Name of Policy: Genetic Testing for Inherited Cancer Predisposition and/or Pharmacogenetics related to Cancer Treatment

Transcription

1 Name of Policy: Genetic Testing for Inherited Cancer Predisposition and/or Pharmacogenetics related to Cancer Treatment Policy #: 133 Latest Review Date: April 2015 Category: Laboratory Policy Grade: D Background/Definitions: As a general rule, benefits are payable under Blue Cross and Blue Shield of Alabama health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage. The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage: 1. The technology must have final approval from the appropriate government regulatory bodies; 2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 3. The technology must improve the net health outcome; 4. The technology must be as beneficial as any established alternatives; 5. The improvement must be attainable outside the investigational setting. Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are: 1. In accordance with generally accepted standards of medical practice; and 2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient s illness, injury or disease; and 3. Not primarily for the convenience of the patient, physician or other health care provider; and 4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient s illness, injury or disease. Page 1 of 28

2 Description of Procedure or Service: A genetic disorder is a disease caused in whole or in part by a mutation of a gene. Genetic disorders can be passed on to family members who inherit the genetic abnormality. A number of disorders are caused by a mistake in a single gene. Genetic testing can be diagnostic, prenatal, presymptomatic, predispositional, and pharmacogenetic. Genetic tests attempt to identify abnormalities in an individual s genes, which include the presence or absence of key proteins whose production is directed by specific noncoding RNAs. These abnormalities in either the presence or absence of proteins could indicate an inherited disposition for a disorder. Genetic testing includes gene, DNA or RNA testing and biochemical or protein testing. Gene tests are performed on DNA taken from blood, body fluids or tissues and examined for the abnormality. Abnormalities may be large or small involving either a piece of a chromosome or an entire chromosome may be missing or added. Genes may be amplified, over-expressed, inactivated or lost. In some instances, genes may become switched, transposed or discovered in the wrong location. Biochemical testing evaluates the presence or absence of key proteins and metabolites that may indicate abnormal or malfunctioning genes. One of the greatest advances in biomedical research is the identification of germline gene mutations associated with cancer. Policy: Inherited Cancer Predisposition Genetic testing meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when ANY of the following apply: The individual displays clinical features; OR The individual is at direct risk of inheriting the mutation in question based on family history or ethnic background; OR The result of the test will directly impact the treatment or management of the individual or other family members. The following conditions are established for the individual diagnoses. Testing is performed in a setting that has adequately trained health care providers who can give appropriate pre-and posttest counseling and that has a qualified laboratory (See Key Points). In the absence of specific information regarding advances in the knowledge of mutation characteristics for a particular disorder, the current literature indicates that genetic tests for each individual mutation need only be conducted once per lifetime of the patient. Genetic testing in the home or home genetics tests do not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and are considered investigational. Genetic testing using the Know Error DNA Specimen Provenance Assay to assign specimen provenance or purity when making the diagnosis of cancer and other histopathological conditions does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational. Page 2 of 28

3 Solid Organ Cancers Breast/Ovarian Cancer Refer to Medical Policy #513, Genetic Testing for Hereditary Breast and/or Ovarian Cancer Refer to Medical Policy #180, Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis in Patients with Breast Cancer Colon Cancer Genetic testing for inherited susceptibility of Colon Cancer meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage per diagnosis when the following criteria are met: Genetic testing for adenosis polyposis coli gene (APC) meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the following: First degree relatives of patients with familial adenomatous polyposis (FAP) and/or a known APC mutation Patients with a differential diagnosis of attenuated FAP vs MYH-associated polyposis vs Hereditary Nonpolyposis Colorectal Cancer (HNPCC) also known as Lynch syndrome. Whether testing begins with APC mutations or screening for MMR mutations depends on clinical presentation. Genetic testing for APC gene mutations does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage for colorectal cancer patients with classical FAP. Genetic testing for MYH gene mutations meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage in the following patients: Patients with a differential diagnosis of attenuated FAP vs MYH-associated polyposis vs Lynch syndrome/hnpcc and a negative result for APC gene mutations. Family history of no parents or children with FAP is consistent with MYH-associated polyposis (autosomal recessive). Genetic testing for the MYH-associated polyposis (MAP) for colorectal cancer (targeted mutation analysis for the two most common variants Y165C and G382D, followed by sequencing if negative) meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when at least ONE of the following criteria are met: Patients with multiple adenomas or polyps (>10); OR Patients in whom FAP or attenuated atypical FAP is suspected but APC genetic testing has been reported as negative for a disease-causing mutation Genetic testing for MMR gene mutations meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage in the following patients: Patients with colorectal cancer, for the diagnosis of Lynch syndrome/hnpcc Page 3 of 28

4 First or second degree relatives of patients with Lynch syndrome with a known MMR mutation Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome/hnpcc. Whether testing begins with APC mutations or screening for MMR mutations depends upon clinical presentation. Patients without colorectal cancer but with a family history meeting the Revised Amsterdam or Revised Bethesda criteria, when no affected family members have been tested for MMR mutations. (See criteria below). Revised Amsterdam criteria (must meet all of the following): o Three or more relatives with a histologically verified Lynch syndrome/hnpcc related cancers, and o One of whom is a first degree relative of the other two; and o Two successively affected generations; and o One or more Lynch syndrome/hnpcc related cancers diagnosed before 50 years of age. Revised Bethesda criteria (must meet one of the following) Colorectal diagnosis is made younger than 50 years of age Individual has or had a second colorectal cancer or another cancer (endometrial, stomach, pancreas, small intestine, ovary, kidney, ureters, or bile duct) that is associated with HNPCC/Lynch syndrome Individual is younger than 60 years and the cancer has certain characteristics seen with HNPCC/Lynch syndrome when viewed under the microscope or with other lab tests. Individual has a first-degree relative younger than 50 who was diagnosed with colorectal cancer or another cancer often seen in HNPCC carriers (endometrial, stomach, pancreas, small intestine, ovary, kidney, ureter, or bile duct). Individual has 2 or more first- or second-degree relatives who had colorectal cancer or an HNPCC-related cancer at any age. Clinical genetic testing is available and appropriate for the I1307K mutation in the APC gene in those individuals that meet the above criteria and are of Ashkenazi Jewish decent. Immunohistochemistry (IHC) and Microsatellite instability (MSI) to identify those at risk for carrying an Hereditary Nonpolyposis Colorectal Cancer (HNPCC) gene mutation and/or genetic testing to determine carrier status of the HNPCC gene meets Blue Cross and Blue Shield s medical criteria for coverage in patients who meet either the Amsterdam Revised or Bethesda criteria: Revised Amsterdam criteria (must meet all of the following): o Three or more relatives with a histologically verified HNPCC related cancers, one of whom is a first degree relative of the other two; and o Two successively affected generations; o One or more HNPCC related cancers diagnosed before 50 years of age. Bethesda criteria (may meet any of the following): Page 4 of 28

5 o Individuals with two HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers, (biliary, endometrial, urinary or ovarian); OR o Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at less than 45 years of age and adenoma diagnosed at less than 40 years of age; OR o Individuals with colorectal cancer or endometrial cancer with an undifferentiated pattern on histopathology diagnosed at less than 45 years of age; OR o Individuals with signet ring cell type colorectal cancer diagnosed at less than 45 years or age; OR o Individuals with adenomas diagnosed at less than 40 years of age. Clinical genetic testing for individuals meeting these criteria can include testing for mutations in any of the following genes: PMS2, MLH1, MSH2, and MSH6. Genetic testing to determine the carrier status of the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) gene meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage in individuals without a personal history of HNPCC but have a first- or seconddegree relative with documented HNPCC gene mutation. Genetic testing using Oncotype DX for colon cancer does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage and is considered investigational for the following, including but not limited to: Predicting the likelihood of disease recurrence for patients with stage II colon cancer following surgery Head and Neck Cancers Refer to Medical Policy #582, Analysis of MGMT Promoter Methylation in Malignant Gliomas Refer to Medical Policy #585, Gene Expression Profiling for Uveal Melanoma Genetic testing for retinoblastoma meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when the following criteria are met: The individual displays clinical features or is at direct risk of inheriting the mutation in question based on family history or ethnic background; The result of the test will directly impact the treatment or management of the individual or other family members; After history, physical examination, pedigree analysis, genetic counseling, completion of appropriate conventional diagnostic studies and a definitive diagnosis remains uncertain Multiple Organ Cancers Refer to Medical Policy #581, Genetic Testing for PTEN Hamartoma Tumor Syndrome (includes Cowden Syndrome, Bannayan-Riley-Ruvalcaba Syndrome, Proteus Syndrome, and Proteus-Like Syndrome) Page 5 of 28

6 Multiple Endocrine Neoplasia Type 1 Genetic testing for MEN 1/MENIN mutations meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the following patients: Individuals with a personal history of 2 of the 3 main MEN 1 related cancers: pancreatic (islet cell) cancer, parathyroid (hyperplasia) and/or pituitary adenoma; OR; Individual with at least 1 main MEN 1 related cancer and a positive family history of 2 cases of pancreatic (islet cell) cancer, parathyroid (hyperplasia) and/or pituitary adenoma (can be the same person), OR; Unaffected individuals who have a family history of a documented MEN 1 gene mutation in a first or second degree relative. Von-Hippel-Lindau (VHL) VHL is characterized by lesions which can include two or more hemangioblastomas of the retina or brain, or a single hemangioblastoma in association with a visceral manifestation, such as kidney or pancreatic cysts; renal cell carcinoma; adrenal or extra-adrenal pheochromocytomas, and, less commonly, endolymphatic sac tumors, papillary cystadenomas of the epididymis or broad ligament, or neuroendocrine tumors of the pancreas. Genetic testing for VHL gene mutations meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the following patients: Any individual who has 1 or more characteristic lesions with or without a family history, OR; Unaffected individuals who have a family history of a documented VHL gene mutation in a first or second degree relative. Peutz-Jeghers Syndrome Genetic testing for the STK11 gene mutations meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the following patients: Any individual with a diagnosis of small bowel hamartomatous polyposis and who demonstrates hyperpigmentation of the digits and mucosa of the external genitalia, OR; Unaffected individuals who have a family history of a documented STK11 gene mutation in a first or second degree relative. Li-Fraumeni Syndrome Genetic testing for p53 gene mutations meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage for the following patients: Any individual who has one first or second degree relative with sarcoma, brain or adrenal cancer diagnosed under the age of 45, AND; One first or second degree relative with sarcoma, breast, brain, adrenal, or leukemia at any age, AND; One first or second degree relative with any cancer diagnosed at or under the age of 60. Page 6 of 28

7 Pancreatic Cancer Genetic testing for inherited BRCA2 mutation meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage in the following conditions: Individuals with a personal history of pancreatic cancer, OR; Unaffected individuals (male or female) with a relative (first or second degree) with a documented BRCA2 mutation, OR; Unaffected individuals (male or female) with two or more first degree relatives with pancreatic cancer, OR; Unaffected individuals with one first-degree relative diagnosed with pancreatic cancer at an early age (under the age of 50), OR Unaffected individuals with two or more second degree relatives with pancreatic cancer, one of whom developed it at an early age (under the age of 50). Skin Cancers Refer to Medical Policy #591, Genetic Testing for Familial Cutaneous Malignant Melanoma Thyroid Cancer Genetic testing for RET proto-oncogene point mutation (associated with inheritance of MEN2A, MEN2B and FMTC) for medullary thyroid cancer meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage when one of the following criteria is met: Asymptomatic members of well-characterized families with defined RET gene mutations, OR; Members of families known to be affected by inherited medullary thyroid carcinoma, but not previously evaluated for RET mutations, OR; Patients with apparently sporadic medullary thyroid carcinoma, OR; Patients with first-degree relatives with apparently sporadic medullary thyroid carcinoma Pharmacogenetics Testing Related to Cancer Treatment Solid Organ Cancer Treatment Breast Cancer Treatment Refer to Policy #586, Genetic Testing for Tamoxifen Treatment Refer to Policy # 425, Cytochrome p450 Genotyping for additional information regarding coverage of testing for drugs for non-cancerous conditions. Colon Cancer Treatment Refer to policy #365, KRAS, NRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer Page 7 of 28

8 Genetic testing for the UGT1A1 gene in patients with metastatic colorectal cancer to determine tolerance to irinotecan (Camptosar ) does not meet Blue Cross and Blue Shield of Alabama s medical criteria for coverage. Lung Cancer Treatment Refer to Policy #468, Molecular Analysis for Targeted Therapy of Non-Small-Cell Lung Cancer (NSCLC) for EGFR, KRAS &ALK analysis Policy #467, KRAS Mutation Analysis in Non-Small-Cell Lung Cancer (NSCLC), has been incorporated into Policy #468. Refer to Policy #468 for KRAS analysis. Hematologic Cancer Treatment Leukemia Treatment Refer to Policy # 583, Genetic Testing for FLT3 and NPM1 Mutations in Acute Myeloid Leukemia. IgV(H) gene mutation analysis meets Blue Cross and Blue Shield of Alabama s medical criteria for coverage in the management of chronic lymphocytic leukemia (CLL). (Effective 03/22/2011) Blue Cross and Blue Shield of Alabama does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Cross and Blue Shield of Alabama administers benefits based on the member s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. Key Points: Testing for cancer-related gene mutations can identify those at high risk and help them to reduce their risk and reduce the burden of cancer. Many inherited cancers have no evidence-based preventive measures available, and for some cancers, the prevention consists of removal of atrisk organs. Most cancer screening tests detect but do not predict disease. Cancer screening tests provide information about the individual tested. Screening tests are for all symptom-free individuals, and if a negative test results will need to be repeated at intervals. Genetic tests are performed on those with or without disease and have a family or personal medical history or belong to an ethnic group with high probability of mutation. Genetic testing can identify cancer-related germline mutations in disease-free individuals or in patients with the disease who have unaffected family members and may be candidates for testing. Disease-free individuals that have positive test results are candidates for aggressive primary preventive measure. Page 8 of 28

9 The following critical issues should be addressed when genetic testing is to be performed responsibly and effectively in the care of patients with a possible inherited genetical cancer predisposition: 1. Cancer-risk counseling should be integrated into the role of the clinical oncologist or clinical medical geneticist. During the evaluation and management or consultation of these patients, the following services should occur: Documentation of a family history for the possible inherited cancer; Counseling regarding familial cancer and options for prevention and early detection; Recognition of those families for which genetic testing may serve as an aid in appropriate counseling. 2. Counseling should be performed by a specialist who is appropriately sanctioned by a genetics credentialing organization (e.g. American Board of Genetic Counseling, Inc.) and who has been trained in the following: Quantitative risk assessment; Genetic testing; Pre and post-test genetic counseling. 3. Proper informed consent must be obtained. Basic elements for informed consent include the following: Information on the specific test being performed. Implication of a positive or negative test result. Possibility that the test will not be informative. Options for risk estimation without genetic testing. Risk of passing a mutation or predisposition to children. Technical accuracy of the test. Fees involved in testing and counseling. Risks of psychological distress. Risks of insurance or employer discrimination. Confidentiality issues. Options and limitations of medical surveillance and screening following the testing. 4. Indications for counseling and testing: The patient has a strong family history of cancer (specific criteria is required for each genetic test to satisfy this requirement), The test can be adequately interpreted, Result will influence medical management of the patient and/or family member. 5. Proper medical management, post-testing and counseling: Discuss possible risks and benefits of cancer early detection and prevention modalities, which have presumed but unproven efficacy for individuals at the highest hereditary risk. Encourage long-term research of outcome studies and/or cooperative studies or registries. Page 9 of 28

10 Know Error DNA Specimen Provenance Assay The Know Error system, produced by Diagnostic ID LLC, provides DNA confirmation between patients and their biopsy tissue sample ensuring that when patients biopsy results arrive, the results are of the tested patient. The system s testing sequence includes a comparison of short tandem repeat, or STR, profiles of both the patient and the biopsy sample cells. The error-elimination system is designed for prostate cancer and breast cancer biopsy samples. Before a biopsy procedure, a reference sample of the patient s DNA is taken by swabbing the inside of the patient s cheek. The swab is sent to an independent forensic DNA lab for testing. When the patient s biopsy result comes back, DNA from the biopsy is double-checked against DNA from the patient s cheek swab. Short tandem repeat (STR) analysis has emerged as the method of choice for testing to resolve specimen source contamination and identify problems that arise in surgical pathology. Pfeifer, et al (2011), studied a series of consecutive cases referred for STR typing during a five-year period to document the usefulness of the approach and to describe the broadening scope of testing. The series demonstrates that STR-based typing can be applied in virtually any setting in which specimen source confirmation is requested, that STR-based typing is informative in 92% of cases, but that exceptions occasionally arise that complicate test interpretation. The series also demonstrates that in addition to traditional uses of STR typing, testing is now performed in the absence of any direct indication that a specimen mix-up or contamination may have occurred, namely, when the pathologic findings are unexpected or the clinical setting is atypical. The case series underscores the ability of STR testing to detect errors that cannot be captured by current laboratory protocols, a finding that has important implications for patient safety. Colon Cancer Colorectal cancer is the third most commonly diagnosed cancer in both men and women, with nearly 150,000 new cases expected in 2003 and the second most common cause of death from cancer. Colorectal cancer screening has been shown to save lives by detection of cancer at an early asymptomatic stage with a better prognosis. The American Cancer Society recommends the following screening. Beginning at age 50, men and women should follow one of these five testing schedules: yearly fecal occult blood test (FOBT), flexible sigmoidoscopy every five years, yearly fecal occult blood tests plus flexible sigmoidoscopy every five years (preferred over either of the tests alone), double-contrast barium enema every five years, or colonoscopy every five years. All positive tests should be followed up with colonoscopy. Age is the number one risk factor as nearly 90% of colon cancer patients are over the age of 50. Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant inherited colorectal cancer syndrome that accounts for 5% to 8% of all colorectal cancers. Familial history is the second most common risk factor for colorectal cancer. HNPCC is caused by mutations resulting in defective mismatch repair gene function although mutations in MLH1 and MSH2 account for more than 95% of HNPCC. Advances in molecular technology have enabled the use of genetic testing for HNPCC. The American Gastroenterology Association (AGA) recently published guidelines and recommendations for genetic testing in HNPCC families. The AGA recommends testing of affected individuals meeting Amsterdam and modified Bethesda criteria and first-degree relatives of mutation carriers. Genetic counseling is an integral part of the testing Page 10 of 28

11 process, during which information about the disease and cancer risk, interpretation of test results, and surveillance and treatment options are provided to the patient. Unrepaired DNA replication errors or mutations, as occurs in HNPCC, are the most easily recognized segments of DNA termed microsatellites. Microsatellites are short, repeated nucleotide sequences located throughout the genome, whose length may change due to insertion or deletion mutations during DNA replication. When multiple microsatellite errors or mutations are detected in the tumor, the cancer is said to exhibit microsatellite instability (MSI). MSI testing has been recommended as a tool to screen for patients who should undergo genetic testing for mismatch repair gene mutations from among those patients who do not meet the Amsterdam criteria but are still suspected of having HNPCC. The susceptibility genes for familial adenomatous polyposis (FAP) or HNPCC are dominantly inherited. Germline mutations in the adenomatous polyposis coli (APC) gene, located on chromosome-5, are responsible for FAP. This specific mutation called (I1307K) has been found in subjects of Ashkenazi Jewish descent. The I1307K mutation is termed a missense mutation. It is hypothesized that this mutation does not cause colon cancer, but appears to create a weak spot in the gene that makes it more susceptible to additional genetic changes that may in turn lead to colon cancer. Familial adenomatous polyposis accounts for less than 1% of colorectal cancers and results from autosomal dominant inheritance of a germline mutation in the adenomatous polyposis coli (APC) gene. Fifty percent of carriers develop adenomas by age 15 and 95% by age 35. Once polyps become evident, colon cancer is inevitable and total colectomy is recommended. APC gene mutations can be detected in the peripheral blood of about 80%-90% of families with FAP. Family members of the patient with the clinical syndrome of FAP should undergo clinical screening. Once identified, clinical screening can be directed toward only those family members in whom the mutation is found. Extracolonic malignancies and benign extracolonic malignancies may also develop in patients with FAP. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Germ-line mutations in the base-excision-repair gene MYH have been recently shown to be associated with autosomal recessive inheritance of multiple colorectal adenomas or atypical polyps. Although MYH is more likely to be the gene involved when there is no prior family history of colorectal cancer, or if there are only siblings affected in a family, there have also been a number of reports of individuals with biallelic MYH mutations and a family history of colorectal cancer, giving the appearance of vertical transmission. This is believed to be due to a high carrier frequency of MYH mutations in the general population or in consanguineous families and is referred to as pseudo-dominant inheritance. Therefore, family history alone should not be determinant of genetic testing for MAP. The active metabolite of the drug irinotecan (Camptosar ) is eliminated from the body by a process called glucuronidation. The UGT1A1 gene is responsible for attaching the glucuronide group onto the drug. Approximately 10% of the population have a genetic change in the UGT1A1 gene, called UGT1A1*28, that hinders their ability to perform this glucuronidation Page 11 of 28

12 process. When patients with this genetic change receive a standard dose of irinotecan, they have a high risk of severe or even fatal neutropenia. Palomaki et al reported that there are gaps in the knowledge of how to utilize this information and that there is no direct or indirect (chain of evidence) evidence to support the clinical utility of modifying an initial and/or subsequent dose of irinotecan in patients with CRC as a way to change the rate of adverse drug events (e.g., severe neutropenia). FAP Familial adenomatous polyposis (FAP) is an inherited disorder characterized by cancer of the colon and rectum. People with the classic type of FAP may begin to develop multiple noncancerous growths (benign polyps) in the colon as early as their teenage years and the numbers of polyps tend to increase with age. Unless the colon is removed, these polyps will become malignant (cancerous). The average age at which an individual develops colon cancer in classic FAP is 39 years. Some people have a variant of the disorder called attenuated familial adenomatous polyposis, in which polyp growth is delayed. The average age for the development of colon cancer is 55. The incidence of FAP varies from 1 in 7,000 to 1 in 22,000. APC Mutations in the APC gene cause both classic and attenuated FAP. These mutations affect the ability of the cell to maintain normal growth and function. Cell overgrowth resulting from the mutations in the APC gene leads to the colon polyps seen in FAP. MYH Mutations can also occur in the MUTYH gene causing autosomal recessive FAP also known as MYH-associated polyposis. MYH mutations prevent cells from correcting mistakes that are made when DNA is copied (DNA replication) in preparation for cell division. As the errors in DNA replication continue, the likelihood of cell overgrowth increases, leading to colon polyps and the possibility of colon cancer. FAP can have different inheritance patterns. Mutations in the APC gene are autosomal dominant, which means that if a parent has FAP with the APC gene mutation, the child has a 50% chance of inheriting FAP. If the mutation for FAP is the result of a MYH mutation, this is an autosomal recessive pattern. This means that both parents of an individual must carry the autosomal recessive condition, but the parents do not show signs or symptoms of the disorder. Lynch Syndrome, HNPCC Hereditary nonpolyposis colorectal cancer is also known as Lynch syndrome. HNPCC (Lynch Syndrome) is an inherited tendency to develop colorectal, endometrial, upper urologic tract, gastric, small bowel, biliary/pancreatic skin, and brain. Lynch syndrome, after Dr. Henry Lynch did much to characterize and emphasize the importance of this familial syndrome and Lynch Syndrome is now being used more commonly. Lynch syndrome is an autosomal dominant disorder that is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes and accounts for about 2 to 3% of all colon cancer cases and 2% of uterine cancer. Variations in the MLH1, MSH2, MSH6, and PMS2 genes increase the risk of Lynch syndrome. The age-incidence and spectrum of cancer in Lynch syndrome vary significantly based upon the Page 12 of 28

13 MMR gene mutated. Those with Lynch syndrome have a higher than usual risk of developing colorectal cancer and tend to occur before the age of 50. The diagnosis of Lynch syndrome (HNPCC) can be made on the basis of the Amsterdam clinical criteria or by molecular genetic testing for germline mutations in one of several MMR genes. The evidence for FAP genetic testing was based originally on a 1998 TEC Assessment, which supplied the following conclusions: Genetic testing for FAP may improve health outcomes by identifying which currently unaffected at-risk family members require intense surveillance or prophylactic colectomy. At-risk subjects are considered to be those with greater than 10 adenomatous polyps; or close relatives of patients with clinically diagnosed FAP or of patients with a n identified APC mutation. The optimal testing strategy is to define the specific genetic mutation in an affected family member and then test the unaffected family members to see if they have inherited the same mutation. Additional policy information on attenuated FAP and on MYH-associated polyposis diagnostic criteria and genetic testing is based on information from GeneReviews and several publications that build on prior, cited research. In addition, GeneReviews summarizes clinical FAP genotypephenotype correlations that could be used to determine different patient management strategies. The authors of the review conclude, however, that there is not yet agreement about using such correlations to direct management choices. The policy for Lynch syndrome/hnpcc is based on an evidence report published by the Agency for Healthcare Research and Quality (AHRQ), a supplemental assessment to that report contract by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, and an EGAPP recommendation for genetic testing in colorectal cancer. Based on the AHRQ report and supplemental assessment, the EGAPP recommendation came to the following conclusions regarding genetic testing for MMR mutations in patients already diagnosed with colorectal cancer: Family history, while important information to elicit and consider in each case, has poor sensitivity and specificity as a screening test to determine who should be considered MMR mutation testing and should not be used as a sole determinant or screening test. MSI and IHC screening tests for MMR mutations have similar sensitivity and specificity. MSI screening has a sensitivity of about 89% for MLH1 and MSH2 and 77% for MSH6, and a specificity of about 90% for all. It is likely that, using high quality MSI testing methods, these parameters can be improved. IHC screening has sensitivity for HLH1, MSH2, and MSH6 of about 83% and a specificity of about 90% for all. Optional BRAF testing can be used to reduce the number of patients, who are negative for MLH1 expression by IHC, needing MLH1 gene sequencing, thus improving efficiency without reducing sensitivity for MMR mutations. Page 13 of 28

14 A chain of indirect evidence can be constructed for the clinical utility of testing all patients with colorectal cancer for MMR mutations. 1. The chain of indirect evidence from well-designed experimental nonrandomized studies (as noted below) is adequate to demonstrate the clinical utility of testing unaffected (without cancer) first- and second-degree relatives of patients with Lynch syndrome who have a known MMR mutation. 2. Seven studies examined how counseling affected testing and surveillance choices among unaffected family member of Lynch syndrome patients. About half of relative received counseling, and 95% of these chose MMR gene mutation testing. Among those positive for MMR gene mutation, uptake of colonoscopic surveillance beginning at age years was high at %. 3. The chain of evidence from descriptive studies and expert opinion is inadequate (inconclusive) to demonstrate the clinical utility of testing the probands with Lynch syndrome (i.e., cancer index patient) Based on an indirect chain of evidence with adequate evidence of benefit to unaffected family members found to have Lynch syndrome, the EGAPP working group recommended testing all patients with colorectal cancer for MMR gene mutations. Although MMR gene sequencing of all patients is the most sensitive strategy, it is highly inefficient and cost-ineffective and not recommended. Rather, a screening strategy of MSI or IHC testing (with or without optional BRAF testing) is recommended and retains a relatively high sensitivity. Some evidence suggests that IHC requires particular training and experience. Although a particular strategy was not recommended by the EGAPP Working Group, several are potentially effective; efficiency and cost effectiveness may depend upon local factors. Previous recommendations have used family history as an initial screen to determine who should proceed further to MMR laboratory testing. A recent study showed that limiting laboratory testing to patients who met even the more sensitive Bethesda criteria (i.e., compared to the Amsterdam II criteria) would miss 28% of Lynch syndrome cases. Family history is important for counseling families, but based on this and similar evidence is not recommended as an initial screening tool to make decisions about testing patients who already have colorectal cancer. However, as noted in the policy statement, the Amsterdam or Revised Bethesda criteria may be used in identifying those without colorectal cancer who might be tested. Limiting testing on the basis of age (e.g., test only patients under age 50) is also not recommended. For example, Hampel et al found that among 18 Lynch syndrome patients discovered among 500 unselected colorectal cancer patients, only eight (44%) patients were diagnosed at age younger than 50 years. Another group screened colorectal cancer patients who were under age 60 and identified 98 likely (MSI-positive, BRAF-negative) Lynch syndrome cases; of these, 47% were between ages 50 and 60. As the EGAPP recommendations noted, the evidence to date is limited to clearly support benefit from genetic testing to the index patient with colorectal cancer if found to have Lynch syndrome. However, professional societies have reviewed the evidence and concluded that genetic testing likely has direct benefits for at least some patients with colorectal cancer and Lynch syndrome who choose prophylactic surgical Page 14 of 28

15 treatment. This policy is based on the evidence and professional society recommendations reviewed below. Early documentation of the natural history of colorectal cancer in highly selected families with a strong history of hereditary colorectal cancer indicated risks of synchronous and metachronous cancers as high as 18% and 24% in patients who already had colorectal cancer. As a result, in 1996, the Cancer Genetic Studies Consortium, a temporary NIH-appointed body, recommended that if colorectal cancer is diagnosed in patients with an identified mutation or a strong family history, a subtotal colectomy with ileorectal anastomosis (IRA) should be considered in preference to segmental resection. Although the average risk of a second primary is now estimated to be somewhat lower overall in patients with Lynch syndrome and colorectal cancer, effective prevention measures remain imperative. One study suggested that subtotal colectomy with IRA markedly reduced the incidence of second surgery for metachronous cancer from 28% to 6% but could not rule out the impact of surveillance. A mathematical model comparing total colectomy and IRA to hemicolectomy resulted in increased life expectancies of 2.3, 1, and 0.3 years for ages 27, 47, and 67, respectively; for Duke s A, life expectancies for the same ages are 3.4, 1.5, and 0.4, respectively. Based on this work, the joint American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) review of risk-reducing surgery in hereditary cancers recommends offering both options to the patient with Lynch syndrome and colorectal cancer, especially those who are younger. This ASCO/SSO review also recommends offering Lynch syndrome patients with an index rectal cancer the options of total proctocolectomy with ileal pouch anal anastomosis or anterior proctosigmoidectomy with primary reconstruction. The rationale for total proctocolectomy is the 17% to 45% rate of metachronous colon cancer in the remaining colon after an index rectal cancer in Lynch syndrome patients. The ASCO/SSO review recommends offering prophylactic total abdominal hysterectomy to female patients with colorectal cancer who have completed childbearing or to women undergoing abdominal surgery for other conditions, especially when there is a family history of endometrial cancer. This recommendation is based on the high rate of endometrial cancer in mutation-positive individuals (30 64% in studies that may be biased by strong family history; overall, possibly as low as 20 25%) and the lack of efficacy of screening. When surgery is chosen, oophorectomy should also be performed because of the high incidence of ovarian cancer in Lynch syndrome. As already noted, in one retrospective study, women who chose this option had no gynecologic cancer over 10 years whereas about one-third of women who did not have surgery developed endometrial cancer, and 5.5% developed ovarian cancer. Clinical Input Received through Physician Specialty Societies and Academic Medical Centers In response to requests by the Blue Cross Blue Shield Association, input was received through three Physician Specialty Societies and three Academic Medical Centers while this policy was under review for October While the various Physician Specialty Societies and Academic Medical Centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the Physician Specialty Societies or Academic Medical Centers, unless otherwise noted. In general, those providing input were in agreement with the overall approach described in this policy. Page 15 of 28

16 Thus, in conclusion, based on changes in recommendations about potential colorectal cancer treatment options as well as enhanced surveillance, and possible prophylactic treatment, for other Lynch syndrome malignancies, testing patients with newly diagnosed colorectal cancer for possible Lynch syndrome is considered medically necessary. Oncotype DX for Colon Cancer A 12-gene expression test (Oncotype DX colon cancer test; Genomic Health, Inc., Redwood City, CA) has been developed to predict the likelihood of disease recurrence for patients with stage II colon cancer following surgery. Of patients with stage II colon cancer, 75 80% are cured by surgery alone, and the absolute benefit of chemotherapy for the patient population is small. Those patients who are most likely to benefit from chemotherapy are difficult to identify by standard clinical and pathologic risk factors. The 12-gene expression test is intended to be used as an aid in indentifying those stage II patients most likely to experience recurrence after surgery and therefore those most likely to benefit from additional treatment. O Connell et al have recently described the development of the 12-gene expression test. A total of 761 candidate genes of possible prognostic value for recurrence or of possible predictive value for treatment were examined by correlating the genes in tumor samples with the clinical outcomes seen in 1,851 patients who had surgery with or without adjuvant 5-fluorouracil (5-FU)- based chemotherapy. Gene expression was quantitated from microdissected fixed paraffinembedded primary colon cancer tissue. Of the 761 candidate genes surveyed, a multivariate analysis including disease severity, stage, and nodal involvement, reduced the genes to a significant 7-gene prognostic signature and a separate 6-gene predictive signature. Five reference genes are also included in the assay. The 7-gene prognosis signature, reported as a recurrence score (RS) using bootstrap methods, was a significant and independent predictor of three-year recurrence risk, which increased continuously with RS in patients with stage II disease. RS scores could separate patients into low-, intermediate-, and high-risk groups. Recurrence risks (95% confidence interval [CI]) of disease at three years for the low-, intermediate-, and high-risk groups were 8% (5-12%), 11% (7-15%), and 25% (18-32%) respectively. The 6-gene predictive signature for 5-FU chemosensitivity did not show significance in the validation study. External validation of the algorithm in an independent study, the Quick and Simple and Reliable (QUASAR) study has been noted to be completed but publication is pending. A summary of results has appeared in abstract form and in a recent review by Rasul and Kerr. Based on information in the review the recurrence score could be used to predict low (12%), intermediate (18%) or high (22%) risk of three year disease recurrence. Methods are not well described in either publication and confidence intervals for recurrent risk are not provided. It was noted in both publications that treatment score was not validated as a predictor of chemotherapy benefit. On January 21, 2010, Genomic Health announced the worldwide commercial availability of its Oncotype DX colon cancer test. As stated in the press release, The 12-gene advanced diagnostic test is clinically validated to predict individual recurrence risk in stage II colon cancer patients following surgery. It is assumed that the test consists of the 7-gene prognostic score Page 16 of 28

17 plus the five reference genes and that the 6-gene predictive signature for chemosensitivity has been removed; however, little detail on the actual test configuration or performance is available on the website. Although the test is offered clinically, it appears on the website in a section classified as Pipeline products. While there is a report clearly detailing the methodology used for developing the algorithms for this test, the only evidence suggesting the RS is prognostically sound is based on bootstrapping methodologies. Preliminary promising reports on the validation of this tool as a prognostic indicator of stage II tumor recurrence have appeared in abstract form and been briefly described in a review article. However, an assessment of both clinical validity and clinical utility of testing awaits publication of more detailed results. The evidence to date is insufficient to permit conclusions concerning the effect of the 12-gene expression test (Oncotype DX colon cancer test) on health outcomes. Therefore, use of this test, including use to predict the likelihood of disease recurrence for patients with stage II colon cancer, is considered investigational. Retinoblastoma Retinoblastoma (RB) is a malignancy of the retinal cell layer of the eye and is the most common eye cancer in children and usually presents itself before the age of five. In about 40% of the cases RB is hereditary. RB is quite rare and occurs in approximately one in every 20,000 births and can occur unilaterally or bilaterally. Those with retinoblastoma of the inherited type have an increased frequency of second malignancies and are most often bone tumors. RB is treated by surgery (enucleation, chemotherapy, cryotherapy, light coagulation, and radiation). Current statistics have an 80-90% five year survival rate. IgV(H) Gene Mutation and Chronic Lymphocytic Leukemia (CLL) Chronic lymphocytic leukemia (CLL) accounts for approximately 11% of hematologic neoplasms and at any time in the United States, approximately 100,000 individuals are living with CLL. Patients with CLL follow heterogeneous clinical courses. Some survive for prolonged periods without definitive therapy, while others die rapidly, despite aggressive treatment. Chin et al (2006) described that CLL patients can be divided into two basic groups on the basis of the mutational status of the immunoglobulin heavy-chain variable-region (IgV(H)) gene in leukemic cells. Patients with the IgV(H) gene mutations have a longer survival than those without. Thus, mutation analysis may be useful for assessing prognosis of patients with CLL and planning management strategies. Thyroid Cancer Thyroid cancer represents approximately 1% of malignancies occurring in the United States, resulting in 22,000 cancer diagnoses and 1,400 cancer deaths per year. Carcinoma of the thyroid is an uncommon cancer and is the most common malignancy of the endocrine system. Differentiated tumors (papillary or follicular) are highly treatable and usually curable. Poorly differentiated cancers (medullary or anaplastic) are much less common, are aggressive, metastasize early, and have a much poorer prognosis. Thyroid cancer affects women more than men and the majority of the cases are between the ages of 25 and 65. Three to four percent of thyroid cancer is medullary thyroid cancer (MTC). MTC arises from the parafollicular calcitonin-secreting cells of the thyroid cells of the thyroid gland. MTC occurs in Page 17 of 28

18 sporadic and familial forms. Familial cases may indicate the presence of multiple endocrine neoplasia Type 2 (MEN2), a group of autosomal dominant genetic disorders caused by inherited mutations in the RET oncogene. This disorder is classified into three subtypes based on the presence of other clinical complications: MEN2A, familial medullary thyroid carcinoma (FMTC) and MEN2B. All three subtypes have a high risk of developing MTC. DNA-based testing of the RET gene identifies disease-causing mutation in 95% of individuals with MEN2A and MEN2B and in about 85% of individuals with FMTC. Genetic testing is considered an important part of the management for at-risk family members. The criteria outlined by the American Society of Clinical Oncology has stated that genetic testing for MEN2 meets the criteria for at-risk individuals for first-degree relatives (parents, siblings, and children) of a person known to have MEN2. Key Words: Genetic testing, genetic test, genetic disorder, mutation, colon cancer, colorectal cancer, adenosis polyposis coli gene, APC, familial adenomatous polyposis, FAP, hereditary non-polyposis colorectal cancer, HNPCC, Amsterdam criteria, Bethesda criteria, I1307K, replication error phenotype, RER, microsatellite instability, MSI, thyroid cancer, carcinoma of the thyroid, RET proto-oncogene, medullary thyroid cancer, medullary thyroid carcinoma, MTC, multiple endocrine neoplasia type 2, MEN2, RET oncogene, MEN2A, MEN2B, familial medullary thyroid carcinoma, FMTC, RET gene, sporadic medullary thyroid carcinoma, germline alterations, fecal occult blood test, FOBT, DNA, DNA replication, microchip array, tumor gene expression, Oncotype test, retinoblastoma, MYH mutation, gefitinib, Iressa, non-small cell lung cancer, NSCLC, CYP2D6, JAK-2, Lynch Syndrome, MYH mutation, MYH, APC, adenosis polyposis coli gene, IgV(H), chronic lymphocytic leukemia, CLL, single-nucleotide polymorphisms (SNF), TMPRSS, Oncotype DX, Genomic Health, uveal melanoma (UM), ocular melanoma, DecisionDx-UM, Know Error DNA specimen provenance assay, (DSPA), glioblastoma multiforme, GBM, MGMT, methylation, UGT1A1 Approved by Governing Bodies: Laboratories performing genetic testing should be certified by the appropriate accrediting agency. Appropriate lab competency for testing: State license, Clinical Laboratory Improvement Amendments (CLIA) certification, American College of Medical Genetics/College of American Pathologist (ACMG/CAP) certification Director and staff credentialed by the American Board of Medical Genetics (ABMG) Credentialed by the American Board of Bioanalysis (ABB) and American Board of Histocompatibility and Immunogenetics (ABHI) Benefit Application: Coverage is subject to member s specific benefits. Group specific policy will supersede this policy when applicable. Page 18 of 28

19 ITS: Home Policy provisions apply FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity. Special benefit consideration may apply. Refer to member s benefit plan. Current Coding: CPT codes: APC (adenomatous polyposis coli) (e.g., familial adenomatosis polyposis [FAP], attenuated FAP) gene analysis; full gene sequence (effective 01/01/2013) ; known familial variants (effective 01/01/2013) ; duplication/deletion variants (effective 01/01/2013) FLT3 (fms-related tyrosine kinase 3) (e.g., acute myeloid leukemia), gene analysis, internal tandem duplication (ITD) variants (i.e., exons 14, 15) (effective 01/01/2012) (*moved to MP#583) IGH@ (immunoglobulin heavy chain locus) (e.g., leukemias and lymphomas, b-cell), gene rearrangement analysis to detect abnormal clonal population(s); amplified methodology (e.g., polymerase chain reaction) (effective 01/01/2012) ; direct probe methodology (e.g., southern blot) (effective 01/01/2012) IGH@ (immunoglobulin heavy chain locus) (e.g. leukemia and lymphoma, B-cell), variable region somatic mutation analysis (effective 01/01/2012) IGK@ (immunoglobulin kappa light chain locus) (e.g. leukemia and lymphoma, B-cell), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) (effective 01/01/2012) MGMT (O-6-methylguanine-DNA methyltransferase) (e.g., glioblastoma multiforme), methylation analysis (effective 01/01/2014) (*moved to MP#582) MLH1 (mutl homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; promoter methylation analysis (Effective 01/01/15) MLH1 (mutl. homolog 1, colon cancer, nonpolyposis type 2) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis (effective 01/01/2012) ; known familial variants (effective 01/01/2012) ; duplication/deletion variants (effective 01/01/2012) MSH2 (muts homolog 2, colon cancer, nonpolyposis type 1) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis (effective 01/01/2012) ; known familial variants (effective 01/01/2012) ; duplication/deletion variants (effective 01/01/2012) MSH6 (muts homolog 6 [E. coli]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis (effective 01/01/2012) ; known familial variants (effective 01/01/2012) Page 19 of 28

20 81300 ; duplication/deletion variants (effective 01/01/2012) Microsatellite instability analysis (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) of markers for mismatch repair deficiency (e.g., BAT25, BAT26), includes comparison of neoplastic and normal tissue, if performed (effective 01/01/2012) NPM1 (nucleophosmin) (e.g., acute myeloid leukemia) gene analysis, exon 12 variants (effective 01/01/2012) (*moved to MP#583) PML/RAR-alpha, (t(15;17)), (promyelocytic leukemia/retinoic acid receptor alpha) (e.g., promyelocytic leukemia) translocation analysis; common breakpoints (e.g., intron 3 and intron 6), qualitative or quantitative (effective 01/01/2012) ; single breakpoint (e.g., intron 3, intron 6 or exon 6), qualitative or quantitative (effective 01/01/2012) PMS2 (postmeiotic segregation increased 2 [s. cerevisiae]) (e.g., hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis (effective 01/01/2012) ; known familial variants (effective 01/01/2012) ; duplication/deletion variants (effective 01/01/2012) PTEN (phosphatase and tensin homolog) (e.g., Cowden syndrome, PTEN hamartoma tumor syndrome) gene analysis; full sequence analysis (effective 01/01/2013) (*moved to MP#581) ; known familial variant (effective 01/01/2013) (*moved to MP#581) ; duplication/deletion variant (effective 01/01/2013) (*moved to MP#581) TRB@ (T cell antigen receptor, beta) (e.g., leukemia and lymphoma), gene rearrangement analysis to detect abnormal clonal population(s); using amplification methodology (e.g., polymerase chain reaction) (effective 01/01/2012) ; using direct probe methodology (e.g., Southern Blot) (effective 01/01/2012) TRG@ (T cell antigen receptor, gamma) (e.g. leukemia and lymphoma), gene rearrangement analysis, evaluation to detect abnormal clonal population(s) (effective 01/01/2012) UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (e.g. irinotecan metabolism), gene analysis, common variants (e.g. *28, *36, *37) (effective 01/01/2012) Molecular pathology procedure, Level 4 (NEW TESTING) (effective 01/01/2013) Molecular pathology procedure, Level 6 (NEW TESTING) (effective 01/01/2013) Hereditary colon cancer syndromes (e.g., Lynch syndrome, familial adenomatosis polyposis); genomic sequence analysis panel, must include analysis of at least 7 genes, including APC, CHEK2, MLH1, MSH2, MSH6, MUTYH, and PMS2 (effective 01/01/15) Page 20 of 28