Clinical Policy Title: Familial polyposis gene testing

Clinical Policy Title: Familial polyposis gene testing Clinical Policy Number: 02.01.08 Effective Date: December 1, 2013 Initial Review Date: August 21, 2013 Most Recent Review Date: October 19, 2017 Next Review Date: October 2018 Related policies: Policy contains: Attenuated familial adenomatous polyposis. Familial polyposis gene testing. Familial adenomatous polyposis. MYH-associated polyposis (MAP). CP# 00.01.03 CP# 02.01.18 CP# 02.01.01 CP# 02.01.02 CP# 02.01.03 CP# 02.01.07 CP# 02.01.09 CP# 02.01.10 CP# 02.01.11 CP# 02.01.12 CP# 02.01.04 CP# 02.01.14 CP# 05.01.04 CP# 09.01.09 CP# 11.04.02 CP# 13.01.01 Genetic testing for cytochrome p450 polymorphisms Genomic testing in sensorineural hearing loss Maternal genetic testing Genetic testing for breast and ovarian cancer Array comparative genomic hybridization testing Genetic testing for cystic fibrosis Genetic testing for rare diseases COLARIS testing for Lynch syndrome Afirma gene expression classifier for indeterminate thyroid nodules CORUS CAD gene expression test Pharmacogenetic testing for warfarin (Coumadin ) sensitivity Gene expression profile testing for breast cancer Molecular analysis for targeted therapy for lung cancer Genomic testing in neurology Genetic testing for autism spectrum disorders Genetic testing for prostate cancer prognosis ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas 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 AmeriHealth Caritas 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. AmeriHealth Caritas 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. AmeriHealth Caritas clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas clinical policies are not guarantees of payment. Coverage policy 1

AmeriHealth Caritas considers the use of genetic testing for familial polyposis genes for the purpose of identifying members at risk for familial adenomatous polyposis (FAP), attenuated FAP (AFAP), colorectal cancer, and MLH1-related Lynch syndrome to be clinically proven and, therefore, medical necessary when the following criteria are met: Members with greater than 20 adenomatous colonic polyps during their lifetime. Members who have a first- or second-degree relative diagnosed with FAP or AFAP. Members have a first- or second-degree relative with a known FAP or AFAP gene mutation or adenomatous polyposis coli (APC gene) (Stoffel, 2015; Balmana, 2013). Limitations: All other uses of familial polyposis gene testing are not medically necessary, including: MutY homologue (MYH) mutation testing, which is considered experimental and investigational for members of a polyposis family with clear autosomal dominant inheritance or for any other indications because its effectiveness for indications other than the ones listed above has not been established. Associated polyposis conditions (APC) genetic testing, which is considered experimental and investigational for all other indications (e.g., desmoid tumor) because its effectiveness for indications other than the ones listed above has not been established. Alternative covered services: Standard diagnostic cancer screening tests are medically necessary as preventive services for members age 50 years and older when the following tests are recommended by their physician: Colonoscopy (considered medically necessary every 10 years for persons at average risk). Double contrast barium enema (DCBE) (considered medically necessary every five years for persons at average risk). Sigmoidoscopy (considered medically necessary every five years for persons at average risk). Background Colorectal cancer is the fourth most commonly-diagnosed cancer in the U.S., trailing only breast, lung/bronchus, and prostate cancer, with an expected 135,430 new cases in 2017 (Howlader, 2017). Colorectal cancer incidence and mortality rates have recently declined, due to the greater ability to detect and remove pre-cancerous polyps after screening but before cancer manifestation. An estimated 5 to 10 percent of the general population has a first-degree family history of colorectal cancer, and almost 30 percent have a first- or second-degree relative affected by the condition (Lin, 2

2012). Lynch syndrome, FAP, and MYH, the known types of inherited colorectal cancer, account for up to five percent of all colon cancers (Hegde, 2014). FAP, caused by germline mutation in the APC, accounts for less than one percent of all colorectal cancers (Vasen, 2008). Classical FAP has three types: attenuated FAP, Gardner syndrome, and Turcot syndrome. FAP is a colon cancer predisposition syndrome in which hundreds to thousands of precancerous colonic polyps develop. The incidence of FAP is between 1 per 7,000 and 1 per 22,000 births (NIH, 2017). By age 35 years, 95 percent of individuals with FAP have polyps; without colectomy, colon cancer is inevitable (Jasperson, 2017). In classical FAP, mean age of colon cancer diagnosis in untreated individuals is 39 years (Jasperson, 2017), and in attenuated FAP, a less severe version in which polyp growth is delayed and the condition defined by the presence of an average of 30 polyps, the mean age at diagnosis is 55 years. (Half, 2009; NIH, 2017). Lifetime risk of colorectal cancer in attenuated FAP is 70 percent (Lodewijk, 2015). In a study of 88 FAP patients (average age 34), the incidence of colorectal cancer was similar for classical and attenuated FAP (de Campos, 2010). Extracolonic manifestations are variably present and include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft tissue tumors, desmoid tumors, and associated cancers. The colorectal cancer risk associated with classical FAP is nearly 100 percent if not treated. Risks of other cancers in persons with FAP include desmoid tumor (10 20 percent), small bowel/intestine (4 12), pancreatic (2), papillary thyroid (2), and brain, stomach, bile duct, and adrenal (all less than 2) (ASCO, 2015). APC mutations are found in 80 percent of persons with over 1000 adenomas; 56 percent of persons with 100-999 adenomas; 10 percent of persons with 20-99 adenomas; and 5 percent of persons with 10-19 adenomas (Grover, 2012). About 75 to 80 percent of children who have an AFP-associated polyposis condition has an affected parent (Jasperson, 2017). A child with a parent who has a mutated familial polyposis gene has a 50 percent chance of inheriting the mutation. A sibling or parents of a persons with a mutation also has a 50 percent chance of having a mutation. About 70 percent of persons with FAP have a family history of the condition (ASCO, 2015). APC-associated polyposis conditions are caused by mutations in APC. The diagnosis relies primarily on clinical findings. Molecular genetic testing of APC detects disease-causing mutations in up to 90 percent of individuals with typical FAP (Jasperson, 2017). Molecular genetic testing is most often used in the early diagnosis of at-risk family members, as well as in confirming the diagnosis of FAP or AFAP in individuals with equivocal findings (e.g., < 100 adenomatous polyps). Colectomy is advised when more than 20 or 30 adenomas or multiple adenomas with advanced histology have occurred. Nonsteroidal anti-inflammatory drugs (NSAIDs), especially sulindac, have 3

caused regression of adenomas in FAP and decreased the number of polyps requiring ablation in the remaining rectum of persons with a subtotal colectomy. Endoscopic or surgical removal of duodenal adenomas is considered if polyps exhibit villous change or severe dysplasia, exceed one centimeter in diameter, or cause symptoms. Osteomas may be removed for cosmetic reasons. Desmoid tumors may be surgically excised or treated with NSAIDs, anti-estrogens, cytotoxic chemotherapy, or radiation. The American Society for Clinical Oncology endorses gene testing for mutations in all patients with colorectal cancer (Stoffel, 2015). A group of 31 European experts recommended flexible sigmoidoscopy in families with classical FAP, every two years starting at age 12-14 and continued lifelong, as adenomas are universally distributed. In attenuated FAP, colonoscopy is recommended every two years starting at age 18-20, as adenomas can be localized in the right colon (Vasen, 2008). These recommendations were accepted by the European Society for Medical Oncology (ESMO) in its guidelines (Balmana, 2013). In turn, ASCO endorsed the ESMO in its guidelines (Stoffel, 2015). If adenomas are detected, annual colonoscopy should be performed, until colectomy is planned (Stoffel, 2015). The American College of Medical Genetics and Genomics (ACMG) 2014 guideline notes that while FAP can be diagnosed by colonoscopy, genetic testing is recommended to inform relatives of any risk (Hegde, 2014). Searches AmeriHealth Caritas searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on September 6, 2017, using the terms genetic testing, familial polyposis and colon cancer. 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 4

Findings A systematic review analyzed colorectal cancer morbidity and mortality for persons in FAP and Lynch syndrome families screened for genetic mutations, versus those not screened. All 33 trials for FAP described a significant reduction of CRC incidence and mortality with registration and screening, along with nine of ten studies for Lynch syndrome (Barrow, 2013). Twenty-four colonoscopy or sigmoidoscopy videos were reviewed by 26 clinicians familiar with diagnosis and treatment of FAP. The reviewers independently assigned a stage to a case by using the proposed system and chose a stage-specific intervention for each case. Sixty-two percent of reviewers agreed on the intervention, 86 percent chose an intervention within one level of the mode (Lynch, 2016). A study of mortality compared 194 probands and 225 call-ups in 154 families with at least one clinically diagnosed FAP patient. The crude mortality rates over time was 34.9 and 8.3 per 100 person-years for probands and call-up; relative survival for probands was significantly lower than call-ups (p=.0018). The finding that 20 year survival rates (after diagnosis) for screened family members of FAP patients is comparable to the general population supports prompt screening of all such persons (Koskenvuo, 2016). A United Kingdom study of 439 FAP patients followed over time determined that crude mortality rates for probands were nearly double that for call-ups (9.71 to 4.85 per 1000 person-years). However, the percent of deaths from extracolonic manifestations was more than double for call-ups than for probands (30.6 versus 13.4 percent); authors state that this phenomenon merits further study (Gibbons, 2011). The Manchester (UK) Polyposis Registry was the source for a study of the effect of screening on survival, colorectal cancer incidence, and age of cancer onset in 353 FAP patients nearly 90 percent of whom were diagnosed after the Registry was established. Survival was increased from 57.8 to 70.4 years by screening (p<.0001); colorectal cancer incidence fell from 43.5 to 3.8 percent by screening. Authors attributed the presence of the Registry for much of this improvement (Mallinson, 2010). The Singapore Polyposis Registry, established 1989, was the basis for a study of 122 (median age 29 years) patients from 88 families with a FAP member screened for colon cancer. A total of 92 percent tested positive for the APC gene, and 42 percent were diagnosed with colorectal cancer. Nearly all underwent either a restorative proctocolectomy or colectomy. The 10 year survival rate was 75.6 percent, and the cancer recurrence rate was 13.5 percent, leading authors to conclude that surveillance programs are helpful in detecting early-stage colorectal cancer in FAP families (Chew, 2011). A study involving 26 experts in FAP screening, detection, and treatment tested a proposed series of five stages according to the number of polyps, which cannot always be counted accurately. Sixty-two percent of reviewers agreed on the FAP stage, and 90 percent of scores were within ±1 stage of the mode. These findings suggest that subsequent screenings for FAP can rely on stage of the conditions, and not solely on the number of polyps observed (Lynch, 2016). 5

Disparities may exist in determinants of colorectal cancer, including Lynch syndrome and FAP. Although African Americans have higher morbidity and mortality of the disorders than do other racial and ethnic groups, they are also less likely to transmit person/family history, creating an opportunity to improve this disparity and reduce gaps in outcomes (Carethers, 2015). Policy updates: A total of 10 guidelines/other and 13 peer-reviewed references were added to this policy in 2017, while seven guidelines/other and seven peer-reviewed references were removed. Summary of clinical evidence: Citation Koskenvuo (2016) Impact of screening on survival in familial adenomatous polyposis Barrow (2013) Impact of FAP and Lynch syndrome screening on colorectal incidence and mortality Gibbons (2011) Causes of mortality in FAP patients Mallinson (2010) Content, Methods, Recommendations Key points: Mortality study, 154 families with at least 1 clinically diagnosed FAP patient Compared mortality for 194 probands and 225 call-ups Crude mortality rates over time was 34.9 and 8.3 per 100 person-years for probands and call-up Survival for probands was significantly lower than call-ups (p=.0018). 20 year survival (after diagnosis) for screened family members of FAP patients is comparable to the general population Key points: Systematic review of family members screened for FAP or Lynch syndrome, versus those not screened All 33 trials for FAP, and 9 of 10 trials for Lynch syndrome described a significant reduction of colorectal cancer incidence and mortality with registration and screening Key points: United Kingdom study of 439 FAP patients followed crude mortality rates Rates for probands exceeded call-ups (9.71 to 4.85/1000 person-years). Percent of deaths from extracolonic manifestations was more than double for call-ups than for probands (30.6 versus 13.4 percent) Key points: Impact of screening and genetic registration on colorectal cancer mortality and incidence in FAP 353 FAP patients in the Manchester (UK) Polyposis Registry were studied for the effect of screening on survival, colorectal cancer incidence, and age of cancer onset Nearly 90 percent were diagnosed after the Registry was established. Survival was increased from 57.8 to 70.4 years by screening (p<.0001) Colorectal cancer incidence fell from 43.5 to 3.8 percent by screening. Authors attributed presence of the Registry for much of this improvement References 6

Professional society guidelines/other: American Society of Clinical Oncology (ASCO). Familial Adenomatous Polyposis. Alexandria VA: ASCO, 2015. http://www.cancer.net/cancer-types/familial-adenomatous-polyposis. Accessed September 6, 2017. Balmana J, Balaguer F, Cervantes A, et al. Familial risk-colorectal cancer. ESMO clinical practice guidelines. Ann Oncol. 2013;24(suppl 6):vi73 vi80. Hayes, Inc. Medical Technology Directory. Genetic Testing for Susceptibility to Familial Adenomatous Polyposis. Lansdale PA: Hayes, Inc. Last Updated February 11, 2008. Hayes, Inc. Genetic Test Evaluation Overview. APC-Associated Polyposis Conditions for Familial Adenomatous Polyposis (Familial Polyposis Coli), Gardner Syndrome, Turcot Syndrome, and Attenuated FAP. Lansdale PA: Hayes, Inc., Last Updated August 20, 2014. Hegde M, Ferber M, Mao R, et al. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1):101 16. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975-2014, Bethesda MD: National Cancer Institute, April 2017. https://seer.cancer.gov/csr/1975_2014/results_merged/sect_01_overview.pdf. Accessed September 6, 2017. Jasperson KW, Patel SG, Ahnen DJ. APC-Associated Polyposis Conditions. Last updated 2017. https://www.ncbi.nlm.nih.gov/books/nbk1345/. Accessed September 6, 2017. Provenzale D, Gupta S, Ahnen DL, et al. Genetic/Familial High-Risk Assessment: Colorectal Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. http://www.jnccn.org/content/14/8/1010/f4.expansion.html. Accessed September 5, 2017. Stoffel EM, Mangu PB, Gruber SB, et al. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015; 33(2):209 91. Syngal S, BrandRE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015;110(2):223 63. Vasen HF, Moslein G, Alonso A, et al. Guidelines for the clinical management of adenomatous polyposis 7

(FAP). Gut. 2008;57(5):704 13. Vasen HFA, Moslein G, Alonso A, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007;44:353 62. U.S. National Institutes of Health (NIH). Genetics Home Reference: Familial Adenomatous Polyposis. Bethesda MD: NIH, 2017. https://ghr.nlm.nih.gov/condition/familial-adenomatous-polyposis. Accessed September 6, 2017. Peer-reviewed references: 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):1719 31. Brosens LAA, Offerhaus GJA, Giareiello FM. Hereditary colorectal cancer: genetics and screening. Surg Clin North Am. 2015;95(5):1067 80. Burn J, Bishop DT, Chapman PD, et al. A randomized placebo-controlled prevention trial of aspirin and/or resistant starch in young people with familial adenomatous polyposis. Cancer Prev Res (Phila). 2011;4:655 65.: 21543343 Carethers JM. Screening for colorectal cancer in African Americans: determinants and rationale for an earlier age to commence screening. Dig Dis Sci. 2015;60(3):711 21. Chew MH, Quah HM, The KL, Loi TT, Eu KW, Tange CL. Twenty years of familial adenomatosis polyposis syndromes in the Singapore Polyposis Registry: an analysis of outcomes. Singapore Med J. 2011;52(4):246 51. De Campos FG, De Freitas I, Imperiale AR, et al. Colorectal cancer in familial adenomatous polyposis: are there clinical predictive factors? Cir Esp. 2010;88(6):390 97. Gibbons DC, Sinha A, Phillips RK, Clark SK. Colorectal cancer: no longer the issue in familial adenomatous polyposis? Fam Cancer. 2011;10(1):11 20. Grover S, Kastrinos F, Steyerberg EW, et al. Prevalance and phenotypes of APC and MuTYH mutations in patients with multiple colorectal adenomas. JAMA. 2012;308:485 92. Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009;4:22. doi: 10.1186/1750-1172-4-22. Koskenvuo L, Pitkaniemi J, Rantanen M, Lepisto A. Impact of screening on survival in familial 8

adenomatours polyposis. J Clin Gastroenterol. 2016;50(1):40 44. Lin OS. Colorectal cancer screening in patients at moderately increased risk due to family history. World J Gastrointest Oncol. 2012;4(6):125 30. Lynch PM, Morris JS, Wen S, et al. A proposed staging system and stage-specific interventions for familial adenomatous polyposis. Gastrointest Endosc. 2016;84(1):115 25. Mallinson EK, Newton KF, Bowen J, et al. The impact of screening and genetic registration on mortality and colorectal cancer incidence in familial adenomatous polyposis. Gut. 2010;59(10):1378 82. Neklason DW, Stevens J, Boucher KM, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2008;6:46 52. CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): L34912, L35024, L35349, L36370, L36374 L36793. MolDX: Genetic Testing for Lynch Syndrome. Effective Date October 1, 2015. https://www.cms.gov/medicare-coverage-database/search/searchresults.aspx?coverageselection=both&articletype=all&policytype=final&s=all&keyword=genetic+testi ng&keywordlookup=title&keywordsearchtype=and&bc=gaaaaaaaaaaaaa%3d%3d&=&. Accessed September 7, 2017. 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 Comment 81201 81202 81203 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; duplication/deletion variants 81406 Molecular pathology procedure level 7 9

ICD-10 Code Description Comment D12.2 D12.6 Benign neoplasm of colon Z83.71 Family history of colonic polyps Z86.010 Personal history of colonic polyps HCPCS Level II Code N/A Description Comment 10