Laboratory Section - Genetic Testing

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

DESCRIPTION

A genetic test is the analysis of DNA, RNA, chromosomes, proteins, or certain metabolites in order to detect changes that may be related to inherited diseases.   Genetic tests are conducted for a number of purposes, including predicting disease risk, screening in newborns, determining clinical management, identifying carriers, and establishing prenatal or clinical diagnoses or prognoses in individuals, families, or populations.

The value of genetic testing for specific conditions is measured by analytical and clinical validity and clinical utility:

• Analytical validity measures whether the test accurately and reproducibly detects the gene markers of interest.
• Clinical validity is a measurement of the accuracy with which a test identifies or predicts a clinical condition.
• Clinical utility refers to the ability of genetic test results, either positive or negative, to provide information that is of value in the clinical setting. Specifically for positive test results, this could involve instituting treatments or surveillance measures, making decisions concerning future conception, or avoiding harmful treatments. Negative test results can have clinical utility in that unnecessary treatments or surveillance can be avoided.

Genetic Counseling

Due to the complexity of interpreting genetic test results, patients should receive pre- and post-test genetic counseling from a qualified professional.  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.  Issues that may be discussed include:

• Positive test results do not necessarily mean that an individual will develop a specific disease.  Conversely, negative test results do not necessarily mean that an individual will not develop the disease.
• Multiple mutations could exist for a single disease, some of which could be missed in testing.
• Not all mutations have the same effects in terms of disease severity.
• Some diseases may be caused by the interaction of both genetic and environmental factors.
• Effective treatments may not be available for some diseases.
• There may be significant emotional and psychological effects as a result of genetic testing.

POLICY/CRITERIA

Genetic testing 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, risk factors, or symptomatology that a genetically inherited condition exists.
2. The analytical and clinical validity of the test must be established.
3. The clinical utility of the test must be established. Test results are necessary to guide decisions concerning disease treatment or prevention, and these decisions would not otherwise be made in the absence of the genetic test results.
4. Genetic testing of children to predict adult onset diseases is not considered 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.

The table below includes, but is not limited to specific conditions for which genetic testing may be considered medically necessary and those for which testing is considered investigational. A link to the position summary for each indication is provided.

POSITION STATEMENT

Genetic tests 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 guide decisions in the clinical setting related to either treatment or prevention.

Genetic Testing Criteria

The rationale for the general policy criteria is addressed below (1-14):

1. There must be a reasonable expectation based on family history, risk factors,  symptomatology, or an analysis of genetic relationships and medical history in a family that a genetically inherited condition exists.

Many genetic tests are imperfect predictors of either existing disease or disease susceptibility, particularly when used in the context of population screening, where individuals without family histories of disease, risk factors or symptoms are tested. For example, the probability exists that a disease may still occur, even when a negative test result is obtained. Conversely, a specific disease may not occur when there is a positive test result. While these concepts hold true for at-risk individuals as well, the probability of both these occurrences is greater in population screening, so test results are more difficult to interpret in a manner that will meaningfully impact health outcomes. With a few limited exceptions (e.g., PKU testing), general screening of populations for diseases that can be attributed to genetic mutations is not advocated in the published scientific literature.

2. The analytical and clinical validity of the test must be established.

There are both benefits and risks associated with genetic tests. Genetic tests that are not fully assessed for analytical and clinical validity prior to their use in clinical practice have the potential for causing harm to patients. For example, patients who are wrongly classified as at-risk may be subjected to increased and unnecessary surveillance or treatments, some of which may be harmful or even irreversible. Likewise, false negative test results may lead to delays in diagnosis and treatment.

3. The clinical utility of the test must be established.

Clinical utility refers to the ability of genetic test results, either positive or negative, to provide information that will direct decisions concerning treatment or prevention.  Specifically for positive test results, this could involve instituting treatments or surveillance measures, making decisions concerning future conception, or avoiding harmful treatments. Negative test results can have clinical utility in that unnecessary treatments or surveillance can be avoided. In the absence of such interventions, the benefits of testing are limited, and in fact, can cause harm.

4. Genetic testing of children to predict adult onset diseases is not considered 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.

It is generally accepted in the published literature that unless useful medical intervention can be offered to children as a result of testing, formal testing should wait until the child is old enough to understand the consequences of testing and request it for him-or herself. Ethical concerns related to the testing of children include the breach of confidentiality that is required by revealing test results to parents, the lack of ability to counsel the child in a meaningful way regarding the risks and benefits of testing, the impact a positive test could have in terms of discrimination, and the potential psychological damage that could occur from distorting a family’s perception of the child.

Familial Alzheimer’s Disease (AD)                                          Back to Table

Available evidence is not yet sufficient to establish how genetic testing improves patient management for either risk assessment or diagnosis of AD. This includes but is not limited to testing for the apolipoprotein E epsilon 4 allele, presenilin genes, or amyloid precursor gene.

• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded that the addition of APOE genetic testing does not improve the sensitivity and only marginally improves the specificity of clinical criteria for the diagnosis of AD. (15,16) The sensitivity and specificity of clinical diagnostic criteria were 93% and 55%, respectively.  The sensitivity and specificity for the presence of at least one APOE epsilon 4 allele for pathogenically diagnosed AD were 65% and 68%, respectively. 
  
  Because of the significant number of false positive tests, the TEC Assessment concluded that  APOE genetic testing does not eliminate additional recommended diagnostic testing to rule out other treatable causes of dementia. No data were available to assess whether AD could be prevented among individuals who carried an epsilon 4 allele, nor were specific therapies developed on the basis of APOE genotype status.  Finally, the evidence did not suggest that APOE epsilon testing was of value in determining rate of progression to AD or mortality from AD.
  
  
• Subsequent published studies report additional associations between late onset AD and more than 20 non-APOE genes; however, they fail to demonstrate how test results alter and improve treatment or predict therapeutic response to treatment. (17-19,24,25 )
  
  
• Several consensus statements regarding APOE genotyping universally conclude that APOE genotyping in asymptomatic patients as a technique of risk assessment is not recommended. (20,21,22,23)

• Statements regarding its use as a diagnostic test in symptomatic patients are mixed:
  
• An evidence-based practice parameter for the diagnosis of dementia by the American Academy of Neurology stated that routine use of APOE or other genetic markers in the diagnosis of AD is not recommended. (26)
• The American College of Medical Genetics/American Society of Human Genetic Working Group on APOE and Alzheimer's Disease stated, " it is not recommended for use in routine clinical diagnosis nor should it be used for predictive testing. Studies to date indicate that the APOE genotype alone does not provide sufficient sensitivity or specificity to allow genotyping to be used as a diagnostic test. Because AD develops in the absence of APOE epsilon-4 and because many with APOE epsilon-4 seem to escape disease, genotyping is also not recommended for use as a predictive genetic test." (20)
• In 1997 a National Study Group, supported by the NIH and composed of AD geneticists, policy experts, and ethicists, stated "The use of APOE genetic testing as a diagnostic adjunct in patients already presenting with dementia may prove useful but it remains under investigation." (21)
• In contrast, a report by the Working Group on Molecular and Biochemical Markers of Alzheimer's Disease stated that APOE genotyping can add "confidence to the clinical diagnosis of AD..." but "...the sensitivity and specificity of the epsilon 4 allele alone are low, indicating that this measure cannot be used as the sole diagnostic test for AD." (23)
  
  
• There are no published clinical studies which demonstrate how genetic testing for AD risk prediction or diagnosis guides prevention or treatment or results in improved health outcomes.

Apolipoprotein E (apo E) Genotyping and Phenotyping in the Management of Cardiovascular Disease                                                               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. (146-152) 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. (153-155) Some larger observational studies and a meta-analysis correlated apo E genotype with clinical disease. (156-159)
• 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. (160)

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. (161-166)
• 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.

Hereditary Breast and/or Ovarian Cancer (BRCA1, BRCA2)  Back to Table

The evidence is sufficient to establish the analytical and clinical validity of BRCA1 and BRCA2 testing and suggest that knowledge of mutation status may be effective in guiding healthcare decisions in individuals at increased risk of a mutation based on personal and/or family history.

• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded that both the clinical validity and clinical utility of BRCA1 and BRCA2 are established in individuals affected with breast or ovarian cancer and are from families with a high risk of BRCA1 or BRCA2 mutation, and in individuals without cancer who are from families with a known mutation. (27,28)  
  
  Once a mutation is identified in a family, tests for that known mutation in other family members should be associated with few false negatives or false positives.  Genotyping can significantly improve the accuracy of risk assessment and provide better information for making decisions concerning prophylactic surgery or early detection methods.
  
  
• Subsequent studies indicate that test results significantly influence treatment choices and prevention management in high risk individuals. (29-31)  
  
  Risk-reducing options include intensive surveillance, prophylactic mastectomy, or prophylactic oophorectomy.  Prophylactic mastectomy reduces the risk of breast cancer in high-risk women (based on family history) by 90% or more. (32)  Prophylactic oophorectomy reduces the risk of ovarian cancer to less than 10% and reduces the risk of breast cancer by approximately 50%. (32-34)  In women who have already had breast cancer, prophylactic oophorectomy reduces the risk of cancer relapse. (35)
  
  
• The National Comprehensive Cancer Network guidelines suggest testing be considered for breast cancer susceptibility in high risk individuals. (36)
  
  
• The United States Preventive Services Task Force (USPSTF) recommends that women whose family history is associated with an increased risk for deleterious mutations in BRCA1 or BRCA2 genes be referred for genetic counseling and evaluation for BRCA testing. (37)  They further recommend against routine referral for genetic counseling or testing for women whose family history is not associated with an increased risk for deleterious BRCA1 or BRCA2 mutations.
  
  
• Genetic testing is not recommended for minors because of a lack of effective interventions to be applied during childhood. (28,38-40) 

Breast Cancer: Biomarker Genes for the Detection of Lymph Node Metastases                                                                                  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. (139, 140)  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. (141)

• In three more recent studies, sentinel lymph nodes were analyzed by the GeneSearch™ assay and postoperative or intraoperative histologic examination. (142-144) 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. (145) 

Congenital Long QT Syndrome (LQTS)                                  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 (42):
  
• 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. (43,44) 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). 

Cutaneous Malignant Melanoma                                             Back to Table

Available evidence is not yet sufficient to establish how genetic testing guides treatment and prevention decisions when mutations associated with cutaneous malignant melanoma are identified.

• Interpretation of test results for cutaneous malignant melanoma is complex. If the unaffected individual is the first to be tested in the family (i.e., no affected relative has been previously tested to define the target mutation), it is very difficult to interpret the clinical significance of a mutation. The likelihood of clinical significance is increased if the identified mutation is the same as one reported in other families, although the issue of penetrance is a confounding factor.  There is insufficient information to know what the likelihood of developing melanoma is with a positive test.  In addition, not finding a mutation does not exclude the presence of hereditary cutaneous malignant melanoma.  There may be other high risk genes for melanoma that have not yet been identified.
  
  
• Regardless of mutation status, management of patients considered at high risk for malignant melanoma focuses on reduction of sun exposure, use of sun screens, vigilant cutaneous surveillance of pigmented lesions, and prompt biopsy of suspicious lesions.  It is unclear how genetic testing results alters these recommendations.  This applies to mutations with high penetrance (CDK2NA) as well as those with low penetrance (MC1R).
  
  
• The published data on genetic testing of the CDKN2A and CDK4 genes focus on the underlying genetics of hereditary melanoma, identification of mutations in families at high risk of melanoma, and risk of melanoma in those harboring these mutations. However, there are no published clinical studies that demonstrate how the presence or absence of genetic mutations impact clinical care — either for those with melanoma or for those at risk due to a family history.
  
  
• The Melanoma Genetics Consortium, comprising familial melanoma researchers from North America, Europe, and Australia, states that genetic testing for melanoma susceptibility might be premature, noting the issues discussed above. (46,47)
  
  
• The National Comprehensive Cancer Network guidelines are silent on genetic testing for melanoma. (48) 

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 (49):

• 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. (49)
  
  
• 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. (50)  A subsequent ACOG Committee opinion further supported the NIH guidelines. (51) 

Cytochrome p450 Genotyping (CYP450, AmpliChip)              Back to Table

Available evidence is not sufficient to establish how cytochrome p450 genotyping improves patient management with respect to drug selection and dosing compared to standard treatment without genotyping.  It is not known if genotyping improves patient outcomes such as therapeutic effect, time to effective dose, and adverse event rate.

• The purpose of genotyping is to tailor drug selection and dosing to individual patients based on their gene composition for drug metabolism.  In theory, this should lead to early selection and optimal dosing of the most effective drugs, while minimizing treatment failures or toxicities.  
• It is important to note that many drugs are metabolized by more than one enzyme, either within or outside of the CYP450 superfamily.  Reduced activity in a particular CYP450 enzyme because of genotype may not affect outcomes when other metabolic pathways are available and when other confounders influence drug metabolism, such as interactions between different metabolizing genes, interactions of genes and environment, and interactions among different non-genetic factors. Therefore, prospective studies for each drug are necessary to compare patient outcomes with the use of genotyping for prescribing and dosing to standard treatment without genotyping. (79,80) 
• In general, most published CYP450 pharmacogenomic studies are retrospective evaluations of CYP450 genotype association, reporting intermediate outcomes (e.g., circulating drug concentrations) or, less often, final outcomes (e.g., adverse events or efficacy).  Studies are mostly small and under-powered. There is a lack of randomized, prospective studies evaluating the clinical utility of CYP450 genotyping for any of the indications discussed below.

Selection or dose of selective serotonin reuptake inhibitors (SSRIs)

• CYP2D6 and CYP2C19 are primary CYP450 enzymes involved in the metabolism of selective serotonin reuptake inhibitors (SSRIs).
• The Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) systematically reviewed the evidence on CYP450 testing for adults treated with SSRIs for nonpsychotic depression. (81) The report concluded, “The data fail to support a clear correlation between CYP polymorphisms and SSRI levels, SSRI efficacy, or tolerability. There are no data regarding whether testing leads to improved outcomes versus not testing in the treatment of depression; whether testing influences medical, personal, or public health decision making; or whether any harms are associated with testing itself or with subsequent management options.”
• Following this commissioned report, the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group published the following recommendation: “The EGAPP Working Group found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for non-psychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed.” (82)
• No prospective trials of genotype-directed SSRI selection or dosing have been reported.

Selection or dose of antipsychotics

• Because most patients with schizophrenia take combinations of psychoactive agents for extended periods of time, drug-drug and drug-environmental interactions may influence the CYP450 metabolic phenotype in addition to genotype. In addition, some antipsychotic medications are metabolized by multiple CYP450 enzymes and dominant pathways may vary. Several classical antipsychotic drugs inhibit the CYP450 enzyme required for their metabolism and may render the patient a phenotypic poor metabolizer despite an extensive metabolizer genotype.  Thus, dosing algorithms need to accommodate both genetic influences and other interactions.
• Prospective randomized controlled clinical trials are needed to determine the independent contribution of CYP450 on both initial dosing and therapeutic drug monitoring.
• No prospective trials of genotype-directed antipsychotic selection or dosing have been reported.

Deciding whether to prescribe codeine for nursing mothers.

• Codeine is metabolized by CYP2D6 to morphine. Enhanced CYP2D6 activity (i.e., in CYP2D6 ultra-rapid metabolizers) predisposes to opioid intoxication. In 2007, the U.S. Food and Drug Administration (FDA) issued a warning regarding codeine use by nursing mothers. Nursing infants “may be at increased risk of morphine overdose if their mothers are taking codeine and are ultra-rapid metabolizers of codeine.” However, the FDA is not recommending genotyping for any population prior to prescribing codeine because “there is only limited information about using this test for codeine metabolism.” (83)
• No prospective trials of genotype-directed codeine dosing in nursing mothers have been reported.

Determining risk of atherothrombotic events in patients treated with clopidogrel after an acute coronary syndrome or a percutaneous coronary intervention

• Dual antiplatelet therapy with aspirin and clopidogrel is currently recommended for the prevention of atherothrombotic events after acute myocardial infarction. However, a substantial number of subsequent ischemic events still occur, which may be at least partly due to interindividual variability in the response to clopidogrel. Several studies found increased risks of thrombotic events in patients treated with clopidogrel who were CYP2C19 variant carriers. (84-87)
• Prospective, randomized controlled clinical trials are needed to demonstrate the clinical utility of CYP450 testing in this patient population.  Specifically, additional studies are needed that demonstrate reduced recurrence rates for carriers of CYP2C19 variants who are prospectively treated according to genotype.
• No randomized prospective trials of genotype-directed treatment have been reported.

Dose of atomoxetine HCl for the treatment of attention-deficit/hyperactivity disorder

• Atomoxetine is primarily metabolized by CYP2D6. The therapeutic window for atomoxetine is wide, and dosing is weight based, initiated at a standard dose per kg and adjusted thereafter according to clinical response and adverse effects.
• At steady state dosing, CYP2D6 poor metabolizers have substantially higher atomoxetine plasma concentrations than  normal, extensive metabolizers (EMs), although because it is generally well tolerated across a wide range, adverse effects do not appear to be significantly associated with poor metabolizers. (88, 89) After titration, mean doses for EMs and poor metabolizers also do not differ significantly. (89, 90) However, more EM patients discontinued in one trial due to lack of efficacy (90) and poor metabolizers improved inattention scores more than EMs in another (89), perhaps suggesting a need to re-examine recommended dosing limits.
• The FDA decided not to include a recommendation to perform genotyping prior to prescribing atomoxetine. Dosing directions recommend a low starting dose to be increased to the target dose if well tolerated. Thus, genotyping for CYP2D6 poor metabolizers of atomoxetine is not recommended because the margin of safety is not exceeded and evidence to support guidelines for dosing such that patient outcomes are improved has not been collected. (91, 92)

Dose of efavirenz for the treatment of HIV infection

• Current guidelines recommend efavirenz as the preferred non-nucleoside reverse transcriptase inhibitor component of highly active antiretroviral therapy for HIV-infected patients. Forty to 70% of patients report adverse central nervous system effects.  While most resolve in the first few weeks of treatment, about 6% of patients discontinue efavirenz due to adverse effects. (93)
• Efavirenz is primarily metabolized by CYP2B6, and inactivating polymorphisms are associated with higher efavirenz exposure, although plasma levels appear not to correlate with side effects.
• Limited reports suggest that CYP2B6 poor metabolizers have markedly reduced side effects while maintaining viral immunosuppression at substantially lower doses. (94, 95) Simulations of such dose adjustments support this position. (96) However, larger prospective studies are needed to support changes in current guidelines.

Dose of immunosuppressant for organ transplantation

• Immunosuppressive drugs administered to organ transplant patients have a narrow therapeutic index with the consequences of rejection or toxicity on either side. In addition, there is variability in patient response, requiring close clinical follow-up and routine therapeutic drug monitoring to maintain safety and efficacy.
• Tacrolimus blood levels are related to CYP3A5 genetic variants, with an approximately 2.3-fold difference in daily dose required to maintain target concentration between CYP3A5*3 and CYP3A5*1 homozygous variants. (97)
• CYP3A5*1 carriers have been reported to have a significant delay in reaching target tacrolimus concentrations compared to non-carriers.  Although the overall rate of acute rejection episodes was not higher in CYP3A5*1 carriers, their rejection episodes did occur earlier. (98)
• Randomized trials are currently underway to test genotype-directed initial tacrolimus dose versus standard dose. While pharmacogenetic applications for sirolimus and cyclosporine have been investigated, results are far less clear that genotyping is likely to have a significant clinical influence.

Managing treatment with Tamoxifen for women at high risk for or with breast cancer (135-136)

• The cytochrome P450 (CYP) metabolic enzyme CYP2D6 has a major role in tamoxifen (TAM) metabolism. Variant DNA gene sequences resulting in proteins with reduced or absent enzyme function may be associated with lower plasma levels of active tamoxifen metabolites, which could have an impact on TAM treatment efficacy.
• Potential indications for CYP2D6 pharmacogenomic testing include patients who are to be treated with TAM (alone or prior to treatment with an aromatase inhibitor) for:
  
• prevention of breast cancer in high risk women or women with DCIS
• adjuvant treatment to prevent breast cancer recurrence
• treatment of metastatic disease.

Post-menopausal patients determined to be CYP2D6 poor metabolizers could avoid TAM therapy and be treated with aromatase inhibitors alone.  Pre-menopausal patients might consider ovarian ablation.

• Based on a 2008 BlueCross BlueShield Association Technology Evaluation Center Assessment, results from clinical validity studies of CYP2D6 for use in tamoxifen management are uncertain. (136)   Evidence from two higher quality trials of adjuvant TAM in relatively homogeneous patient populations suggests that women treated with TAM who are functional poor metabolizers or intermediate metabolizers, whether by genotype or by co-medication with CYP2D6 inhibitors, have significantly reduced time to recurrence and recurrence-free survival (but not overall survival) compared to extensive metabolizers. The significance levels are marginal but might have been stronger and more convincing if poor metabolizers alone could have been compared to extensive metabolizers, but numbers of poor metabolizers were insufficient. Few variant alleles have been typed in these studies; more extensive genotyping and better categorization might also strengthen results.
  
  Three studies provided conflicting evidence; none of the studies found evidence that CYP2D6 genotype is prognostic, but limitations to the analyses of each warrant further study.
• No clinical trials have been conducted that provide direct evidence of clinical utility. Prospective randomized trials are needed to compare health outcomes related to treatment decisions based on usual methods of treatment selection to decisions based on CYP2D6 genotyping. 
  
  In the absence of direct evidence of clinical utility, an evidence chain could link clinical validity to other evidence of treatment benefit to infer outcomes from genotyping patients and making non-TAM treatment choices for CYP2D6 poor metabolizers.  However, the evidence for clinical validity is uncertain.

Management of Helicobactor pylor infection (137)

• Currently, multiple regimens are available for treating H. pylori infection. These include proton pump inhibitors (PPI) to suppress acid production, in combination with antibiotic treatment, consisting of one or more agents such as amoxicillin, clarithromycin, or metronidazole.  Genetic factors may influence the success of H. pylori treatment through effects on PPI metabolism. Individuals with polymorphisms in the CYP2C19 gene, a component of the cytochrome P450 (CYP450) system, metabolize PPIs more slowly than normal.  Observational research suggests that patients who are extensive metabolizers of PPIs have lower eradication rates following standard treatment for H. pylori, compared with poor metabolizers.
• If CYP2C19 status is known prior to treatment, adjustments can be made in the selection of PPI and/or the dosing schedule to achieve optimal acid suppression in all patients. Improved eradication rates for H. pylori could lead to improved health outcomes by reducing the need for re-treatment following treatment failure, reducing recurrences of H. pylori-associated disorders, and reducing the morbidity and mortality associated with disease recurrence.
• A single randomized, controlled trial was identified for use of genetic testing in selecting the treatment regimen for H. pylori infection. (138) This study randomized 300 Japanese patients to a pharmacogenomics-based treatment regimen versus a standard treatment regimen.  Eradication rates after first-line treatment were higher for the pharmacogenomics group compared with the standard treatment group. However, because of numerous variations in treatment protocol within the pharmacogenomics group, it is not possible to determine whether the improvement resulted from the tailored PPI dosages according to CYP2C19 genetic status, or due to other variations in the treatment protocol unrelated to CYP2C19 status. Specifically:
  
• There are numerous variations in the treatment regimen within the experimental group that make it difficult to determine which specific aspects of the treatment regimen may have led to benefit. In particular, it appears that clarithromycin resistance is an important factor in treatment success, and that there may be an interaction between clarithromycin resistance and CYP2C19 status. From the data reported in the study, it is hard to separate the potential impact of clarithromycin resistance on eradication rates from the impact of pharmacogenomically tailored PPI dosage schedules.
• In addition to the limitations on internal validity, the clinical relevance of the study is also limited for several reasons. The treatment approach used was relatively intensive, including genetic testing for CYP2C19, esophagogastroduodenoscopy with biopsy for all patients, and testing of H. pylori isolates for clarithromycin resistance. This treatment approach is much more intensive than that generally used in the United States, where the diagnosis of H. pylori is usually made by noninvasive methods, and initial empiric treatment is instituted without isolating H. pylori or testing for resistance. Furthermore, the patient population was from Japan, limiting the generalizability of the results, especially given the ethnic differences in CYP2C19 genetic status.
• No published clinical practice guidelines were identified that addressed whether to use genetic testing as part of a treatment protocol for H. pylori eradication. 

Familial Adenomatous Polyposis (FAP)                                    Back to Table

The evidence is sufficient to suggest that genetic testing to determine carrier status of the adenosis polyposis coli gene (APC) may be helpful in guiding healthcare decisions related to surveillance and prevention.

• Individuals with FAP have a risk of colorectal cancer approaching 100%. (55)  Confirmation of genetic status may help direct decisions concerning prophylactic colectomy.
• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded the following (53):
  
• 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 20 colon polyps or those with first-degree relatives of patients with known FAP.
• 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. (54) 
• 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. (55)  They further state that genetic testing in children can be delayed until age 10. 

Familial Medullary Thyroid Cancer                                         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:
  
• 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. (60) 

Hereditary Nonpolyposis Colorectal Cancer (HNPCC)           Back to Table

The evidence is sufficient to suggest that genetic testing to determine carrier status for HNPCC may be helpful in guiding healthcare decisions related to surveillance and prevention.

• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded the following (60):
  
• Genetic testing for HNPCC may improve health outcomes by identifying which at-risk patients require intense surveillance or prophylactic colectomy. At-risk patients may be identified either as a first-degree relative of a known carrier of an HNPCC mutation, or they can be identified on the basis of family history, specifically using either the Amsterdam or Bethesda criteria. 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.
• Unlike FAP, where the presence of multiple polyps helps identify the cancer syndrome, clinical identification of HNPCC is largely dependent on family history, which may be incomplete. Subjects meeting either the Amsterdam or Bethesda criteria are considered at high risk for carrying an HNPCC mutation and are appropriate candidates for genetic testing. 

Human DNA in Stool Samples for Colorectal Cancer Screening
                                                                                                       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. (99)

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. (100)  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 (101):
  
• 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. (102)
• 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. (103,104)  This assessment was based on the trial summarized above. (101)
• 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. (105) 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 (101) and additional older studies of diagnostic performance that did not use screening populations but used previously diagnosed or advanced cancer patients.

KRAS Mutation Analysis in Metastatic Colorectal Cancer  Back to Table

The available evidence is sufficient to suggest that KRAS mutation analysis may be helpful in predicting those patients with metastatic colorectal cancer who are not likely to respond to treatment with anti-EGFR monoclonal antibody therapy [cetuximab (Erbitux®) and panitumumab (Vectibix®)].

Cetuximab and panitumumab are monoclonal antibodies that bind to the epidermal growth factor receptor (EGFR), preventing binding and activation of downstream signaling pathways vital for cancer cell proliferation, invasion, metastasis, and stimulation of neovascularization.

Cetuximab and panitumumab are approved by the U.S. Food and Drug Administration (FDA) in the treatment of metastatic colorectal cancer in the refractory disease setting, and ongoing studies are investigating the use of these EGFR inhibitors as monotherapy and as part of combination therapy in first, second, and subsequent lines of therapy. A proportion of patients with colorectal cancer have tumors that harbor a somatic KRAS mutation that may affect tumor response to EGFR inhibitors.

• A BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment concluded the following (64):

• The data are sufficient to demonstrate both the analytic and clinical validity of KRAS mutation testing.
• The evidence from five randomized trials and five single-arm studies is sufficient to conclude that metastatic colorectal cancer patients with mutated KRAS tumors do not respond to anti-EGFR monoclonal antibody therapy (either as monotherapy or in combination with other treatment regimens), do not derive survival benefit, and may experience decreased progression-free survival.
• Identifying patients whose tumors express mutated KRAS avoids exposing them to ineffective drugs, avoids exposure to unnecessary drug toxicities, and expedites the use of the best available alternative therapy.
  
• The National Comprehensive Cancer Network guidelines strongly recommend that tumor KRAS gene status testing be performed for all patients with metastatic colon cancer at the time of diagnosis of metastatic disease. (65)  The guidelines state that “patients with known codon 12 or 13 KRAS mutations should not be treated with either cetuximab or panitumumab, either alone or in combination with other anticancer agents, as there is virtually no chance of benefit and the exposure to toxicity and expense cannot be justified.”  

KRAS Mutation Analysis in Non-small Cell Lung Cancer (NSCLC)  Back to Table

The available evidence is not yet sufficient to determine if KRAS mutation analysis can effectively predict treatment response to erlotinib in patients with NSCLC.

The KRAS gene can harbor oncogenic mutations that may result in tumor resistance to therapies that target the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase.  Erlotinib is a tyrosine kinase inhibitor (TKI) that is approved as salvage therapy for advanced NSCLC.

• Data on the role of KRAS mutations in NSCLC and response to erlotinib are available from two Phase III trials which conducted nonconcurrent subgroup analyses of the efficacy of TKIs in patients with wild-type (nonmutated) versus mutated KRAS lung tumors, three phase II trials, and one retrospective single-arm study. (66-72)
• Taken together these studies suggest that NSCLC patients with KRAS mutations may be nonresponsive to treatment with EGFR TKIs; however, the number of patients in the currently published studies who had KRAS-mutated tumors is relatively small and studies are mostly retrospective in nature.  Prospective controlled studies are needed to better define the role KRAS mutation analysis should play in guiding therapy using TKIs in patients with advanced NSCLC.
• Two Phase III trials are currently ongoing to assess erlotinib treatment in NSCLC patients with concurrent analysis of KRAS mutations:
• One phase III trial will assess whether clinical and biological features are able to predict the efficacy of erlotinib in patients with NSCLC as second and subsequent line therapy (Tarceva Italian Lung Optimization Trial [TAILOR]; NCT00637910). Outcome measures are overall survival, progression free survival and tumor response. Only patients with available tumor tissue will be included, and patients must have an absence of EGFR mutations. KRAS mutation analysis will be performed to determine the value of identifying a KRAS mutation using this type of therapy. Estimated enrollment is 1,500, and study completion date is estimated to be May 2012.
• A second Phase III trial will assess the efficacy of pemetrexed versus erlotinib as second-line therapy in patients with advanced NSCLC (Marker Validation of Erlotinib in Lung Cancer [MARVEL]; NCT00738881). Outcome measures are progression-free survival, overall survival and response rate, with analysis of EGFR and KRAS mutations. Estimated enrollment is 957, and study completion date is estimated to be May 2011.
• The National Comprehensive Cancer Network guidelines state that patients with NSCLC whose tumors harbor KRAS mutations should be considered for therapy other than erlotinib, stating “…k-ras gene sequencing could be useful for the selection of patients as candidates for TKI therapy.” (73)

Microarray-based Gene Expression Testing (Pathwork Tissue of Origin) Back to Table

There is insufficient evidence to determine if the Pathwork Tissue of Origin test can identify cancers of unknown primary or distinguish a primary from a metastatic tumor.

The Pathwork Tissue of Origin test is a gene expression, microarray-based test that measures the expression of more than 1,500 genes, and compares the similarity of the gene expression profile of a cancer of unknown primary to a database of known profiles from 15 cancer types with more than 60 histologic morphologies.  The benefit of identifying cancers of unknown primary is to identify appropriate cancer-specific treatment, expected outcome and prognosis.

• Although the Pathwork Tissue of Origin test received clearance for marketing through the U.S. Food and Drug Administration’s (FDA) 510(k) process, limitations were placed on the approval:
  
  “It is not intended to establish the origin of tumors that cannot be diagnosed according to current clinical and pathological practice (e.g., carcinoma of unknown primary). It is not intended to subclassify or modify the classification of tumors than can be diagnosed by current clinical and pathological practice, nor to predict disease course or survival or treatment efficacy, nor to distinguish primary from metastatic tumors.  Tumor types not in the Pathwork Tissue of Origin Test database may have RNA expression patterns that are similar to RNA expression patterns in tumor types in the database, leading to indeterminate results or misclassifications.” (75)
  
  
• While some studies suggest that microarray technology may have analytical and clinical validity, results are uncertain as they have not been reproduced in other clinical trials. (75-77)
  
  
• There are no published clinical trials that provide direct evidence of the clinical utility of the Pathwork® Tissue of Origin test.  No prospective studies have been published which compare patient management and tumor site-specific therapy based on gene expression profiling to direct patient management with current clinical, radiologic and histopathologic practices.
  
  
• The National Comprehensive Cancer Network guidelines for the work-up of an occult primary malignancy do not address the use of molecular methods in the classification of tumors. (78)

PathFinderTG® Molecular Testing (133)                             Back to Table

There is insufficient evidence to determine whether PathFinderTG Molecular Testing improves health outcomes for any indication with respect to diagnosis, determining prognosis or predicting response to chemotherapy.

The PathFinderTG® test is a molecular test used adjunctively in cases in which a definitive pathologic diagnosis cannot be rendered on a tissue or cytology specimen, either due to inadequate specimen or equivocal histologic or cytologic findings.  Potential uses described by the manufacturer involve multiple organ systems and clinical scenarios, such as determining reactive versus neoplastic lesions, benign versus malignant lesions, biologically indolent versus aggressive tumors, which premalignant lesions will or will not progress into cancer, whether a synchronous or metachronous tumor represents metastatic spread or a new primary, and expected responses to treatment for various tumors.

• While integrating the molecular information that a test like PathFinderTG® provides is of interest and the subject of research for neoplasms, currently the specific molecular features, associated genetic biomarkers, and their relationships with clinical outcomes are not well defined. Accordingly, their role in clinical decision-making, including selecting treatment options, has not been defined.
• Although the manufacturer cites over 500 papers to support the clinical efficacy of PathFinderTG®, these studies focus on analytical and clinical validity. (134)  Collectively, this body of evidence is unreliable due to a number of study limitations, including retrospective design, patient selection bias, lack of investigator blinding, sampling variability of specimens, small sample sizes, lack of adequate follow-up, incomplete follow-up, and lack of validation/replication of findings.
• Evidence of clinical utility is uncertain as there are no randomized studies in which PathFinderTG® is prospectively compared to existing alternatives and used to direct treatment decisions.

Prostate Cancer                                                                       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. (106, 107)

Single-nucleotide polymorphisms (SNPs) for risk assessment (106,107)

• 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 (106,107)

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. (108-115)  One study reported that incorporating the PCA3 Score into the Prostate Cancer Prevention Trial risk calculator improved the diagnostic accuracy of the calculator. (116).
• One preliminary study suggests that PCA3 Score may also have value in identifying patients with less aggressive cancer who may only need surveillance. (117) Another suggests that PCA3 Score predicts extracapsular extension. (118) 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 (106,107)

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. (123,127)  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. (119-125)  TMPRSS2 fusion genes are strongly associated with higher disease stage (120,121,126), but associations with Gleason scores (used to help determine the stage of cancer) are conflicting (120-122,124,126).
• 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. (128)

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. (129-132)  No studies evaluated the clinical utility of GSTP1.

Warfarin Dose                                                                         Back to Table

Available evidence is not yet sufficient to establish that CYP2C9 and VKORC1 genetic testing improves management of warfarin dosing, including use in guiding the initial warfarin dose.

• The purpose of genetic testing in this clinical scenario is to predict an individual’s likely stable warfarin dose by incorporating demographic, clinical, and genotype data.  Warfarin is then initiated at that predicted dose as a way to limit over-anticoagulation and increased risk of serious bleeding events.
• A systematic review commissioned by the American College of Medical Genetics, evaluated CYP2C9 and VKORC1 genetic testing prior to warfarin dosing and concluded that no large study has yet shown this to be acceptable or effective. (62)  Several randomized trials were noted to be underway to determine the clinical utility of testing.

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56. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 2.04.05
57. 1997 TEC Assessment: Genetic testing for germline mutations of the RET proto-oncogene in medullary carcinoma of the thyroid.
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Cross References

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

Laboratory Section Table of Contents