Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer - Medicare Advantage Form

Please refer to CMS website for the most current applicable CMS Online Manual System (IOMs)/National Coverage Determination (NCD)/ Local Coverage Determination (LCD)/Local Coverage Article (LCA)/ Transmittals.
Type NCD LCD Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 2 of 31 Title ID Number Jurisdiction Medicare Administrative Contractors (MACs) Applicable States/Territories Next Generation Sequencing NGS) MolDX: Lab-Developed Tests for Inherited Cancer Syndromes in Patients with Cancer
MolDX: Molecular Diagnostic Tests (MDT) 90.2 L39040 L36807 MolDX: Repeat Germline Testing L38429 J5, J8 - Wisconsin Physicians Service Insurance Corporation IA, IN, KS, MI, MO, NE
LCD Molecular Pathology Procedures L35000 J6, JK - National Government Services, Inc.
CT, IL, ME, MA, MN, NH, NY, RI, VT, WI MolDX: Lab-Developed Tests for Inherited Cancer Syndromes in Patients with Cancer L39017 LCD MolDX: Molecular Diagnostic Tests (MDT) L36021 J15 - CGS Administrators, LLC
KY, OH LCD LCA MolDX: Repeat Germline Testing L38288 MolDX: Lab-Developed Tests for Inherited Cancer Syndromes in Patients with Cancer L38972 MolDX: Molecular Diagnostic Tests (MDT) L35160 Billing and Coding: MolDX: Germline testing for use of PARP inhibitors MolDX: Repeat Germline Testing MolDX: Lab-Developed Tests for Inherited Cancer Syndromes in Patients with Cancer A55294 L38351 L38974 JE - Noridian Healthcare Solutions, LLC CA, HI, NV, American Samoa, Guam, Northern Mariana Islands JF - Noridian Healthcare Solutions, LLC AK, AZ, ID, MT, ND, OR, SD, UT, WA, WY

LCD LCA LCD Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 3 of 31 MolDX: Molecular Diagnostic Tests (MDT) L36256 Billing and Coding: MolDX: Germline testing for use of PARP inhibitors A55295 MolDX: Repeat Germline Testing L38353 Biomarkers Overview BRCA1 and BRCA2 Genetic Testing MolDX: Lab-Developed Tests for Inherited Cancer Syndromes in Patients with Cancer
JH, JL - Novitas Solutions, Inc.
AR, CO, DE, LA, MD, MS, NJ, NM, OK, PA, TX, D.C. L35062 L36715 L38966 L35025 JJ, JM - Palmetto GBA
AL, GA, NC, SC, TN,
VA, WV LCD MolDX: Molecular Diagnostic Tests (MDT) MolDX: Repeat Germline Testing
L38274 LCD BRCA1 and BRCA2 Genetic Testing L36499 JN - First Coast Service Options, Inc. (Part A/B MAC) FL, PR, U.S. VI Description Genetic testing is a laboratory method that is performed to analyze an individual’s deoxyribonucleic acid (DNA) to detect gene variants (mutations) associated with inherited conditions including hereditary cancer such as breast, ovarian (including fallopian tube and peritoneal), pancreatic and prostate. Testing may be appropriate for an affected individual. This type of testing may also be referred to as germline genetic testing. Additional inherited cancers include Li-Fraumeni syndrome (LFS) and PTEN hamartoma tumor syndrome/Cowden syndrome. Both are rare, inherited conditions that are associated with increased risk of many types of cancer.
Multigene (or expanded) panels analyze a broad set of genes simultaneously (as opposed to single gene testing that searches for variants in one specific gene) and have been proposed to evaluate the DNA of an individual with a personal and/or family history of more than one hereditary condition or syndrome or hereditary conditions/syndromes associated with more than one gene. Panels often include medically actionable genes but may also include those with unclear medical management. Targeted (or focused) multigene panels analyze a limited number of genes targeted to a specific condition.

Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 4 of 31 Coverage Determination Humana follows the CMS requirements that only allows coverage and payment for services that are reasonable and necessary for the diagnosis and treatment of illness or injury or to improve the functioning of a malformed body member except as specifically allowed by Medicare. Genetic tests must demonstrate clinical utility, analytical and clinical validity and fulfill the CMS “reasonable and necessary” criteria. Analytic validity (test accurately identifies the gene variant), clinical validity (test identifies or predicts the clinically defined disorder) and clinical utility (test measurably improves clinical outcomes) of the genetic test is supported by generally accepted standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, specialty society recommendations, and views of physicians practicing in relevant clinical areas. The test must be ordered by a physician who is treating the beneficiary and the results will be used in the management of a beneficiary’s specific medical problem. For jurisdictions with no Medicare guidance for a particular test, Humana will utilize the MolDX program and Technical Assessments for molecular assays as the standard to evaluate clinical utility, analytical and clinical validity in conjunction with adhering to Medicare’s reasonable and necessary requirement. In interpreting or supplementing the criteria above and in order to determine medical necessity consistently, Humana may consider the following criteria: Multigene Next-Generation Sequencing Panel Testing Multigene next-generation sequencing (NGS) panel testing will be considered medically reasonable and necessary when the following requirements are met: • Requirements of NCD 90.2 Section B2 have been met;29,30 AND • Test is FDA approved/cleared; AND • Analytic validity, clinical validity and clinical utility of the genetic test is supported by the MolDX program; AND • All genes in the panel are relevant to the personal and family history of the individual being tested;29,30 AND • Criteria #1 and #2 or #3 or #4 or #5 listed below for BRCA1 and BRCA2 testing are met;29,30 AND • Individual also meets criteria for at least one BRCA-related cancer syndrome for which National Comprehensive Cancer Network (NCCN) guidelines (category 1 or 2A recommendations) provide clear testing criteria and management including, but not limited to, BRCA-related breast or ovarian cancer syndrome, Li-Fraumeni syndrome, Cowden syndrome or Lynch syndrome29,30

Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 5 of 31 BRCA1 and BRCA2 Gene Testing For multigene panel testing for BRCA1 and BRCA2, please refer to the Multigene Next-Generation Sequencing Panel Testing Criteria above. BRCA1 and BRCA2 full gene sequencing and deletion/duplication analysis will be considered medically reasonable and necessary when the following requirements are met (based on NCCN guidelines category 1 or 2A recommendations);47

1. Results of testing will be used to benefit the individual tested in terms of potential to guide therapeutic decision making;47 AND

2. Personal history of breast cancer with any of the following:111 • Diagnosed at 50 years of age or younger;111 OR • Diagnosed at any age and any of the following:111 o To aid in systemic treatment decisions using PARP inhibitors for metastatic breast cancer;111 OR o To aid in adjuvant treatment decisions with olaparib (Lynparza) for high-risk HER2-negative breast cancer;111 OR o Triple-negative breast cancer;111 OR o Multiple primary breast cancers (synchronous or metachronous);111 OR o Lobular breast cancer with personal or family history of diffuse gastric cancer;111 OR o Male breast cancer;111 OR o Ashkenazi Jewish ancestry; OR o At least one first-, second- or third-degree relative diagnosed with any of the following:111 ▪ Breast cancer at 50 years of age or younger;111 OR ▪ Male breast cancer;111 OR ▪ Ovarian cancer;111 OR ▪ Pancreatic cancer;111 OR ▪ Prostate cancer with metastatic* or high- or very-high-risk group;111 OR

   Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 6 of 31 ▪ At least three diagnoses of breast and/or prostate cancer (any grade) on the same side of the family including the individual with breast cancer;111 OR

3. Personal history of epithelial ovarian cancer (including fallopian tube cancer or peritoneal cancer) at any age;111 OR
4. Personal history of exocrine pancreatic cancer at any age;111 OR
5. Personal history of prostate cancer with any of the following:111 • Metastatic;111 OR • High- or very-high-risk group;111 OR • At least one first-, second- or third-degree relative with any of the following:111 o Breast cancer at 50 years of age or younger;111 OR o Triple-negative breast cancer at any age;111 OR o Male breast cancer at any age;111 OR o Ovarian cancer at any age;111 OR o Pancreatic cancer at any age;111 OR o Metastatic, high-, or very-high-risk group prostate cancer diagnosed at any age;111 OR o At least three first-, second- or third-degree relatives on the same side of the family with breast and/or prostate cancer (any grade) including the individual with prostate cancer;111 OR o Ashkenazi Jewish ancestry111
6. A pathogenic or likely pathogenic variant identified on tumor genomic testing that has clinical implications if also identified in the germline;111 OR

7. Personal history of breast, ovarian, pancreatic or prostate cancer and any blood relative with a pathogenic or likely pathogenic variant in the BRCA1 or BRCA2 gene111 *Biopsy-proven and/or with radiographic evidence and includes distant metastasis and regional bed or nodes. It is not a biochemical recurrence only.111 TP53 Gene Testing for Li-Fraumeni Syndrome

   Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 7 of 31 For multigene panel testing for Li-Fraumeni syndrome, please refer to the Multigene Next-Generation Sequencing Panel Testing Criteria TP53 full gene sequencing and deletion/duplication analysis will be considered medically reasonable and necessary for Li-Fraumeni syndrome (LFS) when the following requirements are met (based on NCCN guidelines category 1 or 2A recommendations);111 • Individual to be tested meets classic LFS criteria, as demonstrated by the presence of ALL of the following: o Diagnosed with a sarcoma before 45 years of age; AND o First-degree relative diagnosed with cancer before 45 years of age; AND o An additional first-, or second-degree relative, on the same side of the family, diagnosed with cancer before 45 years of age or diagnosed with a sarcoma at any age; OR • Individual to be tested meets Chompret criteria as demonstrated by the presence of at least 1 of the following:
   o Diagnosed with a tumor from LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, central nervous system [CNS] tumor, breast cancer, adrenocortical carcinoma) before 46 years of age, AND at least one first- or second-degree relative with any of the previously mentioned cancers (other than breast cancer if the proband has breast cancer) before 56 years of age or with multiple primaries at any age; OR o Diagnosed with multiple tumors (except multiple breast tumors), 2 of which belong to LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, CNS tumor, breast cancer, adrenocortical carcinoma) with the initial cancer occurring before 46 years of age; OR o Diagnosed with adrenocortical carcinoma or choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype at any age of onset, regardless of the family history; OR o Diagnosed with breast cancer before 31 years of age; OR • Individual to be tested diagnosed with pediatric hypodiploid acute lymphoblastic leukemia; OR • Individual to be tested is affected and has a blood relative with a pathogenic or likely pathogenic variant in the TP53 gene; OR • Individual with cancer with a pathogenic or likely pathogenic TP53 variant identified on tumor-only genomic testing and any of the following: o Individual meets at least one of the other LFS testing criterion above after reevaluation of personal and family history; OR

   Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 8 of 31 o Individual diagnosed at less than 30 years of age with any cancer; OR o Individual presenting with a clinical scenario not meeting these criteria but warrants germline evaluation per clinician discretion PTEN Gene Testing for PTEN Hamartoma Tumor Syndrome/Cowden Syndrome For multigene panel testing for PTEN hamartoma tumor syndrome/Cowden syndrome, please refer to the Multigene Next-Generation Sequencing Panel Testing Criteria. PTEN full gene sequencing and deletion/duplication analysis will be considered medically reasonable and necessary for PHTS/CS (PHTS) when the following requirements are met (based on NCCN guidelines category 1 or 2A recommendations);111 • Individual to be tested does NOT meet PHTS Clinical Diagnostic Criteria and has a personal history of any of the following: o Adult Lhermitte-Duclos disease (cerebellar tumors); OR o Autism spectrum disorder and macrocephaly; OR o 4 or more minor PHTS/CS Testing Criteria; OR o 1 major and 3 or more minor PHTS/CS Testing Criteria (If an individual has 2 or more major criteria, such as breast cancer and nonmedullary thyroid cancer, but does not have macrocephaly, one of the major criteria may be included as 1 of the 3 minor criteria to meet testing criteria); OR o 3 or more major PHTS/CS Testing Criteria without macrocephaly; OR o 2 or more biopsy-proven trichilemmomas; OR o 2 or more major PHTS/CS Testing Criteria (one must be macrocephaly); OR • Individual to be tested has a personal history of Bannayan-Ryile-Ruvalcaba syndrome (BRRS); OR • Individual to be tested meets PHTS Clinical Diagnostic Criteria as demonstrated by: o 3 major criteria of the PHTS Clinical Diagnostic Criteria (one must include macrocephaly, Lhermitte- Duclos disease or gastrointestinal [GI] hamartomas); OR o 2 major and 3 minor criteria of the PHTS Clinical Diagnostic Criteria; OR • Individual to be tested is affected and has a blood relative with a pathogenic or likely pathogenic variant in the PTEN gene; OR

   Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 9 of 31 • PTEN pathogenic or likely pathogenic variant detected by tumor genomic testing on any tumor type in the absence of germline analysis The use of the criteria in this Medicare Advantage Medical Coverage Policy provides clinical benefits highly likely to outweigh any clinical harms. Services that do not meet the criteria above are not medically necessary and thus do not provide a clinical benefit. Medically unnecessary services carry risks of adverse outcomes and may interfere with the pursuit of other treatments which have demonstrated efficacy. Coverage Limitations US Government Publishing Office. Electronic code of federal regulations: part 411 – 42 CFR § 411.15 - Particular services excluded from coverage The following tests may not be considered a benefit (statutory exclusion):116 • Tests considered screening in the absence of clinical signs and symptoms of disease that are not specifically identified by the law; OR • Tests that confirm a diagnosis or known information; OR • Tests to determine risk for developing a disease or condition; OR • Tests performed to measure the quality of a process; OR • Tests without diagnosis specific indications; OR • Tests identified as investigational by available literature and/or the literature supplied by the developer and are not a part of a clinical trial These treatments and services fall within the Medicare program’s statutory exclusion that prohibits payment for items and services that have not been demonstrated to be reasonable and necessary for the diagnosis and treatment of illness or injury (§1862(a)(1) of the Act). Other services/items fall within the Medicare program’s statutory exclusion at 1862(a)(12), which prohibits payment.
   The following items will not be considered medically reasonable and necessary: • Any laboratory test that investigates the same germline genetic content, for the same genetic information, that has already been tested in the same individual42,43,44,45,46 • Deletion/duplication analysis is obtained as part of the sequencing procedure but submitted as an independent analysis

   Genetic Testing for Hereditary Breast, Ovarian, Pancreatic and Prostate Cancer Page: 10 of 31 • Genetic tests that have not demonstrated clinical utility, analytical and clinical validity via the MolDX Program • Multigene panel if only a single gene on the panel is considered reasonable and necessary • Multigene panel with genes that are not relevant to the individual’s personal and family history • Multigene panel used to confirm a variant(s) detected by somatic tumor testing that can be confirmed by a test targeted to that specific variant(s)32,33,34,35,36 • Multigene panel used to identify a KFV that could be identified with a test targeted to that specific variant32,33,34,35,36 • Previous test performed for the same genetic content32,33,34,35,36 • Repeat germline testing (testing is limited to once-in-a-lifetime)42,43,44,45,46 A review of the current medical literature shows that the evidence is insufficient to determine that these services are standard medical treatments. There remains an absence of randomized, blinded clinical studies examining benefit and long-term clinical outcomes establishing the value of these services in clinical management.