Evaluation Of Genomic Applications In Practice And Prevention Research Articles

Evidence-based consensus guidelines for ALS genetic testing and counseling.

Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet "standard of care." Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS. Core clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement. A total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single-step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories. These evidence-based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.

Recommendations from the EGAPP Working Group: Routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members

Summary of RecommendationsThe Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found adequate evidence to recommend against routine testing for Factor V Leiden (FVL) and/or prothrombin 20210G>A (PT) in the following circumstances: (1) adults with idiopathic venous thromboembolism (VTE). In such cases, longer term secondary prophylaxis to avoid recurrence offers similar benefits to patients with and without one or more of these mutations. (2) Asymptomatic adult family members of patients with VTE and an FVL or PT mutation, for the purpose of considering primary prophylactic anticoagulation. Potential benefits are unlikely to exceed potential harms. The overall certainty of these findings was deemed “moderate.” The evidence was insufficient to determine whether FVL/PT testing might have clinical utility in some circumstances, such as for identifying FVL homozygosity among asymptomatic family members of adults with idiopathic VTE or counseling patients about the risks and benefits of antithrombotic therapy. Based on the available evidence, the certainty of net health benefit was deemed “low.” The recommendations do not extend to patients with other risk factors for thrombosis, such as contraceptive use, as the evidence review that serves as the basis for the recommendations focused primarily on idiopathic VTE. RationaleIn developing these recommendations the EGAPP Working Group considered evidence in the following three areas. Analytic ValidityThere is adequate evidence that testing accurately and reliably detects the R506Q (FVL) and 20210G>A (PT) variants in the Factor V and PT genes, respectively (a more complete definition of analytic validity, clinical validity, and clinical utility is contained under the “Clinical Considerations” section). Clinical ValidityThe presence of a heterozygous FVL variant seems to be a weak risk factor for recurrence of VTE (odds ratio [OR]: 1.56). Rare homozygous FVL mutations present somewhat greater risks of VTE recurrence (OR: 2.65). The evidence for this increased risk is convincing, but the magnitude of excess risk is not as great as previously thought. The evidence is insufficient to draw conclusions about excess VTE recurrence risk resulting from compound heterozygosity (FVL and PT), but it is likely to be at least as high as with FVL alone. The OR for compound heterozygosity is 6.69. The evidence is insufficient to draw conclusions about VTE recurrence risks associated with PT mutations alone. For family members of index VTE cases, there is convincing evidence that both heterozygosity and homozygosity for FVL are associated with higher risks for VTE occurrence (ORs 3.49 and 17.84, respectively) than for family members without FVL variants. Clinical UtilityThere is convincing evidence that longer term secondary prophylaxis after an initial idiopathic VTE event yields comparable benefits to those with and without a FVL or PT mutation. For asymptomatic family members of index cases, no prophylaxis trials have been reported. Hence, there is no direct evidence of particular benefit to family members. Potential net harm is possible if primary prophylaxis is administered to asymptomatic family members with one or more mutations, because the absolute risk of an initial VTE event is low, and the risk of anticoagulant-induced hemorrhage is relatively high.

OA01.04 A Comparability Study Verifying the Analytic Performance of a Blood-based Gene Expression Classifier to Identify Benign Pulmonary Nodules: Topic: Pulmonology

We developed a blood gene expression classifier for lung cancer in current and former smokers with pulmonary nodules. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group and the Centers for Disease Control’s ACCE Project (analytic validity, clinical validity, clinical utility, and associated ethical, legal, and social implications) recommend studies to evaluate analytical validity of novel genomic tests. Here we report results of the test’s analytic performance. A total of 299 previous or current smokers with nodules ranging from 5-30mm were enrolled in a multicenter prospective observational study. A blood sample was obtained at baseline. RNA was isolated from PAXgene tubes and analyzed utlilizing three separate NanoString nCounter® gene expression platforms. Using NanoString’s recommended protocol, we evaluated: accuracy across repeat samples (n=134); reproducibility across multiple instruments (n=24) and across multiple operators (6 unique runs); analytical precision (one benign and one malignant pool run 33 times, total n=66); analytic sensitivity/limits of detection (two benign and two malignant samples at eight different concentrations, total n=32); and analytic specificity/interfering substances (n=10). The accuracy study resulted in sensitivity 94.4% and specificity 67.5%. Reproducibility was measured at 93.1% and analytic precision at 100%. The analytic sensitivity study confirmed NanoString’s published RNA input recommendations, and the presence of interfering substances did not impact final test results. We developed a gene expression classifier that demonstrated reproducibility and robustness across multiple studies. These studies are consistent with EGAPP recommendations. Additional studies to show consistent performance when the test is transferred from the research lab to a CLIA setting as well as to demonstrate clinical validity and clinical utility are planned.

Abstract IA07: Using genetic information in screening and prevention: Perspective of clinicians and policy-makers

Abstract How can genetic information be effectively used in screening and prevention? The conceptual framework and rules of evidence for answering this question - widely used by clinicians, policy-makers, and payors - has been developed over decades in the field of Evidence-Based Medicine, exemplified by the approach of the USPSTF (US Preventive Services Task Force) and EGAPP (Evaluation of Genomic Applications in Practice and Prevention). The framework's principles include using the best evidence (clinical trials where available, and observational data where necessary) assessed in systematic searches that consider quality of each study using specific rules of evidence. Outcomes are projected quantitatively to assess net benefit (benefits vs harms) of prevention and screening strategies. In this framework, genetic data may provide information about the magnitude of lifetime risk of developing a specific cancer, while other data (including genomic data) may provide information about the current risk that a cancer is present. Risks of appropriate magnitude may direct interventions that can prevent cancer (for example chemoprevention or preventive surgery) or that can detect the presence of early curable cancer or an important precursor. This talk will describe the quantitative conceptual framework and its rationale, along with the implications, challenges, and opportunities for the use of genetic and genomic information for cancer prevention and screening. Citation Format: David F. Ransohoff. Using genetic information in screening and prevention: Perspective of clinicians and policy-makers. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr IA07.

PHP134 - PAYER DECISION MAKING FOR NOVEL GENOMIC DIAGNOSTICS FOR PRECISION MEDICINE

Genomic-based diagnostic products combined with targeted therapeutics are increasingly contributing to better clinical decisions by early detection, accurate prediction and maximizing health outcomes for patients. However, the reimbursement landscape for these novel diagnostics is not well understood. Our objective was to better understand the criteria and evidentiary frameworks that the major insurers in the United States use for reimbursement decisions for novel genomic diagnostics and drug-diagnostic combinations products. We conducted a review of publicly available data and the literature from January 2004 to November 2015, to assess the evidence that payers used to evaluate genomic diagnostics and drug-diagnostic products. A search of PubMed and Ovid databases was conducted. We included studies that were relevant to novel genomic diagnostics and FDA approved drug-diagnostic combination products. We also studied policies relevant to genomic diagnostics of the 10 largest payers. We initially identified 205 studies of which 25 studies met our inclusion criteria. We found variation among payers in the type of health technology assessments and levels of evidence in evaluating novel genomic diagnostics and drug-diagnostics. Clinical utility, safety and benefits were key criteria used to decide for coverage of novel products. Reimbursement decisions of the major insurers were primarily based on data from randomized clinical trials, clinical practice guidelines, and approval from regulatory bodies. The CDC’s Evaluation of Genomic Applications in Practice and Prevention (EGAPP) recommendations was one of the most commonly used evidentiary frameworks. There appears to be considerable variation among US payers in conducting health technology assessments to evaluate novel genomic diagnostics and drug-diagnostics for reimbursement decisions. Standards for coverage criteria and health technology assessments, based upon evidentiary frameworks and accepted levels of evidence will facilitate the reduction of the current uncertainty around coverage of novel genomic diagnostics and drug-diagnostics, ultimately impacting manufacturers, providers and patients.

Recommendations from the EGAPP Working Group: does the use of Oncotype DX tumor gene expression profiling to guide treatment decisions improve outcomes in patients with breast cancer?

of The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient evidence to recommend for or against the use of Oncotype DX testing to guide chemotherapy treatment decisions in women with hormone receptor-positive, lymph node-negative, or lymph node-positive early breast cancer who are receiving endocrine therapy. This recommendation statement updates a 2009 EGAPP statement on the use of gene expression profiling tests in breast cancer. Evidence of clinical validity for Oncotype DX was confirmed as adequate. With regard to clinical utility, although there was evidence from prospective retrospective studies that the Oncotype DX test predicts benefit from chemotherapy, and there was adequate evidence that the use of Oncotype DX gene expression profiling in clinical practice changes treatment decisions regarding chemotherapy, no direct evidence was found that the use of Oncotype DX testing leads to improved clinical outcomes. In women with early-stage invasive breast cancer, gene expression profiling is increasingly being used as an aid to estimate the likely benefit from chemotherapy treatment. In a previous recommendation statement, the EGAPP Working Group (EWG) found adequate evidence for clinical validity of some gene expression profiling tests in predicting distant disease recurrence in women with early-stage, hormone receptor-positive, lymph-node-negative breast cancer who are treated with tamoxifen, but insufficient evidence that use of these tests for decisions about chemotherapy treatment has clinical utility. The current recommendation statement updates these findings for Oncotype DX and extends them to the population of women with lymph node-positive disease, using evidence from recent systematic reviews and other sources. The previous recommendation statement found that evidence was inadequate to enable quantitative determination of the analytic validity of Oncotype DX. Analytic validity was not reconsidered in the updated recommendation statement because there remains no gold-standard test for comparison. The EWG found that new evidence published since the original evidence review supports the clinical validity of Oncotype DX in predicting risk of distant metastases in women with hormone receptor-positive, early-stage breast cancer that is either node-negative or node-positive. No direct evidence was found that use of Oncotype DX tumor gene expression profiling to guide treatment decisions improves clinical outcomes in women with early breast cancer. There is indirect evidence, from prospective retrospective studies on archived tissue samples from randomized controlled trials, that the Oncotype DX test can predict benefit from chemotherapy. Large, prospective, randomized, controlled trials currently in progress may provide evidence of clinical utility. Until definitive evidence for clinical utility is available, clinicians must decide on a case-by-case basis whether to offer the test to patients. Although Oncotype DX testing has been reported, on the basis of economic modeling studies, to be cost-effective in several different health-care systems and to save costs in the US health-care setting, studies were based on assumptions regarding the clinical utility of the test that require confirmation by clinical trial results.Genet Med 18 8, 770-779.

Implementing Lynch syndrome screening utilizing a community partnership.

203 Background: Lynch syndrome (LS) is an autosomal dominant condition associated with an 80% risk of colorectal cancer, a 60% risk of endometrial cancer, and additional risks for extra-colonic cancers. Amsterdam and Bethesda criteria can be used to identify patients who may be at risk. However, 25% of colon cancer and 65% of endometrial cancer patients with LS will be missed by using family history criteria alone. LS is caused by mutations in mismatch repair genes (MMR): MLH1, MSH2, MSH6, PMS2, and EPCAM. Tumor screening by immunohistochemistry (IHC) is available, and abnormal results can be flagged for more definitive genetic counseling and testing. Recommendations from the 2009 EGAPP (Evaluation of Genomic Applications in Practice and Prevention) Working Group concluded there is sufficient evidence to use this tumor testing for LS, and the screening would provide moderate population benefits. Cost effectiveness studies have shown universal screening detects nearly twice as many cases of LS and is < $25,000 per life year saved. Methods: St. Luke’s Mountain States Tumor Institute (MSTI) implemented these recommendations in 2012 using a unique strategy: collaborating with a community organization. The Brian Olson Foundation (BOF) strives to “prevent(ing) colon cancer through community outreach and education and saving lives by detecting colon cancer as early as possible.”These objectives were aligned with the MSTI screening program for LS in Idaho by using BOF funding to eliminate a financial burden to the patient for 12 months. Results: 204 specimens were screened for LS using IHC with the following results: 73% normal, 21% abnormal staining for MLH1/PMS2, and 6% abnormal staining for a single protein. Three families were confirmed to have LS after molecular genetic testing, and 6 families have genetic test results pending. Conclusions: Our system had IHC numbers consistent with national data, if not slightly higher. MSTI has elected to continue the program long-term. This kind of collaboration eased the change in practice such that LS screening could become a standard of care in Idaho.

Recommendations from the EGAPP Working Group: does PCA3 testing for the diagnosis and management of prostate cancer improve patient health outcomes?

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found insufficient evidence to recommend prostate cancer antigen 3 (PCA3) testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination).The EGAPP Working Group found insufficient evidence to recommend PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan.Based on the available evidence, the overall certainty of clinical validity to predict the diagnosis of prostate cancer using PCA3 is deemed "low." The EGAPP Working Group discourages clinical use for diagnosis unless further evidence supports improved clinical validity.Based on the available evidence, the overall certainty of net health benefit is deemed "low." The EGAPP Working Group discourages clinical use unless further evidence supports improved clinical outcomes. It has been suggested that PCA3 testing in the general male population might lead to earlier diagnosis and management changes (e.g., earlier detection and earlier initiation or higher rates of medical interventions) that improve outcomes. EGAPP Working Group found no direct evidence to support this possibility, so we sought indirect evidence aimed at documenting the extent to which PCA3 testing alters prostate cancer diagnosis or management, alone and in combination with traditional clinical management factors, and the extent to which this testing improves health outcomes. Assay-related evidence was deemed adequate for the PROGENSA PCA3 assay approved by the US Food and Drug Administration, available from Gen-Probe. Very few studies were available that investigated preanalytical effects, analytical performance, and diagnostic accuracy of other quantitative assays for PCA3. Evidence on clinical validity was rated inadequate to derive any conclusions about performance of PCA3 testing to inform decisions for when to rebiopsy previously biopsy-negative patients for prostate cancer, or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g., previous elevated prostate-specific antigen test or suspicious digital rectal examination). Furthermore, there was little evidence to derive any conclusions about performance of PCA3 testing in men with cancer-positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan. No studies were available to provide direct evidence on the balance of benefits and harms related to PCA3 testing for diagnosis and management in the general male population. Evidence for other populations (e.g., high risk) was not evaluated in the review. Early diagnosis of prostate cancer is central to minimizing morbidity and mortality. Prevention of prostate cancer mortality is a public health priority. Improvements in outcomes associated with PCA3 testing could have important impacts.

Recommendations from the EGAPP Working Group: does genomic profiling to assess type 2 diabetes risk improve health outcomes?

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found insufficient evidence to recommend testing for predictive variants in 28 variants (listed in Table 1) to assess risk for type 2 diabetes in the general population, on the basis of studies in populations of northern European descent. The EWG found that the magnitude of net health benefit from the use of any of these tests alone or in combination is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes.The EWG found insufficient evidence to recommend testing for the TCF7L2 gene to assess risk for type 2 diabetes in high-risk individuals. The EWG found that the magnitude of net health benefit from the use of this test is close to zero. The EWG discourages clinical use unless further evidence supports improved clinical outcomes.On the basis of the available evidence for both the scenarios, the overall certainty of net health benefit is deemed "low." It has been suggested that genomic profiling in the general population or in high-risk populations for type 2 diabetes might lead to management changes (e.g., earlier initiation or higher rates of medical interventions, or targeted recommendations for behavioral change) that improve type 2 diabetes outcomes or prevent type 2 diabetes. The EWG found no direct evidence to support this possibility; therefore, this review sought indirect evidence aimed at documenting the extent to which genomic profiling alters type 2 diabetes risk estimation, alone and in combination with traditional risk factors, and the extent to which risk classification improves health outcomes. Assay-related evidence on available genomic profiling tests was deemed inadequate. However, on the basis of existing technologies that have been or may be used, the analytic sensitivity and specificity of tests for individual gene variants might be at least satisfactory. Twenty-eight candidate markers were evaluated in the general population. Evidence on clinical validity was rated inadequate for 24 of these associations (86%) and adequate for 4 (14%). Inadequate grades were based on limited evidence, poor replication, existence of possible biases, or combinations of these factors. Type 2 diabetes genomic profiling provided areas under the receiver operator characteristics curve of 55%-57%, with 4, 8, and 28 genes. Only TCF7L2 had convincing evidence of an association with type 2 diabetes with an odds ratio of 1.39 (95% confidence interval: 1.33-1.46).TCF7L2 was evaluated for high-risk populations, and the overall odds ratio was 1.66 (95% confidence interval: 1.22-2.27) for association with progression to type 2 diabetes. No studies were available to provide direct evidence on the balance of benefits and harms for genetic profiling for type 2 diabetes alone or in addition to traditional risk factors in the general population.Evidence for high-risk populations and TCF7L2 was inadequate on the basis of two identified studies. These studies found close to zero additional benefit with the addition of genomic markers to traditional risk factors (diet, body mass index, and glucose tolerance). Prevention of type 2 diabetes is a public health priority. Improvements in the outcomes associated with genomic profiling could have important impacts. Traditional risk factors (e.g., body mass index, weight, fat mass, and exercise) have an advantage in clinical screening and risk assessment strategies because they measure the actual targets for therapy (e.g., fasting plasma glucose and medical interventions). To be useful in predicting disease risk, genomic testing should improve the predictive value of these traditional risk factors. Some issues important for clinical utility remain unknown, such as the level of risk that changes intervention, whether long-term disease outcomes will improve, how individuals being tested will understand/respond to test results and interact with the health-care system, and whether testing will motivate behavior change or amplify potential harms.

Recommendations from the EGAPP Working Group: can testing of tumor tissue for mutations in EGFR pathway downstream effector genes in patients with metastatic colorectal cancer improve health outcomes by guiding decisions regarding anti-EGFR therapy?

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group (EWG) found that, for patients with metastatic colorectal cancer (mCRC) who are being considered for treatment with cetuximab or panitumumab, there is convincing evidence to recommend clinical use of KRAS mutation analysis to determine which patients are KRAS mutation positive and therefore unlikely to benefit from these agents before initiation of therapy. The level of certainty of the evidence was deemed high, and the magnitude of net health benefit from avoiding potentially ineffective and harmful treatment, along with promoting more immediate access to what could be the next most effective treatment, is at least moderate.The EWG found insufficient evidence to recommend for or against BRAF V600E testing for the same clinical scenario. The level of certainty for BRAF V600E testing to guide antiepidermal growth factor receptor (EGFR) therapy was deemed low. The EWG encourages further studies of the potential value of testing in patients with mCRC who were found to have tumors that are wild type (mutation negative) for KRAS to predict responsiveness to therapy.The EWG found insufficient evidence to recommend for or against testing for mutations in NRAS, or PIK3CA, and/or loss of expression of PTEN or AKT proteins. The level of certainty for this evidence was low. In the absence of supporting evidence, and with consideration of other contextual issues, the EWG discourages the use of these tests in guiding decisions on initiating anti-EGFR therapy with cetuximab or panitumumab unless further evidence supports improved clinical outcomes. It has been suggested that patients with mCRC whose tumors harbor certain mutations affecting EGFR pathway signaling are typically unresponsive to therapy with anti-EGFR antibodies (cetuximab and panitumumab). The EWG identified recent evidence reviews that have addressed this topic, and this recommendation statement is based on results of these reviews. In developing these recommendations the EWG considered evidence in the areas described below. Although no research syntheses that have formally evaluated analytic validity of these tests were found, the EWG was able to draw the following conclusions from assessments included in the evidence reviews under consideration. There is adequate evidence that KRAS mutation analysis reliably and accurately detects common mutations (codons 12 and 13), whereas evidence was inadequate for less frequent KRAS mutations (e.g., codon 61). There is also adequate evidence that testing for BRAF V600E accurately and reliably detects the mutation. For common mutations in NRAS, PIK3CA, and expression of PTEN AKT, there is adequate evidence of accurate and reliable detection. However, much less data exist in support. Furthermore, in the specific context of mCRC, no evidence was found on the analytic validity of immunohistochemistry (IHC) assays for PTEN or AKT expression. For KRAS mutation analysis, the EWG found convincing evidence for association with treatment response to anti-EGFR therapy, independent of prognostic association. For BRAF V600E mutation testing, the EWG found insufficient evidence for association with treatment response to anti-EGFR therapy independent of prognostic association. The EWG found insufficient evidence for association of results of testing for mutations in NRAS or PIK3CA, and loss of expression of PTEN or ATK proteins, with treatment response to anti-EGFR therapy. For KRAS mutation analysis, the EWG found adequate evidence that improved health outcomes are achieved by avoiding ineffective chemotherapy and potential side effects and expediting access to the next most effective treatment. Inadequate evidence was found regarding association of BRAF V600E mutation testing or loss of PTEN expression with improved health outcomes among patients with mCRC undergoing anti-EGFR therapy as compared with patients with tumors bearing wild-type BRAF sequence and PTEN expression levels, respectively. No evidence was found to support improved health outcomes associated with testing results for NRAS or PIK3CA variants, or AKT protein expression levels in this clinical scenario. CRC is an important and highly prevalent health problem. Improvements in mCRC outcomes associated with pharmacogenetic testing could have important clinical, and potentially public health, impacts. Adverse events related to cancer chemotherapy can be common and severe. Therefore, successfully optimizing treatment to maximize efficacy and minimize side effects is important for reducing mCRC-related morbidity and mortality.

Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update.

To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.

Contribution of biomarkers to personalized medicine.

Contribution of biomarkers to personalized medicine.

To Screen or Not To Screen for Lynch Syndrome

rosatellite instability (MSI) test. Patients with an abnormal screen can then have a diagnostic DNA test for mismatch repair mutations to confi rm or rule out Lynch syndrome. Family history is the basis for two different sets of criteria to determine which patients should be considered at risk for Lynch syndrome: the Amsterdam criteria and the Bethesda guidelines. But family history isn’t always available, and many patients are thus missed, along with the opportunity to identify their at-risk relatives. That’s why the federal Centers for Disease Control and Prevention (CDC) convened its independent panel — the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group — to consider a broader screening strategy. The working group released its fi ndings in January 2009. According to the CDC website, the group “found good scientifi c evidence to recommend that all individuals with a new diagnosis of colorectal cancer (regardless of age or family history) be offered genetic testing for Lynch syndrome, in order to help prevent cancer in their close relatives.” It did not fi nd enough evidence to recommend any specifi c preliminary screening strategy, e.g., MSI versus IHC.

Personalized cancer therapy coming of age: clinical highlights in 2009 and future directions.

Brigette BY Ma Author for correspondence: LKS Specialist Clinic, Department of Clinical Oncology, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China Tel.: +852 2632 2118 Fax: +852 2648 7097 brigette@clo.cuhk.edu.hk and State Key Laboratory in Oncology in South China, Hong Kong SAR, China and Sir YK Pao Centre for Cancer, Hong Kong SAR, China and Hong Kong Cancer Institute, Hong Kong SAR, China and Chinese University of Hong Kong, Hong Kong SAR, China

Nurses transforming health care using genetics and genomics

Nurses are well positioned to incorporate genetic and genomic information across all aspects of the United States (U.S.) health care system. Nurses, the most trusted health professionals [1], make unique contributions to the field of human genetics and genomics and complement the work of other health care providers to improve the health of the public. Health care benefits greatly from the unprecedented and ongoing work elucidating the genetic/genomic basis of health, illness, disease risk, and treatment response. The progress in genetics and genomics is applicable to the entire spectrum of health care and all health professionals and as such to the entire nursing profession (2.9 million) [2] in the United States regardless of role, clinical specialty, or academic preparation. The majority of disease risk, health conditions and the therapies used to treat those conditions have a genetic and/or genomic element influenced by environmental, lifestyle, and other factors therefore impacting the entire nursing profession [3]. Nurses have intimate knowledge of the patient’s, family’s, and community’s perspectives; an understanding of biologic underpinnings; experience with genetic/genomic technologies and information; skills in communication and building coalitions; and most importantly, the public’s trust. Across the lifespan, nursing focuses on health promotion and disease prevention, which is an integral component of genetic/genomic health care practices. Awareness of nurses’ strengths and skills, together with the recognition that prevention is the hallmark of genetic/genomic health care, will inform public policymaking groups as they address issues that affect heath care practice in the area of genetics/genomics. Policy making process will be informed with new insights will be gained with inclusion of nurses and professional nursing organizations. These policies can facilitate the ability of U.S. health care systems to use genetic/genomic knowledge to promote health and manage disease.

Identifying Lynch syndrome

Identifying Lynch syndrome

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP Working Group

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative, established by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention, supports the development and implementation of a rigorous, evidence-based process for evaluating genetic tests and other genomic applications for clinical and public health practice in the United States. An independent, non-federal EGAPP Working Group (EWG), a multidisciplinary expert panel selects topics, oversees the systematic review of evidence, and makes recommendations based on that evidence. This article describes the EGAPP processes and details the specific methods and approaches used by the EWG.

Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?

Summary of RecommendationsThe Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia). RationaleThe EGAPP Working Group (EWG) found no intervention trials showing that targeted dosing of irinotecan based on UGT1A1 genotyping could reduce the rates of two specific adverse drug events, severe (Grade 3–4) neutropenia or diarrhea. Observational studies indicate a significant association between UGT1A1 genotypes, particularly *28/*28 and *1/*28, and the occurrence of severe neutropenia. Observational studies also indicate a possible association between severe diarrhea and these UGT1A1 genotypes, but the association is not statistically significant. An additional finding was the suggestion that reducing irinotecan dose may result in patient harms due to diminished effectiveness of treatment in highest risk individuals (*28/*28 homozygotes), and that a higher dose might be warranted among individuals at lower risk of adverse drug events (*1/*1 and *1/*28 genotypes). This review did not consider higher risk patients (e.g., having previous adverse reactions to irinotecan or additional risk factors for neutropenia). Analytic ValidityThe EWG found adequate evidence to conclude that analytic sensitivity and specificity were high for the commonly tested alleles, but evidence was inadequate for rarer alleles. Clinical ValidityThe EWG found adequate evidence of a significant association between UGT1A1 genotype and the incidence of severe neutropenia at standard doses of irinotecan. The EWG found adequate evidence of a possible association between genotype and severe diarrhea, but the effect was smaller and not statistically significant. The EWG found adequate evidence of a significantly higher rate of tumor response to standard irinotecan dosing among individuals with the genotype at highest risk of adverse drug events (*28/*28). Clinical UtilityThe EWG found no evidence to support clinical utility in the proposed clinical scenario. Preliminary modeling suggests that, even if targeted dosing were to be highly effective, it is not clear that benefits (reduced adverse drug events) outweigh harms (unresponsive tumors). Contextual IssuesAddressing patient preferences regarding risk of side effects and quality of life, versus aggressive treatment to potentially improve effectiveness, is expected practice. In addition, a recent study reported that risk for neutropenia was lower at lower irinotecan doses. For treatment regimens utilizing lower irinotecan doses, UGT1A1 genotype may not be a useful indicator of risk for adverse drug events. Further rigorous evaluation of UGT1A1 genotyping using current and promising irinotecan treatment protocols is warranted.

Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives

Summary of RecommendationsThe Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined. RationaleGenetic testing to detect Lynch syndrome in individuals with newly diagnosed colorectal cancer (CRC) is proposed as a strategy to reduce CRC morbidity and mortality in their relatives (see Clinical Considerations section for definition of Lynch syndrome). The EGAPP Working Group (EWG) constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives. We found that assessing patients who have newly diagnosed CRC with a series of genetic tests could lead to the identification of Lynch syndrome. Relatives of patients with Lynch syndrome could then be offered genetic testing, and, where indicated, colorectal, and possibly endometrial, cancer surveillance, with the expectation of improved health outcome. The EWG concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit. Analytic ValidityThe EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high. Clinical ValidityAfter accounting for the specific technologies and numbers of markers used, the EWG found at least adequate evidence to describe the clinical sensitivity and specificity for three preliminary tests, and for four selected testing strategies. These measures of clinical validity varied with each test and each strategy (see Clinical Considerations section). Clinical UtilityThe EWG found adequate evidence for testing uptake rates, adherence to recommended surveillance activities, number of relatives approachable, harms associated with additional follow-up, and effectiveness of routine colonoscopy. This chain of evidence supported the use of genetic testing strategies to reduce morbidity/mortality in relatives with Lynch syndrome. Several genetic testing strategies were potentially effective, but none was clearly superior. The evidence for or against effectiveness of identifying mismatch repair (MMR) gene mutations in reducing endometrial cancer morbidity or mortality was inadequate. Contextual IssuesCRC is a common disease responsible for an estimated 52,000 deaths in the United States in 2007. In about 3% of newly diagnosed CRC, the underlying cause is a mutation in a MMR gene (Lynch syndrome) that can be reliably identified with existing laboratory tests. Relatives inheriting the mutation have a high (about 45% by age 70) risk of developing CRC. Evidence suggests these relatives will often accept testing and increased surveillance.

Correcting the Record on DNA Direct

In reference to the Policy Forum “A case study of personalized medicine (S. H. Katsanis et al. , 4 April, p. 53), we would like to correct some inaccuracies regarding DNA Direct and comment on the misrepresentation of the findings of the Evaluation of Genomic Applications in Practice and