LETTER OF MEDICAL NECESSITY FOR HEREDITARY CANCER GENETIC TESTING (CancerNext)

Date: Date of service/claim

To: Utilization Review Department Insurance Company Name, Address, City, State

Re: Patient Name, DOB, ID #: ICD-10 Codes: (quick reference suggestions – Active diagnosis: C50.919 female breast cancer, unspecified; C18.9 colon cancer, unspecified; Personal history: Z85.3 breast cancer; Family history: Z80.3 breast cancer; Z83.71 colon cancer)

This letter is in regards to my patient and your subscriber, First, Last Name to request full coverage of medically-indicated genetic testing for hereditary cancer to be performed by Ambry Genetics Corporation.

Cancer is thought to have a hereditary component in up to 10% of cases; evaluating personal and family histories is a major part of hereditary cancer risk assessment. Mutations in multiple genes cause hereditary cancer, which markedly increase the lifetime risk for many types of cancer (such as up to 87% for breast cancer for women with BRCA1 and BRCA2 mutations).1 Some of these gene mutations also increase the lifetime risk for other cancers (such as ovarian, uterine, colorectal, sarcomas, brain, leukemia, gastric, thyroid, and prostate).

Significant aspects of my patient’s personal and/or family medical history that suggest a reasonable probability of hereditary cancer are below [check all that apply]:

 A history clearly suggestive of hereditary cancer  Several cancers in the family that do not seem to fit a particular hereditary cancer syndrome (demonstrating a need for a multi-gene approach to testing)  A family history with features of several hereditary cancer syndromes  Cancer diagnosed at a younger age than expected for the general population (≤ 50 years, for most cancers)  Multiple people with cancer on the same side of the family across generations, and in multiple generations  An individual with multiple primary cancers  A family history of cancer that is typical of a known cancer predisposition syndrome

Based on this, I am requesting coverage for this test (CancerNext). CancerNext includes comprehensive analysis of 34 genes associated with hereditary cancer relevant to this patient’s personal and/or family history: APC, ATM, BARD1, BRCA1, BRCA2, BRIP1, BMPR1A, CDH1, CDK4, CDKN2A, CHEK2, DICER1, EPCAM, GREM1, HOXB13, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, POLD1, POLE, PTEN, RAD50, RAD51C, RAD51D, SMAD4, SMARCA4, STK11, TP53. According to published guidelines, more than one gene may explain an inherited cancer syndrome, thus multi-gene testing may be more efficient and/or cost-effective.2,3

This genetic testing will help estimate my patient’s risk to develop cancer/another primary cancer and directly impact my patient’s medical management. An aggressive approach following established screening and management guidelines is indicated in individuals that carry a mutation found by this test. Management options may include2,3 [check all that apply]:  Increased breast screening including self-examinations, clinical breast examinations, mammogram, ultrasound, and MRI  Breast cancer risk reduction using prophylactic mastectomies and/or chemoprevention  Risk-reducing salpingo-oophorectomy  Prostate cancer screening (PSA and DRE)4,5  Annual thyroid ultrasound and exam  More frequent colonoscopy screening  Avoidance of radiation treatment when possible  Consideration of other MRI-based screening/technologies6

Several studies have indicated that genetic testing results significantly influence treatment choices.7-9 As one example, the 2014 systematic review by the U.S. Preventive Services Task Force determined the efficacy of risk-reducing surgery in BRCA1/2 mutation-positive women. For high- risk women and mutation carriers, bilateral mastectomy reduced breast cancer incidence by 85- 100% and breast cancer mortality by 81% and 100%, respectively; salpingo-oophorectomy reduced breast cancer incidence by 37-100%, ovarian cancer incidence by 69-100%, and all-cause mortality by 55-100%, respectively.10

I am ordering this testing as medically necessary and affirm that my patient has provided informed consent for genetic testing. Specifically for this patient, the results of the genetic test are necessary to consider in the following areas [check all that apply]:

 Genetic testing will lead to changes in my medical management strategies as mentioned above; AND/OR  Genetic testing will lead to changes in diagnostic procedures such that more potentially invasive alternative procedures could be avoided, reducing unnecessary tests and cost; AND/OR  Genetic testing will lead to informed decisions for other family members with similar conditions, or that may be at risk for similar conditions

I am specifying Ambry Genetics Corporation which provides highly-sensitive11 and cost-effective testing for hereditary cancer, along with a large database of previously tested patients to ensure highly validated, accurate, and informative test interpretation.

I recommend that you support this request for coverage of diagnostic genetic testing for hereditary cancer in my patient. Genetic testing can take up to several weeks to complete, and the laboratory will not bill until testing is concluded. Therefore, we are requesting that the authorization be valid for 3 months.

Thank you for your time, and please don’t hesitate to contact me with any questions.

Sincerely,

Ordering Clinician Name (Signature Provided on Test Requisition Form) (MD/DO, Clinical Nurse Specialist, Nurse-Midwives, Nurse Practitioner, Physician Assistant, Genetic Counselor*)

*Authorized clinician requirements vary by state Test Details

CPT codes: 81201x1, 81203x1, 81211x1, 81213-59x1, 81292x1, 81294-59x1, 81295, 81297- 59x1, 81298, 81300-59x1, 81317x1, 81319-59x1, 81231x1, 81323-59x1, 81404x2, 81405x2, 81406x2, 81408x2

Laboratory: Ambry Genetics Corporation (TIN 33-0892453 / NPI 1861568784), a CAP- accredited and CLIA-certified laboratory located at 7 Argonaut, Aliso Viejo, CA 92656

References:

1. Chen S and Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007 Apr 10;24(1):1329- 33. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ). Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2017, 12/07/2016. 3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2016, 09/26/2016. 4. Kirchhoff T, et al. BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res. 2004 May;10(9):2918-2921. 5. Castro E, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May;31(14):1748-1757. 6. Villani A, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011 Jun;12(6):559-67 7. Menkiszak J, et al. Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in Poland. Eur J Gynaecol Oncol. 2004;25(1):93-95. 8. Scheuer L, et al. Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol. 2002 Mar;20(5):1260-1268. 9. Weitzel JN, et al. Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis. Arch Surg. 2003 Dec;138(12):1323-1328; discussion 1329. 10. Nelson HD, et al. Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: Systematic Review to Update the U.S. Preventive Services Task Force Recommendation. Evidence Synthesis No. 101 (AHRQ Publication No. 12-05164-EF-1). Rockville, MD Agency for Healthcare Research and Quality; 2013. 11. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Design. 2016 Nov;18(6):923-932.