MP-09 Genetic Testing for Colorectal Cancer Inherited Risk Form

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Policy Number: MP-09 Current Effective Date: 12/13/2019 Original Effective Date: 1/1/2016 Next Review/Revision Date: 12/1/2020 Plans: QUEST Integration (Medicaid) & Medicare

1. Purpose 1.1 The purpose of this policy is to establish the indications for coverage of genetic testing for inherited colorectal cancer syndromes. Genetic testing is available for both those with and those at risk for hereditary colon cancer.
2. Policy 2.1 Colorectal cancer (CRC) is one of the most common types of cancers as well as one of the leading causes of cancer-related death in the United States. The majority of CRC cases are sporadic, but an estimated 5% to 6% are hereditary, including Lynch syndrome, familial adenomatous polyposis (FAP), attenuated FAP (AFAP), MUTYH-associated polyposis (MAP), and familial CRC type X (FCCXS). 2.2 Lynch syndrome is the most common form of hereditary CRC, accounting for 2% to 3% of all CRCs. Historically called hereditary nonpolyposis colorectal cancer (HNPCC), the syndrome is an autosomal dominant condition affecting patients in their 40’s or 50’s. It is associated with mutations in mismatch repair (MMR) genes, which lead to microsatellite instability (MSI). 2.3 Familial adenomatous polyposis (FAP) is estimated to account for no more than 1% of all CRC cases. This autosomal dominant condition is characterized by the presence of at least 100 colon polyps (adenomas), often presenting in adolescents or young adults. FAP is associated with mutations in the APC gene. In 30% of FAP cases, there is no family history of colon polyps. 2.4 Attenuated FAP (AFAP) is characterized by the presence of between 10 and 100 adenomas and typically has a later onset of disease than FAP (around age 50 to 60). 2.5 MUTYH-associated polyposis (MAP) is an autosomal recessive disorder with high penetrance, characterized by the presence of up to 100 adenomas, with an average age of onset around the mid 50’s. 2.6 Currently the specific genetic changes associated with familial CRC type X (FCCXS) are unknown.
3. Definitions 3.1 Amsterdam I and II criteria – sets of diagnostic criteria for hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, as defined by the following: a. Amsterdam I criteria:
4. At least three relatives with histologically verified colorectal cancer (CRC), one of which is a first-degree relative of the other two; and
5. Familial adenomatous polyposis has been excluded; and

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3. One or more family members diagnosed with CRC before the age of 50 years; and
4. At least two affected generations. b. Amsterdam II criteria:
5. At least three relatives have histologically verified colorectal, endometrial, small bowel, ureter, or renal pelvis cancer, one of which is a first-degree relative of the other two; and
6. Familial adenomatous polyposis has been excluded; and
7. One or more family members diagnosed with cancer before the age of 50 years; and
8. At least two generations affected with cancer. 3.2 Bethesda (revised) guidelines – set of diagnostic criteria to guide the testing of CRC for microsatellite instability. Microsatellite instability testing is considered appropriate when a patient with CRC meets one of the following: a. CRC diagnosed before 50 years of age; or b. Synchronous or metachronous colorectal, or other HNPCC-related cancers, regardless of age; or c. CRC with microsatellite instability-high (MSI-H)-like histology diagnosed before 60 years of age; or d. CRC in one or more first-degree relatives with a Lynch Syndrome –associated cancer, with one of the cancers diagnosed under age 50 years; or e. CRC in two or more first-degree relatives with Lynch Syndrome –associated cancers, regardless of age. 3.3 Close Blood Relative - any first-, second-, or third-degree blood relative a. First-Degree Relative - parent, child, full sibling b. Second-Degree Relative - aunt, niece, uncle, nephew, grandparent, grandchild, half sibling c. Third-Degree Relative - cousins, great-grandparents 3.4 Immunohistochemistry (IHC) – Selectively imaging antigens (e.g. proteins) in cells of a tissue section using the principles of antibodies binding to specific antigens in biological tissue. Absence of staining is indicative of protein loss, which can aid in hereditary CRC diagnosis. 3.5 Lynch Syndrome associated aka HNPCC-Related Cancer – include colorectal, endometrial, gastric, biliary tract, brain, small bowel, ureter, pancreas, ovarian, renal pelvis, and sebaceous gland adenomas and keratocanthomas. 3.6 Microsatellite Instability (MSI) – the condition of genetic hypermutability that results from impaired DNA mismatch repair (MMR) genes. MSI-H `is evidence that MMR is functioning abnormally, and is indicative of certain hereditary CRCs. 3.7 Prediction Models – Clinical prediction models designed to evaluate an individual’s risk for Lynch syndrome. These algorithms give probabilities of mutations and/or of the development of future cancers based on family and personal history. These models may be particularly useful when there is insufficient tumor available for MSI or IHC analysis. a. PREMM5 model (http://premm.dfci.harvard.edu/) – estimates the cumulative probability of an individual carrying a germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM genes. A referral for genetic evaluation is recommended for individuals with an overall predicted probability of at least 2.5%. Required variables include the individual’s age, sex, and personal and family history (including age at diagnosis) of CRC, endometrial cancer, and other Lynch syndrome-associated cancers. b. HNPCC predict (MMRpredict) model (http://hnpccpredict.hgu.mrc.ac.uk/) –

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predicts DNA mismatch repair gene mutation status in incident colorectal cancer cases (not validated in patients over 55 years), using sex, age at diagnosis, tumor information, and family history to calculate the risk of a patient having an MLH1, MSH2, or MSH6 gene mutation. A referral for genetic evaluation is recommended for individuals with an overall predicted probability of at least 5%. c. • MMRpro model (http://www4.utsouthwestern.edu/breasthealth/cagene/) – predicts an individual’s probability of having a mutation in the MLH1, MSH2, or MSH6 genes using the personal and family history of CRC/endometrial cancer, age at diagnosis (or current age in unaffected family members) and the results of tumor testing (when available). A referral for genetic evaluation is recommended for individuals with an overall predicted probability of at least 5%.

4. Procedure 4.1 Prior authorization is required. Genetic testing is covered only when test results will change the clinical management of the patient and lead to improved health outcomes. 4.2 Quest Criteria: a. Genetic testing for Lynch Syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) is covered for the following:
5. Known Lynch syndrome (LS) pathogenic variant in family (testing for known variant only); or
6. Personal history of CRC, or other LS-associated cancer (see definitions); meeting one of the following: i. CRC or endometrial cancer which is: o Diagnosed at any age and is MSI-H or shows loss of MMR expression by IHC; or o Diagnosed younger than age 50; or o Patient has another synchronous or metachronous LS-associated cancer; or o One or more first or second degree relative with LS-associated cancer diagnosed younger than age 50; or o Two or more first or second degree relatives with LS-associated cancers diagnosed any age; or ii. CRC with MSI-H-like histology on pathology report
7. Family history of: i. One or more first degree relatives with CRC or endometrial cancer diagnosed younger than age 50; or ii. One or more first degree relative with CRC or endometrial cancer diagnosed any age and a second LS-associated cancer; or iii. Two or more first or second degree relative with LS-associated cancer, if one or more was diagnosed younger than age 50; or iv. Three or more first or second degree relatives with LS-associated cancers, diagnosed any age.
8. Model-predicted risk for Lynch syndrome ≥ 5% (PREMM5, MMRpro, or MMRpredict) b. Genetic testing for APC mutations is covered for the following:

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1. Personal history of at least 10 adenomas; or
2. Personal history of desmoid tumor, hepatoblastoma, cirbiform-morular variant of papillary thyroid cancer, or multifocal/bilateral CHRPE (congenital hypertrophy of retinal pigment epithelium); or
3. No personal history of adenoma or cancer but at least one close blood relative with a diagnosis FAP or AFAP. c. Genetic testing for MUTYH is covered for the following:
4. Personal history of at least 10 adenomas and normal APC gene testing (if performed); or
5. Known deleterious MUTYH mutation in a close blood relative and any personal history of adenomas; or

6. No current history of adenomas but at least one close blood relative with a diagnosis of MAP.

   4.3 Genetic Counseling: a. One pre‐test genetic counseling visit and one post‐genetic counseling visit for is covered for a family history of FAP, APC mutation, Lynch Syndrome-associated cancer, or a personal history of features of FAP or Lynch syndromes. 4.4 Example testing Algorithm

   4.5 Medicare Criteria - Prior authorization is required. a. Refer to Local Coverage Determination (LCD) on Genetic Testing for Lynch Syndrome

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(L36370). https://med.noridianmedicare.com/documents/10546/6990981/MolDX+Genetic+Testing+for+ Lynch+Syndrome+LCD/714c18f3‐0ebb‐4d18‐aaad‐f714a5801a6f

5. Limitations 5.1 Genetic testing for colon cancer risk is once in a lifetime test. Requests for repeat testing must include clear documentation of the need for repeat testing to include the following (when applicable): recurrence of disease, change in behavior of disease, etc. 5.2 Due to the complexity of these laboratory tests, testing must only be performed in laboratories with CLIA (Clinical Laboratory Improvement Amendments of 1988) and CAP (College of American Pathologists) certifications to adhere to U.S. federal standards and regulations on quality. 5.3 The following are considered not medically necessary because they have not been shown to improve long-term health outcomes: a. Genetic screening/testing for the general population. b. Genetic testing for APC gene mutations to confirm a FAP diagnosis in patients with classical FAP. c. Testing of any other genes for hereditary CRCs. d. Testing of unaffected relatives if testing in the family member affected by cancer fails to identify a pathogenic variant. e. MMR tumor gene sequencing for individuals with normal MSI and/or IHC results. f. Additional MMR gene testing for individuals with an identified abnormality in EPCAM, MLH1, MSH2, MSH6, or PMS2. g. Testing of individuals under the age of 18, unless onset of disease may occur in adolescence, as documented by family or personal history of hereditary CRCs. h. Multigene panels – unless every gene in the panel has clinical utility for the individual being tested. i. For individuals being tested for carrier status without pretest genetic counseling documentation. j. Genetic testing in patients with a diagnosis of FCCXS. k. For any other indication not specified above.

6. Coding Information The following medical codes are relevant codes for diagnosis and procedures for genetic testing for inherited risk for colon cancer and for informational purposes only. All the medical codes listed in this policy do not constitute or imply benefit coverage or provider reimbursement.

   CPT Description 81201 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence 81202 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; known familial variants 81203 APC (adenomatous polyposis coli) (eg, familial adenomatosis polyposis [FAP], attenuated

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FAP) gene analysis; duplication/deletion variants 81288 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis 81292 MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis: full sequence analysis 81293,
MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; known familial variants
81294
MLH1 (mutL homolog 1, colon cancer, nonpolyposis type 2) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants
81295 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis 81296 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis, known familial variants 81297 MSH2 (mutS homolog 2, colon cancer, nonpolyposis type 1) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants 81298 MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis 81299 MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome ) gene analysis; known familial variants 81300 MSH6 (mutS homolog 6 [E. coli]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; duplication/deletion variants 81301 Microsatellite instability analysis (eg., hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (eg, BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed 81317 PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis 81318 PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis, known familial variants 81319 PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis, duplication/deletion variants 81401 Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat); 81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)’ MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), full gene sequence

Medicare Only 81435 Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include sequencing of at least 10 genes, including APC, BMPR1A, CDH1, MLH1,

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MSH2, MSH6, MUTYH, PTEN, SMAD4, and STK11 81436 Hereditary colon cancer disorders (eg, Lynch syndrome, PTEN hamartoma syndrome, Cowden syndrome, familial adenomatosis polyposis); duplication/deletion analysis panel, must include analysis of at least 5 genes, including MLH1, MSH2, EPCAM, SMAF4, and STK11

7. References/Resources 7.1 National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal. Version: 2.2019. Issued: 8/8/2019. http://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf 7.2 National Institute for Health and Clinical Excellence (NICE). Diagnostics Guidance (DG). Molecular testing strategies for Lynch syndrome in people with colorectal cancer. DG27. Published: Feb. 22, 2017. https://www.nice.org.uk/guidance/dg27 7.3 Stoffel EM, Mangu PB, Gruber SB, et al. [American Society of Clinical Oncology.; European Society of Clinical Oncology]. 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 Jan 10;33(2):209-217. doi: 10.1200/JCO.2014.58.1322. http://ascopubs.org/doi/pdf/10.1200/JCO.2014.58.1322 7.4 Kasttinos F, Uno H, Ukaegbu C, et. al.;Development and Validation of the PREMM5 Model for Comprehensive Risk Assessment of Lynch Syndrome; J Clin Oncol, 2017 July 35:19, 2165-2172. DOI: 10.1200/JCO.2016.69.6120 https://ascopubs.org/doi/full/10.1200/JCO.2016.69.6120 7.5 Vasen HFA, Möslein G, Alonso A, et al, Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer) Journal of Medical Genetics 2007;44:353-362. https://jmg.bmj.com/content/44/6/353 7.6 Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb 18;96(4):261-268 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933058/pdf/nihms231084.pdf 7.7 Serrano, M., Lage, P., Belga, S. et al. Bethesda criteria for microsatellite instability testing: impact on the detection of new cases of Lynch syndrome; Familial Cancer (2012) 11: 571. https://doi.org/10.1007/s10689-012-9550-6 https://link.springer.com/article/10.1007%2Fs10689-012-9550-6#citeas 7.8 Lorans M, Dow E, Macrae FA, et al. Update on Hereditary Colorectal Cancer: Improving the Clinical Utility of Multigene Panel Testing. Clin Colorectal Cancer. 2018 Jun;17(2):e293-e305. doi: 10.1016/j.clcc.2018.01.001. Epub 2018 Jan 11. https://www.clinical-colorectal-cancer.com/article/S1533-0028(17)30366-3/fulltext
8. Review/Revision History 1/1/2016 - New policy 6/2017 - Revised the Criteria and Coding Information based on the guidelines of National

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Comprehensive Cancer Network and CMS. 10/2019 - Align with updated NCCN guidelines, new template, updated references, moved indications for genetic testing for treatment of CRC to new policy 12/1/2020 - Retired