Genetic Testing Section - Genetic and Molecular Diagnostic Testing

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

DESCRIPTION

Genetic testing is performed to detect changes in DNA, RNA, chromosomes, proteins, or certain metabolites. A number of molecular diagnostic techniques (described by the molecular diagnostic CPT codes range) are used to conduct this analysis.

Genetic testing may be performed for several different purposes, including:

• Diagnosing or predicting susceptibility for inherited conditions
• Screening for common disorders
• Selecting appropriate treatments (also known as pharmacogenetic testing).

Genetic Counseling

Due to the complexity of interpreting genetic test results, patients should receive pre- and post-test genetic counseling from a qualified professional when testing is performed to diagnose or predict susceptibility for inherited diseases.  The benefits and risks of genetic testing should be fully disclosed to individuals prior to testing, and counseling concerning the test results should be provided.

POLICY/CRITERIA

The following general criteria are applied to genetic and molecular diagnostic testing.  In addition, the list in criterion III below provides links to policies for specific genetic test indications.

1. Genetic Testing for Inherited Diseases
   1. Genetic testing  to establish a diagnosis or susceptibility for an inherited disease may be medically necessary when all of the following criteria are met:
      1. There must be a reasonable expectation based on family history, an analysis of genetic relationships and medical history in a family (pedigree analysis), risk factors, and symptomatology that a genetically inherited condition exists.
      2. Diagnostic results from physical examination, pedigree analysis, and conventional testing are inconclusive.
      3. The clinical utility of the genetic test must be established. The clinical records must document:
         1. How test results will guide decisions concerning disease treatment, management , or prevention; and
         2. These treatment decisions would not otherwise be made in the absence of the genetic test results.
   2. Genetic testing to establish a diagnosis or susceptibility for an inherited disease is considered not medically necessary if any of criteria I.A.1- I.A.3.b above are not met.
   3. Genetic testing of children to predict adult onset diseases is considered not medically necessary unless test results will guide current decisions concerning prevention and this benefit would be lost by waiting until the child has reached adulthood.
      
      
2. Genetic Testing Not Related to Inherited Conditions
   
   Genetic testing for indications other than determining risk or establishing a diagnosis for a genetically inherited disease (e.g., genotyping for drug selection and dosing) may be considered medically necessary when all of the following criteria are met:
   
   
   1. Diagnostic results from physical examination and conventional testing are inconclusive; and
   2. The clinical records document how results of genetic testing are necessary to guide treatment decisions; and
   3. There is reliable evidence in the peer-reviewed scientific literature that health outcomes are improved as a result of treatment decisions based on molecular genetic test results.
      
      
3. Specific Test Indications
   
   Note: If a policy for a specific test is not listed in the table below, then the policy criteria in I or II above must be applied.

POSITION STATEMENT

Molecular diagnostic testing must have analytical and clinical validity before clinical utility can be established.  The focus of the position summary for specific tests is on evidence related to the ability of test results to both guide decisions in the clinical setting related to either treatment or prevention and to improve health outcomes as a result of those decisions.

Apolipoprotein E (apo E) Genotyping and Phenotyping in the Management of Cardiovascular Disease ^[4]                                                            Back to Table

• There is insufficient evidence to determine whether apo E genotyping or phenotyping improves coronary artery disease risk prediction compared to traditional risk factor measurement.  
• There is insufficient evidence to determine whether apo E genotyping or phenotyping is useful in the selection of specific components of lipid-lowering therapy, such as medication selection.

Apo E is the primary apolipoprotein found in very-low-density lipoproteins and chylomicrons and is thought to play an important role in lipid metabolism. The apo E gene is polymorphic, consisting of 3 alleles (e2, e3, and e4) that code for 3 protein isoforms, known as E2, E3, and E4. These molecules mediate lipid metabolism through their different interactions with the LDL receptors. The genotype of apo E alleles can be assessed by gene amplification techniques, or the apo E phenotype can be assessed by measuring plasma levels of apolipoprotein E.

Apo E as a Predictor of Cardiovascular Disease

• A large body of research has established a relationship between the underlying apo E genotype and lipid levels, physiologic markers of atherosclerotic disease, or surrogate outcomes such as carotid intima-media thickness. ^[5-11] Other studies have suggested that carriers of apo e4 are more likely to develop signs of atherosclerosis independent of total and low-density lipoprotein (LDL) cholesterol levels. ^[12-14] Some larger observational studies and a meta-analysis correlated apo E genotype with clinical disease. ^[15-18]
• Despite these correlations, there are no prospective clinical trials that demonstrate whether apo E genotyping provides additional clinically relevant information beyond established risk factors. There are no studies comparing health outcomes related to clinical decisions based on apoE genotypying or phenotyping to those based on standard risk factor measurements.
• Apo E has not been incorporated into standardized cardiac risk assessment models and was not identified as one of the important “emerging risk factors” in the most recent Adult Treatment Panel (ATP III) recommendations from the National Cholesterol Education Program. ^[19]

Apo E as a Predictor of Response to Therapy

• Dietary modifications are a universal recommendation for those with elevated cholesterol or LDL levels, and statin medications are the overwhelmingly preferred agents for lipid-lowering therapy.
• The evidence from lipid-lowering trials indicates that the apo E genotype may be a predictor of response to statins and may allow clinicians to better gauge an individual’s chance of successful treatment, although not all studies are consistent in reporting this relationship. ^[20-25]
• However, there are no prospective clinical studies that demonstrate how apo E genotyping or phenotyping changes clinical management or improves health outcomes in patients with an apo E phenotype that indicates diminished response to statin drugs.  Specifically, it is not known whether a clinician would choose alternative therapies that could result in better treatment response.

Breast Cancer: Biomarker Genes for the Detection of Lymph Node Metastases ^[26]                                                                                Back to Table

There is insufficient evidence to determine whether any gene-based test improves detection of lymph node metastases in patients with breast cancer compared to current pathologic and histologic examinations.

The GeneSearch™ breast lymph node (BLN) assay is an intraoperative test to evaluate lymph nodes for metastases in patients with breast cancer.  The assay is proposed as an alternative to standard postoperative histology or to intraoperative frozen section histology or imprint cytology. This assay uses real-time polymerase chain reaction to qualitatively evaluate nodal sections for the presence of two gene expression markers, mammaglobin and cytokeratin 19. These genes are expressed at higher levels in breast tissue, but not in normal nodal tissue. Test results are available in 35 to 40 minutes. The assay cutoff for positivity is designed to allow detection of metastases that are larger than 0.2 mm in size; however, the assay does not discriminate between micrometastases (between 0.2 mm and 2 mm) and macrometastases (larger than 2 mm).

Several reports from European centers describe the use of tests similar to the GeneSearch™ assay; however, published data are limited and none of these tests have FDA approval.

The key factor in assessing these assays is the tradeoff between avoiding a second surgery to remove axillary lymph nodes if the sentinel node is positive versus risking unnecessary axillary lymph node dissection (ALND) if the assay produces a false positive result. The reason sentinel lymph node biopsy is the standard of care in early breast cancer, in spite of the fact that trials on its impact are still incomplete, is the desire to avoid ALND when possible, given the potential for significant, long-term morbidity.

GeneSearch™ BLN Assay

• A 2007 BlueCross BlueShield Association Technology Evaluation Center Assessment concluded that the scientific evidence for intraoperative use of the GeneSearch™ BLN assay was not sufficient to permit conclusions concerning its impact on final health outcomes. ^[27,28] Specific observations included the following:
  
• There was only one published study on the performance of the GeneSearch™ assay, which reported on the same study used by the FDA to determine approval. 
• The study presented to the FDA had a number of strengths, including the clear distinction between the training and test sets and double-reading of the permanent histology slides to increase the reliability of the reference standard.
• A number of weaknesses were present as well, such as lack of description regarding patient recruitment; substantial variation in assay performance across sites; lack of corroborating studies; inability of the assay to distinguish between micro- and macrometastases; and a learning curve for those performing the assay. 
• The GeneSearch™ results were not used for clinical management of the patient. 
• The GeneSearch™ assay provides less information for staging as it cannot distinguish between micro- and macrometastases, and it cannot indicate the location of the metastasis (inside or outside of the node).  Postoperative histology is still required in all cases for staging.
• Additional validation studies are needed that address the limitations noted in the data, including information on patient preferences between avoiding second surgeries versus running the risk of unnecessary axillary lymph node dissection.
  
  
• Although the FDA granted approval for marketing of the GeneSearch™ BLN Test Kit, post-operative histological evaluation of permanent sections of the tissue specimen is required according to the approval.  In addition, the FDA has mandated two postmarketing studies to address some of the data limitations noted in the TEC Assessment. ^[29]

• In three more recent studies, sentinel lymph nodes were analyzed by the GeneSearch™ assay and postoperative or intraoperative histologic examination. ^[30-32] These prospective studies focused on clinical validity and reported overall agreement between the tests of 90.8 - 96%.  Reported sensitivities and specificities were 77.8-92% and 94.6-97%, respectively.  Positive and negative predictive values of the assay were 66.7-86% and 92.9-98.6%, respectively.
  
  
• No clinical decisions were made based on assay results — the clinical utility of the GeneSearch™ (or any other molecular assay) remains uncertain.

Other Assays

• Although research is ongoing for other tests, no other assay has received FDA approval.

National Comprehensive Cancer Network (NCCN) Guidelines

• NCCN guidelines acknowledge the revised cancer staging manual by the American Joint Committee on Cancer (January 2003, sixth edition) which addresses the increasing use of novel pathology diagnostic techniques, and the addition of identifiers to indicate the use of sentinel lymph node molecular pathology techniques in staging a patient. However, the NCCN makes no recommendations on how to incorporate molecular testing of a sentinel lymph node into clinical practice. ^[33]

Colon Cancer: Inherited Susceptibility ^[34]                               Back to Table

Familial Adenomatous Polyposis (FAP) ^[35,36]

Background

FAP typically develops by age 16 years and can be identified by the appearance of hundreds to thousands of characteristic, precancerous colon polyps. If left untreated, all affected individuals will go on to develop colorectal cancer.  The mean age of colon cancer diagnosis in untreated individuals is 39 years.   Germline mutations in the adenomatous polyposis coli (APC) gene are responsible for FAP and are inherited in an autosomal dominant manner.

A subset of FAP patients may have attenuated FAP (AFAP), characterized by 10-99 cumulative colorectal adenomas occurring later in life than in classical FAP, colorectal cancer occurring at an average age of 50-55 years, fewer extraintestinal cancers, but a high lifetime risk of colorectal cancer of about 70% by age 80. Only 30% or fewer of AFAP patients have APC mutations; some of these patients instead have mutations in the MYH gene and are then diagnosed with MYH-associated polyposis (MAP).

MAP occurs with a frequency approximately equal to FAP, with some variability among prevalence estimates for both. While clinical features of MAP are similar to FAP or AFAP, a strong multigenerational family history of polyposis is absent. Biallelic MYH mutations are associated with a cumulative colorectal cancer risk of about 80% by age 70, whereas monoallelic MYH mutation-associated risk of colorectal cancer appears to be relatively minimal. Inheritance for high-risk colorectal cancer predisposition is autosomal recessive in contrast to FAP. When relatively few (10 - 99) adenomas are present and family history is unavailable, the differential diagnosis may include both MAP and Lynch syndrome; genetic testing in this situation could include APC, MYH if APC is negative for mutations, and screening for mutations associated with Lynch syndrome.

Position Statement

• The evidence is sufficient to suggest that genetic testing for adenosis polyposis coli (APC) gene mutations may be helpful in guiding healthcare decisions related to surveillance and prevention in the following groups of patients:

• Family members of patients with FAP and a known APC mutation.
  Those that test positive for an APC mutation may use the information to make surveillance and treatment decisions.  Those without the specific mutation have not inherited the susceptibility gene and can forego intense surveillance (although they retain the same risk as the general population and should continue an appropriate level of surveillance).
• Patients with a differential diagnosis of attenuated FAP vs. MYH-associated polyposis vs. Lynch syndrome. These patients do not meet the clinical diagnostic criteria for classical FAP, and have few adenomatous colonic polyps.
  
  
• The evidence is sufficient to conclude that genetic testing for APC gene mutations is not medically necessary for the diagnosis or management of patients with a clinical presentation of classical FAP.  In this group of patients, testing for the APC mutation provides no additional information that will impact treatment decisions.

 
A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded the following ^[37]:

• 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 close relatives of patients with clinically diagnosed FAP, or close relatives of patients with an 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.
  

The National Comprehensive Cancer Network guidelines recommend APC testing for at-risk family members who are from families with a history of classical FAP. ^[38]

Clinical practice guidelines published by the American Gastroenterological Association state genetic testing should be considered in patients with FAP who have relatives at risk, and genetic counseling should guide genetic testing and considerations of colectomy. ^[39] They further state that genetic testing in children can be delayed until age 10.

Lynch Syndrome (Hereditary nonpolyposis Colorectal Cancer [HNPCC])

Background ^[35]

Patients with Lynch syndrome have a predisposition to colorectal cancer and other extracolonic malignancies as a result of an inherited mutation in a DNA mismatch repair (MMR) gene. The term “HNPCC” originated prior to the discovery of explanatory MMR mutations for many of these patients, and now includes some who are negative for MMR mutations and likely have mutations in as-yet unidentified genes. For purposes of clarity and analysis, the use of Lynch syndrome in place of HNPCC has been recommended in several recent editorials and publications.

Lynch syndrome is estimated to account for 2% to 4% of colorectal cancer and is also associated with an increased risk of other cancers such as endometrial, ovarian, urinary tract, and biliary tract cancer. Lynch syndrome is associated with a risk of developing colorectal cancer of approximately 15% by age 40, and 40% by age 70, although these estimates vary considerably among studies. Lynch syndrome patients who have colorectal cancer also have an estimated 16% risk of a second primary within 10 years. The risk for other Lynch syndrome-related cancers is about 22% for men and 34% for women by age 70.

Lynch syndrome is associated with any of a large number of possible mutations in 1 of 4 MMR genes, known as MLH1, MSH2, MSH6, and PMS2. About 70% of Lynch syndrome patients have mutations in either MLH1 or MSH2. Testing for MMR gene mutations is often limited to MLH1 and MSH2 and, sometimes, MSH6; clinical testing for PMS2 mutations has only more recently become available. Gene sizes and the difficulty of detecting mutations in these genes make direct sequencing a time- and cost-consuming process. Thus, additional indirect screening methods are needed to determine which patients should proceed to direct sequencing for MMR gene mutations. Available screening methods are microsatellite instability (MSI) testing or immunohistochemical (IHC) testing. BRAF gene mutation testing is an optional screening method that may be used in conjunction with IHC testing for MLH1 to improve efficiency.

Mutations in MMR genes result in a failure of the mismatch repair system to repair errors that occur during the replication of DNA in tumor tissue. Such errors are characterized by the accumulation of alterations in the length of simple, repetitive microsatellite sequences that are distributed throughout the genome (MSI).  Absent or reduced protein expression may be a consequence of an MMR gene mutation. IHC assays for the expression of MLH1, MSH2, MSH6, and PMS2 can be used to detect loss of expression of these genes and to focus sequencing efforts on a single gene. It is also possible for IHC assays to show loss of expression, and thus indicate the presence of a mutation, when sequencing is negative for a mutation. In such cases, mutations may be in unknown regulatory elements and cannot be detected by sequencing of the protein coding regions. Thus IHC may add additional information.

The BRAF gene is often mutated in colorectal cancer.  To date no MLH1 gene mutations have been reported when a particular BRAF mutation (1799 T>A transversion, also identified as V600E) is present. Therefore, patients negative for MLH1 protein expression by IHC, and therefore potentially positive for an MLH1 mutation, could first be screened for a BRAF mutation. BRAF-positive samples need not be further tested by MLH1 sequencing.

Position Statement

The evidence is sufficient to suggest that genetic testing for MMR mutations may be effective in guiding surveillance and treatment decisions in select individuals based on personal and/or family history (see criteria).  

The evidence from an Agency for Healthcare Research and Quality [AHRQ] report ^[40], a supplemental assessment to that report contracted by the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group ^[41], and an EGAPP recommendation for genetic testing in colorectal cancer ^[42] provides the basis for this policy.  The EGAPP recommendation reached the following conclusions concerning genetic testing for MMR mutations:

• 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 for 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 a sensitivity for MLH1, MSH2, and MSH6 of about 83% and a specificity of about 90% for all.
• For patients who are negative for MLH1 expression by IHC, optional BRAF testing can be used to reduce the number of patients needing MLH1 gene sequencing, thus improving efficiency without reducing sensitivity for MMR mutations.
• The chain of indirect evidence from well-designed experimental nonrandomized studies was 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. Seven studies examined how counseling affected testing and surveillance choices among unaffected family members of Lynch syndrome patients. About half of relatives received counseling, and 95% of these chose MMR gene mutation testing. Among those positive for MMR gene mutations, uptake of colonoscopic surveillance beginning at age 20–25 years was high at 53–100%.   One long-term, nonrandomized controlled study and one cohort study of Lynch syndrome family members found significant reductions in colorectal cancer among those who followed recommended colonic surveillance vs. those who did not.
• The chain of evidence from descriptive studies and expert opinion was inadequate (inconclusive) to demonstrate the clinical utility of testing the probands with Lynch syndrome (i.e., cancer index patient). In other words, clinical treatment decisions were not changed for Lynch syndrome patients with cancer.
• Based on an indirect chain of evidence with adequate evidence of improved health outcomes 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.   A particular strategy was not recommended by the EGAPP Working Group.

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. ^[43] 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, the Amsterdam or Revised Bethesda criteria may be used in identifying those without colorectal cancer who might be tested.

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 treatment. ^[44-49]

Congenital Long QT Syndrome (LQTS) ^[50]                                Back to Table

The evidence is sufficient to suggest that knowledge of LQTS mutation status may be effective in guiding healthcare decisions in individuals who do not meet the clinical criteria for the condition but who are at risk based on personal or family history.

• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded the following ^[51,52]:
  
• Although there are limitations in the evidence on clinical validity and utility, the overall case strongly suggests that genetic testing will improve outcomes in selected patient populations.
• Two large (n>500) studies compared the diagnostic performance of clinical criteria and genetic testing. ^[53,54] Both showed that genetic testing identified more individuals with a LQTS mutation compared to the number of patients diagnosed clinically (which is known to substantially under diagnose LQTS).
• Due to the catastrophic outcomes associated with LQTS and the availability of low-risk treatments that are efficacious in reducing adverse outcomes, the clinical utility of genetic testing is high for individuals with a known LQTS mutation in the family but who do not themselves meet the clinical criteria for LQTS . The risk of undertreatment of such individuals is likely to far outweigh the risk of overtreatment.  Also, the disease can be ruled out with certainty if results are negative because the specific mutation is known prior to testing.
• For patients who have some signs and symptoms of LQTS, but no known mutation in the family, testing may also be beneficial. In this situation, LQTS can be diagnosed with reasonable certainty if a class I mutation is identified, however the likelihood of false-positive results is higher than if a known mutation was present in the family. In patients with lower pretest probabilities of disease, the utility of testing declines.
• Genetic testing for LQTS has not been demonstrated to improve outcomes when used to direct therapy or determine prognosis in those individuals who already meet clinical criteria for LQTS. There is no evidence to suggest that genetic testing influences clinical decisions concerning treatment (beta blockers, lifestyle change, implantable cardioverter-defibrillator).

Cystic Fibrosis (CF)                                                                  Back to Table

The evidence is sufficient to suggest that genetic testing to determine carrier status for CF may be helpful in guiding healthcare decisions related to reproduction.

• The goal of screening for CF carrier status is to identify couples at risk for having a child with CF, allowing them to consider a range of reproductive options.  For example, knowledge of carrier status may affect decisions concerning conception, use of donor gametes, preimplantation genetic diagnosis, or prenatal genetic testing.
  
  
• The National Institutes of Health (NIH) published an evidence-based consensus statement which concluded that genetic testing for cystic fibrosis  should be offered to the following groups ^[55]:

• Adults with a positive family history of CF and partners of those with CF
  
  Individuals with a family history of CF have relatively high frequencies of mutations in the CFTR gene, so testing in this population can be helpful with regard to reproductive decision-making.
  
  
• Couples currently planning a pregnancy or couples seeking prenatal testing, particularly those in high-risk populations
  
  Data indicated there was a significant level of interest in testing in this population, more so than in the general population, and knowledge of CF carrier status influenced reproductive decision-making.  The NIH panel noted that there were several specific populations (Ashkenazi Jews, Celtic Bretons, French Canadians from Quebec, some Native Americans, and U.S. Caucasians) for which 90-95 percent sensitivity could be achieved when testing for the most common detectable mutations.
   
• The NIH did not recommend large-scale testing of the general population due to the low incidence and prevalence of CF and the demonstrated lack of interest in testing from this population.  Likewise, testing in the general newborn population was not recommended as there was insufficient evidence to demonstrate that earlier identification of CF improved health outcomes. ^[55]
  
  
• The American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG) jointly issued clinical and laboratory guidelines for preconception  and prenatal carrier screening for CF that mirror the NIH guidelines. ^[56] A subsequent ACOG Committee opinion further supported the NIH guidelines. ^[57]

Familial Medullary Thyroid Cancer ^[58]                                   Back to Table

The evidence is sufficient to suggest that genetic testing for germline point mutations in the RET gene may be helpful in guiding healthcare decisions related to surveillance and prevention.

• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment which evaluated data from 35 clinical studies concluded the following ^[59,60]:
  
• Genetic tests for germline point mutations in the RET gene can identify those with an inherited susceptibility for medullary thyroid cancer earlier and more definitively than is possible with annual biochemical tests.
• In newly diagnosed patients without a family history, testing distinguishes sporadic from inheritable tumors.
• Test results affect patient management by prompting thyroidectomy or continued biochemical monitoring in affected patients, and by prompting discontinuation of monitoring in patients who test negative.
  
• The National Comprehensive Cancer Network guidelines recommend genetic counseling (which may include testing) once a diagnosis of either MEN 1 or MEN 2 syndromes is made. ^[61]

Human DNA in Stool Samples for Colorectal Cancer Screening ^[62]
                                                                                                           Back to Table

The available evidence is uncertain with respect to how results from genetic testing of stool samples can be used to benefit patient management.  Specifically for high risk patients, it is uncertain if the test should be used in lieu of routinely scheduled surveillance colonoscopies or during intervals between scheduled colonoscopies.  For average risk patients, it is uncertain if testing should be offered in lieu of, or as an adjunct to other recommended colorectal cancer screening tests, including fecal occult blood testing and colonoscopy. ^[63]

High Risk

• In patients at high risk for colon cancer due to either family history or HNPCC mutation, colonoscopy at varying intervals is recommended by the American Society of Colorectal Surgeons, the American Gastroenterological Society, and the American Cancer Society. ^[64] Therefore, the diagnostic performance of DNA analysis of stool samples should be compared with colonoscopy.
• No clinical trials have been published that evaluate use of genetic testing of stool samples in those at high risk for colon cancer.

Average Risk

• For patients at average to moderate risk of colon cancer, genetic testing of stool samples should be compared to colonoscopy and also to fecal occult blood testing, the other entirely noninvasive technique.  Patient acceptance of the different options is also a relevant outcome as there is a need to increase screening compliance.
• Results from the largest study of patients at average risk for colon cancer were unreliable due to the following limitations ^[65]:
  
• An intention-to-treat analysis was not conducted, so results from this data are uncertain. Approximately 20% of subjects were not evaluated (12% did not provide an adequate stool sample for DNA testing; 8% did not complete FOBT cards; 14% did not complete colonoscopy).
• The observed sensitivity for cancer of the Hemoccult II FOBT (one of the comparator tests) was lower at 13% than reported in other studies.  This difference requires additional study. 
• The confidence intervals around the sensitivity of fecal DNA ranged from 35–68%.  This wide interval precludes any firm estimates of the magnitude of benefit associated with fecal DNA testing. ^[66]
• The Hemoccult II FOBT tests were performed at each of the 81 study sites (including private-practice and university-based settings); quality control procedures were not described. In contrast, the DNA test was conducted in a single laboratory. Screening requires dissemination of the DNA test to more laboratories, which could introduce greater variability in results.
• The U.S. Preventive Services Task Force judged fecal DNA testing to have insufficient evidence to assess the benefits and harms of testing for all populations. ^[67,68] This assessment was based on the trial summarized above. ^[65]
• Updated guidelines for colon cancer screening were also issued in 2008 by a group consisting of the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. ^[69] This guideline endorses the use of fecal DNA testing as an acceptable means of colon cancer screening. However, unlike all the other recommendations in this guideline which recommended specific time intervals between tests, the recommended interval for fecal DNA testing is “uncertain.” The document notes that the manufacturer of the one commercially available test recommends a 5-year interval after an examination with normal results. Such an interval was judged by the committee to be only suitable for a test that has high sensitivity for both cancer and adenomatous polyps—a standard that has not been documented for fecal DNA to date.
  
  The evidence supporting this joint guideline consisted of the previously summarized study ^[65] and additional older studies of diagnostic performance that did not use screening populations but used previously diagnosed or advanced cancer patients.

Prostate Cancer ^[70]                                                                       Back to Table

There is insufficient evidence to determine whether any gene-based tests improve screening, detection, or clinical management of prostate cancer.

• Gene-based tests are being studied to address several challenges in the clinical management of prostate cancer:
  
• risk assessment
• early and accurate detection
• monitoring low-risk patients undergoing surveillance only
• prediction of recurrence after initial treatment
• detection of recurrence after treatment
• assessing efficacy of treatment for advanced disease
  
• The evidence for genetic tests related to prostate cancer screening, detection, and management addresses clinical validity rather than clinical utility. 
• There is currently no evidence that using gene-based tests will change prostate cancer treatment decisions and improve subsequent health outcomes such as mortality, morbidity, or quality of life. ^[71]

Single-nucleotide polymorphisms (SNPs) for risk assessment  ^[71]

• Specific SNP panels are being developed for use as risk assessment tools to identify those men who should start disease surveillance early and be monitored frequently.  However, these tests do not predict certainty of disease, nor do they clearly predict aggressive versus indolent disease.
• There are no prospective studies which demonstrate that monitoring of high-risk men identified by SNP assays compared to standard clinical predictors (age, serum PSA, and family history) improves health outcomes.

PCA3 for disease diagnosis  ^[71]

PCA3 is overexpressed in prostate cancer and PCA3 mRNA can be detected in urine samples collected after prostate massage. When normalized using PSA to account for the amount of prostate cells released into the urine (“PCA3 Score”) the test has significantly improved specificity compared to PSA.  It may better discriminate patients with eventual benign (first or second) biopsies from those with malignant biopsy results. In particular, the test may be especially helpful at identifying patients with elevated PSA but negative first biopsy who need a follow-up biopsy.

• Based on several studies, average PCA3 Score sensitivity and specificity for a positive prostate biopsy result is about 61% and 74%, respectively. ^[72-79]  One study reported that incorporating the PCA3 Score into the Prostate Cancer Prevention Trial risk calculator improved the diagnostic accuracy of the calculator. ^[80]
• One preliminary study suggests that PCA3 Score may also have value in identifying patients with less aggressive cancer who may only need surveillance. ^[81] Another suggests that PCA3 Score predicts extracapsular extension. ^[82] These applications, however, have not yet been pursued in larger studies.
• In general, studies of PCA3 are preliminary.  They report on clinical performance characteristics at various assay cutoff values.  Interpretation of results has not been standardized, and clinical utility studies using assay results for decision-making for initial biopsy, repeat biopsy or treatment have not been reported.

TMPRSS fusion genes for diagnosis and prognosis ^[71]

TMPRSS2 fusion gene detection has been studied to identify aggressive disease or to predict disease recurrence.

• Fusion gene structure is variable and complex, making it a difficult assay target. ^[83,84] As a result, assays have not yet been standardized.
• There is conflicting evidence regarding the association of TMPRSS2 fusion gene detection and biochemical recurrence or survival outcomes of prostate cancer. ^[83,85-90] TMPRSS2 fusion genes are strongly associated with higher disease stage ^[86,87,91], but associations with Gleason scores (used to help determine the stage of cancer) are conflicting. ^[86-89,91]
• There are no prospective studies in which TMPRSS fusion gene detection was used to direct clinical management of patients, so the impact of these tests on health outcomes are unknown.

Candidate gene panels for prostate cancer diagnosis

Because no single gene markers have been found that are both highly sensitive and highly specific for diagnosing prostate cancer, particularly in men already known to have elevated PSA levels, some investigators are combining several markers into a single diagnostic panel.

• Only single studies of various panels have been published.  None were offered as clinical services.
• Clarient, Inc. launched a patent protected combination of four genes to identify the presence of Grade 3 or higher prostate cancer in prostate tissue. This test is reportedly based on a study that has been submitted for publication but is not yet accepted or available for evaluation. ^[92]

Gene hypermethylation for diagnosis and prognosis

Chromatin protein modifications that do not involve changes to the underlying DNA sequence but which can result in changes in gene expression are known as epigenetic changes.  These changes have been identified in specific genes associated with prostate cancer.

• Studies are primarily small, retrospective pilot evaluations of the hypermethylation status of various candidate genes for discriminating prostate cancer from benign conditions (diagnosis) or for predicting disease recurrence and association with clinicopathologic predictors of aggressive disease (prognosis).
• Standardized assays and interpretation criteria have not yet been agreed upon to enable consistency and comparison of results across studies.
• GSTP1 is the most widely studied methylation marker for prostate cancer, usually as a diagnostic application. Many studies have reported on the association of GSTP1 with prostate cancer; however results from these studies are contradictory. ^[93-96] No studies evaluated the clinical utility of GSTP1.

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CROSS REFERENCES

Genetic Testing for Familial Alzheimer's Disease, Regence Medical Policy Manual, Genetic Testing, Policy No. 01

Genetic Testing for Hereditary Breast and/or Ovarian Cancer, Regence Medical Policy, Genetic Testing, Policy No. 02

Non-BRCA Breast Cancer Risk Assessment (OncoVue), Regence Medical Policy, Genetic Testing, Policy No. 03

Genetic Testing for Cutaneous Malignant Melanoma, Regence Medical Policy, Genetic Testing, Policy No. 08

Cytochrome p450 Genotyping, Regence Medical Policy Manual, Genetic Testing, Policy No. 10

KRAS and BRAF Mutation Analysis in Metastatic Colorectal Cancer, Regence Medical Policy, Genetic Testing, Policy No. 13

KRAS Mutation Analysis in Non-Small Cell Lung Cancer (NSCLC), Regence Medical Policy, Genetic Testing, Policy No. 14

Microarray-Based Gene Expression Testing for Cancers of Unknown Primary, Regence Medical Policy, Genetic Testing, Policy No. 15

PathFinderTG® Molecular Testing, Regence Medical Policy, Genetic Testing, Policy No. 16

Preimplantation Genetic Testing, Regence Medical Policy, Genetic Testing, Policy No. 18

Multigene Expression Assay for Predicting Recurrence in Colon Cancer, Regence Medical Policy, Genetic Testing, Policy No. 22

BCR-ABL 1 Testing for Chronic Myeloid Leukemia, Regence Medical Policy Manual, Genetic Testing, Policy No. 27

KIF6 Genotyping for Predicting Cardiovascular Risk and/or Effectiveness of Statin Therapy, Regence Medical Policy Manual, Genetic Testing, Policy No. 32

BRAF Gene Mutation Testing To Select Melanoma Patients for BRAF Inhibitor Targeted Therapy, Regence Medical Policy Manual, Genetic Testing, Policy No. 41

Assays of Genetic Expression in Tumor Tissue as a Technique to Determine Prognosis In Patients With Breast Cancer, Regence Medical Policy, Genetic Testing, Policy No. 42

Epidermal Growth Factor Receptor (EGFR) Mutation Analysis for Patients with Non-Small Cell Lung Cancer (NSCLC), Regence Medical Policy, Genetic Testing, Policy No. 56

Array Comparative Genomic Hybridization (aCGH) for the Genetic Evaluation of Patients with Developmental Delay/Mental Retardation or Autism Spectrum Disorder, Regence Medical Policy, Genetic Testing. Policy No. 58

JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms, Regence Medical Policy, Genetic Testing, Policy No. 59

Dectection of Circulating Tumor Cells in the Management of Patients with Cancer, Regence Medical Policy Manual, Laboratory, Policy No. 46

Genetic Testing Section Table of Contents