: /bjs Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011;305(22): Doi: /jama Bouzourene H, Hutter P, Losi L, et al. Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation. Fam Cancer. 2010;9(2): Doi: /s

11 Canard G, Lefevre JH, Colas C, et al. Screening for Lynch syndrome in colorectal cancer: are we doing enough? Ann Surg Oncol. 2012;19(3): Doi: /s Capper D, Voigt A, Bozukova G, et al. BRAF V600E-specific immunohistochemistry for the exclusion of Lynch syndrome in MSI-H colorectal cancer. Int J Cancer. 2013;133(7): Doi: /ijc Coates R, Willliams M, Melilo S, Gudgeon J. Genetic testing for Lynch syndrome in individuals newly diagnosed with colorectal cancer to reduce morbidity and mortality from colorectal cancer in their relatives. PLoS Curr. 2011;3:RRN1246. Doi: /currents.RRN1246. de la Chapelle A. The incidence of Lynch syndrome. Familial Cancer. 2005;4(3): Doi: /s Goel A, Nagasaka T, Spiegel J, et al. Low frequency of Lynch syndrome among young patients with nonfamilial colorectal cancer. Clin Gastroenterol Hepatol. 2010;8(11): Doi: /j.cgh Grandval P, Baert-Desurmont S, Bonnet F, et al. Colon-specific phenotype in Lynch syndrome associated with EPCAM deletion. Clin Genet. 2012;82(1): Doi: /j x. Hampel H. NCCN increases the emphasis on genetic/familial high-risk assessment in colorectal cancer. J Natl Comp Cancer Netw. 2014;12: Doi: /jnccn Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26(35): Doi: /JCO Jenkins MA, Dowty JG, Ait Ouakrim D, et al. Short-term risk of colorectal cancer in individuals with Lynch syndrome: a meta-analysis. J Clin Oncol. 2015;33(4): Doi: /JCO Jin M, Hampel H, Zhou X, et al. BRAF V600E mutation analysis simplifies the testing algorithm for Lynch syndrome. Am J Pathol. 2013;140(2): Doi: /AJCPB9FOVH1HGKFR. Kempers MJ, Kuiper RP, Ockeloen CW, et al. Risk of colorectal and endometrial cancers in EPCAM-positive Lynch syndrome; a cohort study. Lancet Oncol. 2011;12(1): Doi: /S (10) Kuiper RP, Vissers LE, Venkatachalam R, et al. Recurrence and variability of germline EPCAM deletions in Lynch syndrome. Hum Mutat. 2011;32(4): Doi: /humu Kwon JS, Scott JL, Gilks CB, et al. Testing women with endometrial cancer to detect Lynch syndrome. J Clin Oncol. 2011;29(16): Doi: /JCO

12 Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med. 2011;155: Doi: / Moreira L, Balaguer F, Lindor N, et al. Identification of Lynch syndrome among patients with colorectal cancer. JAMA. 2012;308(15): Doi: /jama Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009;11(1): Doi: /GIM.0b013e31818fa2db. Prince AE, Cadigan RJ, Henderson GE, et al. Is there evidence that we should screen the general population for Lynch syndrome with genetic testing? A systematic review. Pharmgenomics Pers Med. 2017;10: Doi: /PGPM.S Schofield L, Watson N, Grieu F, et al. Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. Int J Cancer. 2009;124(5): Doi: /ijc Snowsill T, Coelho H, Huxley N, et al. Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation. Health Technol Assess. 2017;21(51): Doi: /hta Tognetto A, Michelazzo MB, Calabro GE, et al. A Systematic Review on the Existing Screening Pathways for Lynch Syndrome Identification. Front Public Health. 2017;5:243. Doi: /fpubh CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Under Medicare, genetic tests for cancer are a covered benefit only for a beneficiary with a personal history of an illness, injury or signs and/or symptoms thereof (i.e., clinically affected). A person with a personal history of a relevant cancer is a clinically affected person, even if the cancer is considered cured. Predictive or presymptomatic genetic tests and services, in the absence of past or present illness in the beneficiary, are not covered under national Medicare rules. CMS recognizes Lynch syndrome as an autosomal dominant syndrome that accounts for about 3 percent to 5 percent of colorectal cancer cases. [Lynch] syndrome mutations occur in the following genes: hmlh1, hmsh2, hmsh6, PMS2 and EPCAM. CMS also recognizes FAP and MAP syndromes and their associated mutations. Local Coverage Determinations (LCDs): Genetic Testing for Lynch syndrome. CMS Medicare Coverage Database website. 12

13 results.aspx?coverageselection=both&articletype=all&policytype=final&s=all&keyword=lynch&keyword LookUp=Title&KeyWordSearchType=And&bc=gAAAAAAAAAAAAA%3d%3d&=&. Accessed January 19, Includes: L34912 Genetic testing for Lynch syndrome First Coast Service Options, Inc. L35349 MolDx: Genetic testing for Lynch syndrome CGS Administrators LLC L36370 MolDx: Genetic testing for Lynch syndrome Noridian Healthcare Solutions LLC L36374 MolDx: Genetic testing for Lynch syndrome Noridian Healthcare Solutions LLC L35024 MolDx: Genetic testing for Lynch syndrome Palmetto GBA L36793 MolDx: Genetic testing for Lynch syndrome Wisconsin Physicians Service Insurance Corporation L35553 Pathology and Laboratory: Genetic testing for Lynch syndrome Cahaba Government Benefit Administrators LLC Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments MLH1 (muhtl homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants MSH6 (muts homolog 6 [E. coli]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis MSH6 (muts homolog 6 [E. coli]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis PMS2 (postmeiotic segregation increased 2[S. cerevisae]) (hereditary nonpolyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) 13

14 ICD-10 Code Description Comments C18.0 Malignant neoplasm of cecum C18.1 Malignant neoplasm of appendix C18.2 Malignant neoplasm of ascending colon C18.3 Malignant neoplasm of hepatic flexure C18.4 Malignant neoplasm of transverse colon C18.5 Malignant neoplasm of splenic flexure C18.6 Malignant neoplasm of descending colon C18.7 Malignant neoplasm of sigmoid colon C18.8 Malignant neoplasm of overlapping sites of colon C18.9 Malignant neoplasm of colon, unspecified C19 Malignant neoplasm of rectosigmoid junction C54.1 Malignant neoplasm of endometrium K63.5 Polyp of colon Z80.0 Family history of malignant neoplasm of digestive organs Z83.71 Family history of colonic polyps Z Personal history of other malignant neoplasm of large intestine Z Personal history of other malignant neoplasm of rectum, rectosigmoid junction, and anus Z Personal history of colonic polyps HCPCS Level II Code N/A Description Comments 14