Clinical utility of gene-expression profiling in women with early breast cancer: an overview of systematic reviews

PurposeThis overview systematically evaluates the clinical utility of using Oncotype DX and MammaPrint gene-expression profiling tests to direct treatment decisions in women with breast cancer. The findings are intended to inform an updated recommendation from the Evaluation of Genomic Applications in Practice and Prevention Working Group.MethodsEvidence reported in systematic reviews evaluating the clinical utility of Oncotype DX and MammaPrint, as well as the ability to predict treatment outcomes, change in treatment decisions, and cost-effectiveness, was qualitatively synthesized.ResultsFive systematic reviews found no direct evidence of clinical utility for either test. Indirect evidence showed Oncotype DX was able to predict treatment effects of adjuvant chemotherapy, whereas no evidence of predictive value was found for MammaPrint. Both tests influenced a change in treatment recommendations in 21 to 74% of participants. The cost-effectiveness of Oncotype DX varied with the alternative compared. For MammaPrint, lack of evidence of the predictive value led to uncertainty in the cost-effectiveness.ConclusionNo studies were identified that provided direct evidence that using gene-expression profiling tests to direct treatment decisions improved outcomes in women with breast cancer. Three ongoing studies may provide direct evidence for determining the clinical utility of gene-expression profiling testing.Genet Med 17 7, 519–532.     

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?

Summary of RecommendationsThe 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.RationaleIn 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.Analytic validityThe 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.Clinical validityThe 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.Clinical utilityNo 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.Contextual issuesUntil 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.     

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.     

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

Summary of recommendationsThe 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.”RationaleIt 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.Analytic validityAssay-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.Clinical validityTwenty-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.Clinical utilityNo 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).Contextual issuesPrevention 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.Genet Med 2013:15(8):612–617     

Implementation of routine screening for Lynch syndrome in university and safety-net health system settings: successes and challenges

PurposeRoutine screening for evidence of DNA mismatch repair abnormalities can identify colorectal cancer patients with Lynch syndrome, but impact in usual care settings requires study. After implementing routine screening at our university and safety-net health systems as usual practice, our aims were to determine outcomes, including screening process quality.MethodsWe conducted a retrospective cohort study from 1 May 2010 to 1 May 2011. Screening included reflexive immunohistochemistry to evaluate DNA mismatch repair protein expression for patients with colorectal cancer aged ≤70 years, with a cancer genetics team following up results. Screening outcomes, as well as challenges to a high-quality screening process were evaluated.ResultsWe included 129 patients (mean age 56 years, 36% female); 100 had immunohistochemistry screening completed. Twelve patients had abnormal immunohistochemistry: four with definite Lynch syndrome, four with probable Lynch syndrome, and three without Lynch syndrome; one patient had an incomplete work-up. Lynch syndrome was confirmed for 6/13 asymptomatic relatives tested. Screening process quality was optimal for 77.5% of patients. Barriers to optimal quality screening included ensuring reflexive immunohistochemistry completion, complete follow-up of abnormal immunohistochemistry, and timely incorporation of results into clinical decision making.ConclusionUsual care implementation of routine screening for Lynch syndrome can result in significant rates of detection, even in a largely safety-net setting. To optimize implementation, challenges to high-quality Lynch syndrome screening, such as ensuring reflexive screening completion and clinically indicated genetic testing and follow-up for abnormal screens, must be identified and addressed.Genet Med15 12, 925–932.     

Establishing the value of genomics in medicine: the IGNITE Pragmatic Trials Network

PurposeA critical gap in the adoption of genomic medicine into medical practice is the need for the rigorous evaluation of the utility of genomic medicine interventions.MethodsThe Implementing Genomics in Practice Pragmatic Trials Network (IGNITE PTN) was formed in 2018 to measure the clinical utility and cost-effectiveness of genomic medicine interventions, to assess approaches for real-world application of genomic medicine in diverse clinical settings, and to produce generalizable knowledge on clinical trials using genomic interventions. Five clinical sites and a coordinating center evaluated trial proposals and developed working groups to enable their implementation.ResultsTwo pragmatic clinical trials (PCTs) have been initiated, one evaluating genetic risk APOL1 variants in African Americans in the management of their hypertension, and the other to evaluate the use of pharmacogenetic testing for medications to manage acute and chronic pain as well as depression.ConclusionIGNITE PTN is a network that carries out PCTs in genomic medicine; it is focused on diversity and inclusion of underrepresented minority trial participants; it uses electronic health records and clinical decision support to deliver the interventions. IGNITE PTN will develop the evidence to support (or oppose) the adoption of genomic medicine interventions by patients, providers, and payers.     

Trends in utilization and costs of BRCA testing among women aged 18–64 years in the United States, 2003–2014

PurposeWe examined 12-year trends in BRCA testing rates and costs in the context of clinical guidelines, national policies, and other factors.MethodsWe estimated trends in BRCA testing rates and costs from 2003 to 2014 for women aged 18–64 years using private claims data and publicly reported revenues from the primary BRCA testing provider.ResultsThe percentage of women with zero out-of-pocket payments for BRCA testing increased during 2013–2014, after 7 years of general decline, coinciding with a clarification of Affordable Care Act coverage of BRCA genetic testing. Beginning in 2007, family history accounted for an increasing proportion of women with BRCA tests compared with personal history, coinciding with BRCA testing guidelines for primary care settings and direct-to-consumer advertising campaigns. During 2013–2014, BRCA testing rates based on claims grew at a faster rate than revenues, following 3 years of similar growth, consistent with increased marketplace competition. In 2013, BRCA testing rates based on claims increased 57%, compared with 11% average annual increases over the preceding 3 years, coinciding with celebrity publicity.ConclusionThe observed trends in BRCA testing rates and costs are consistent with possible effects of several factors, including the Affordable Care Act, clinical guidelines and celebrity publicity.     

Stakeholders’ views on the value of outcomes from clinical genetic and genomic interventions

PurposeRobust evidence about the value of clinical genomic interventions (CGIs), such as genetic/genomic testing or clinical genetic evaluation, is limited. We obtained stakeholders’ perspectives on outcomes from CGIs to help inform their value.MethodsWe used an adapted Delphi expert panel process. Two anonymous survey rounds assessed the value of 44 CGI outcomes and whether a third party should pay for them, with discussion in between rounds.ResultsSixty-six panelists responded to the first-round survey and 60 to the second. Policy-makers/payers gave the lowest ratings for value and researchers gave the highest. Patients/consumers had the most uncertainty about value and payment by a third party. Uncertainty about value was observed when evidence of proven health benefit was lacking, potential harms outweighed benefits for reproductive outcomes, and outcomes had only personal utility for individuals or family members. Agreement about outcomes for which a third party should not pay included prevention through surgery with unproven health benefits, establishing ancestry, parental consanguinity, and paternity.ConclusionResearch is needed to understand factors contributing to uncertainty and stakeholder differences about the value of CGI outcomes. Reaching consensus will accelerate the creation of metrics to generate the evidence needed to inform value and guide policies that promote availability, uptake, and coverage of CGIs.     

A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients

PurposeDespite the rapid uptake of multigene panel testing (MGPT) for hereditary cancer predisposition, there is limited guidance surrounding indications for testing and genes to include.MethodsTo inform the clinical approach to hereditary cancer MGPT, we comprehensively evaluated 32 cancer predisposition genes by assessing phenotype-specific pathogenic variant (PV) frequencies, cancer risk associations, and performance of genetic testing criteria in a cohort of 165,000 patients referred for MGPT.ResultsWe identified extensive genetic heterogeneity surrounding predisposition to cancer types commonly referred for germline testing (breast, ovarian, colorectal, uterine/endometrial, pancreatic, and melanoma). PV frequencies were highest among patients with ovarian cancer (13.8%) and lowest among patients with melanoma (8.1%). Fewer than half of PVs identified in patients meeting testing criteria for only BRCA1/2 or only Lynch syndrome occurred in the respective genes (33.1% and 46.2%). In addition, 5.8% of patients with PVs in BRCA1/2 and 26.9% of patients with PVs in Lynch syndrome genes did not meet respective testing criteria.ConclusionOpportunities to improve upon identification of patients at risk for hereditary cancer predisposition include revising BRCA1/2 and Lynch syndrome testing criteria to include additional clinically actionable genes with overlapping phenotypes and relaxing testing criteria for associated cancers.     

The cost-effectiveness of genetic testing strategies for Lynch syndrome among newly diagnosed patients with colorectal cancer

PurposeTo estimate the cost-effectiveness of genetic testing strategies to identify Lynch syndrome among newly diagnosed patients with colorectal cancer and to offer targeted testing to relatives of patients with Lynch syndrome.MethodsWe calculated incremental costs per life-year saved for universal testing relative to no testing and age-targeted testing for strategies that use preliminary genetic tests (immunohistochemistry or microsatellite instability) of tumors followed by sequencing of mismatch repair genes. We also calculated incremental cost-effectiveness ratios for pairs of testing strategies.ResultsStrategies to test for Lynch syndrome in newly diagnosed colorectal tumors using preliminary tests before gene sequencing have incremental cost-effectiveness ratios of ≤$45,000 per life-year saved compared with no testing and ≤$75,000 per life-year saved compared with testing restricted to patients younger than 50 years. The lowest cost testing strategies, using immunohistochemistry as a preliminary test, cost ≤$25,000 per life-year saved relative to no testing and ≤$40,000 per life-year saved relative to testing only patients younger than 50 years. Other testing strategies have incremental cost-effectiveness ratios ≥$700,000 per life-year saved relative to the lowest cost strategies. Increasing the number of relatives tested would improve cost-effectiveness.ConclusionLaboratory-based strategies using preliminary tests seem cost-effective from the US health care system perspective. Universal testing detects nearly twice as many cases of Lynch syndrome as targeting younger patients and has an incremental cost-effectiveness ratio comparable with other preventive services. This finding provides support for a recent US recommendation to offer testing for Lynch syndrome to all newly diagnosed patients with colorectal cancer.     

Outcomes of prior authorization requests for genetic testing in outpatient pediatric genetics clinics

PurposeGenetic testing is an important diagnostic tool in pediatric genetics clinics, yet many patients face barriers to testing. We describe the outcomes of prior authorization requests (PARs) for genetic tests, one indicator of patient access to clinically recommended testing, in pediatric genetics clinics.MethodsWe retrospectively reviewed PARs for genetic tests (n = 4,535) recommended for patients <18 years of age (n = 2,798) by pediatric medical geneticists at two children’s hospitals in Texas, 2017–2018. We described PAR outcomes, accompanying diagnostic codes, and diagnostic yield.ResultsThe majority (79.9%) of PARs received a favorable outcome. PARs submitted to public payers were more likely to receive a favorable outcome compared with private payers (85.5% vs. 70.3%, respectively; p < 0.001). No diagnostic codes were associated with higher likelihood of PAR approval for exome sequencing. Among the 2,685 tests approved and completed, 522 (19.4%) resulted in a diagnosis.ConclusionThough there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.     

Diagnosing hereditary cancer predisposition in men with prostate cancer

PurposeWe describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer.MethodsOne thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms.ResultsA yield of 9.4–12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97–1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37–9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48–3.65); and family history of Lynch syndrome–associated cancers (OR 1.97; 95% CI 1.23–3.15) were predictors of positive results.ConclusionThese results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.     

Universal tumor screening for Lynch syndrome: health-care providers’ perspectives

PurposePopulation-based reflex testing of colorectal tumors can identify individuals with Lynch syndrome (LS), but there is debate regarding the type of patient discretion such a program warrants. We examined health-care providers’ views and experiences to inform the design of a reflex-testing program and their perspectives regarding an opt-out option.MethodsWe interviewed providers managing LS or colorectal cancer patients, including surgeons, genetic counselors, oncologists, primary-care physicians, and gastroenterologists. Qualitative data were analyzed thematically using constant comparison techniques.ResultsProviders supported a reflex-testing program because of the current lack of coordinated immunohistochemistry (IHC) testing and underascertainment of LS patients as well as the opportunity to standardize the increasing use of genomic tests in practice. Most supported an opt-out after reflex testing because they felt that IHC is akin to other pathology tests, which are not optional. Some favored an opt-out before testing because of concern for patients experiencing distress, insurance discrimination, or a diagnostic odyssey that may be inconclusive.ConclusionProviders support a reflex-testing program to improve the identification and management of suspected LS patients. However, how to support meaningful information provision to enable an opt-out without jeopardizing testing uptake and the anticipated public health benefits remains a policy challenge.Genet Med advance online publication 06 October 2016     

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing

PurposeGerm-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance.MethodsClinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history.ResultsOverall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2.ConclusionThe high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes.     

Prostate cancer incidence in males with Lynch syndrome

PurposeAn increased risk of prostate cancer is currently not considered a part of the Lynch syndrome spectrum. The purpose of this study was to retrospectively examine prostate cancer incidence in the Lynch syndrome cohort at the Ohio State University in comparison with that in the general population.MethodsWe included all males diagnosed with Lynch syndrome from June 1998 to June 2012 at the Ohio State University and obtained baseline information including cancer history. If patients had not been seen in the 12 months before June 2012, they were contacted to document changes in their cancer history. We compared prostate cancer incidence among the Lynch syndrome families with that of the general population by using the Surveillance, Epidemiology, and End Results registry 1999–2009.ResultsOf the 188 males identified with Lynch syndrome, 11 males were diagnosed with prostate cancer during the study period. The ratio of observed to expected numbers of prostate cancer cases resulted in a standardized rate ratio of 4.87 (95% confidence interval: 2.43–8.71). Impaired mismatch repair expression and microsatellite instability were seen in one out of two prostate cancer specimens available for testing.ConclusionMales with Lynch syndrome had a nearly fivefold increased risk of developing prostate cancer but did not appear to have earlier onset or a more aggressive phenotype.Genet Med16 7, 553–557.     

Recommendations from the EGAPP Working Group: can tumor gene expression profiling improve outcomes in patients with breast cancer?

Summary of RecommendationsThe EGAPP Working Group (EWG) found insufficient evidence to make a recommendation for or against the use of tumor gene expression profiles to improve outcomes in defined populations of women with breast cancer. For one test, the EWG found preliminary evidence of potential benefit of testing results to some women who face decisions about treatment options (reduced adverse events due to low risk women avoiding chemotherapy), but could not rule out the potential for harm for others (breast cancer recurrence that might have been prevented). The evidence is insufficient to assess the balance of benefits and harms of the proposed uses of the tests. The EWG encourages further development and evaluation of these technologies.RationaleThe measurement of gene expression in breast tumor tissue is proposed as a way to estimate the risk of distant disease recurrence in order to provide additional information beyond current clinicopathological risk stratification and to influence decisions about treatment in order to improve health outcomes. Based on their review of the EGAPP-commissioned evidence report, Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes¹ and other data summaries, the EWG found no direct evidence linking tumor gene expression profiling of women with breast cancer to improved outcomes, and inadequate evidence to construct an evidence chain. However, further evaluation on the clinical utility of some tests and management algorithms, including well-designed randomized controlled trials, is warranted.Analytic ValiditySome data on technical performance of assays were identified for MammaPrint and Oncotype DX, though estimates of analytic sensitivity and specificity could not be made. Published performance data on the laboratory developed Quest H:I Test were limited. Overall, the EWG found the evidence to be inadequate.Clinical ValidityThe EWG found adequate evidence regarding the association of the Oncotype DX Recurrence Score with disease recurrence and adequate evidence for response to chemotherapy. The EWG found adequate evidence to characterize the association of MammaPrint with future metastases, but inadequate evidence to assess the added value to standard risk stratification, and could not determine the population to which the test would best apply. The evidence was inadequate to characterize the clinical validity of the Quest H:I Test.Clinical UtilityThe EWG found no evidence regarding the clinical utility of the MammaPrint and Quest H:I Ratio tests, and inadequate evidence regarding Oncotype DX. These technologies have potential for both benefit and harm.Contextual IssuesThe EWG reviewed economic studies that used modeling to predict potential effects of using gene profiling, and judged the evidence inadequate.     

Insurance denials and diagnostic rates in a pediatric genomic research cohort

PurposeThis study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials.MethodsAnalysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts.ResultsOf the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials).ConclusionMany patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers’ coverage policies.     

The economic value of personalized medicine tests: what we know and what we need to know

PurposeThere is uncertainty about when personalized medicine tests provide economic value. We assessed evidence on the economic value of personalized medicine tests and gaps in the evidence base.MethodsWe created a unique evidence base by linking data on published cost–utility analyses from the Tufts Cost-Effectiveness Analysis Registry with data measuring test characteristics and reflecting where value analyses may be most needed: (i) tests currently available or in advanced development, (ii) tests for drugs with Food and Drug Administration labels with genetic information, (iii) tests with demonstrated or likely clinical utility, (iv) tests for conditions with high mortality, and (v) tests for conditions with high expenditures.ResultsWe identified 59 cost–utility analyses studies that examined personalized medicine tests (1998–2011). A majority (72%) of the cost/quality-adjusted life year ratios indicate that testing provides better health although at higher cost, with almost half of the ratios falling below $50,000 per quality-adjusted life year gained. One-fifth of the results indicate that tests may save money.ConclusionMany personalized medicine tests have been found to be relatively cost-effective, although fewer have been found to be cost saving, and many available or emerging medicine tests have not been evaluated. More evidence on value will be needed to inform decision making and assessment of genomic priorities.Genet Med 2014:16(3):251–257     

GUÍA: a digital platform to facilitate result disclosure in genetic counseling

PurposeUse of genomic sequencing is increasing at a pace that requires technological solutions to effectively meet the needs of a growing patient population. We developed GUÍA, a web-based application, to enhance the delivery of genomic results and related clinical information to patients and families.MethodsGUÍA development occurred in five overlapping phases: formative research, content development, stakeholder/community member input, user interface design, and web application development. Development was informed by formative qualitative research involving parents (N = 22) whose children underwent genomic testing. Participants enrolled in the NYCKidSeq pilot study (N = 18) completed structured feedback interviews post–result disclosure using GUÍA. Genetic specialists, researchers, patients, and community stakeholders provided their perspectives on GUÍA’s design to ensure technical, cultural, and literacy appropriateness.ResultsNYCKidSeq participants responded positively to the use of GUÍA to deliver their children’s results. All participants (N = 10) with previous experience with genetic testing felt GUÍA improved result disclosure, and 17 (94%) participants said the content was clear.ConclusionGUÍA communicates complex genomic information in an understandable and personalized manner. Initial piloting demonstrated GUÍA’s utility for families enrolled in the NYCKidSeq pilot study. Findings from the NYCKidSeq clinical trial will provide insight into GUÍA’s effectiveness in communicating results among diverse, multilingual populations.     

An overview of recommendations and translational milestones for genomic tests in cancer

PurposeTo understand the translational trajectory of genomic tests in cancer screening, diagnosis, prognosis, and treatment, we reviewed tests that have been assessed by recommendation and guideline developers.MethodsFor each test, we marked translational milestones by determining when the genomic association with cancer was first discovered and studied in patients, and when a health application for a specified clinical use was successfully demonstrated and approved or cleared by the US Food and Drug Administration. To identify recommendations and guidelines, we reviewed the websites of cancer, genomic, and general guideline developers and professional organizations. We searched the in vitro diagnostics database of the US Food and Drug Administration for information, and we searched PubMed for translational milestones. Milestones were examined against type of recommendation, Food and Drug Administration approval or clearance, disease rarity, and test purpose.ResultsOf the 45 tests we identified, 9 received strong recommendations for their usage in clinical settings, 14 received positive but moderate recommendations, and 22 were not currently recommended. For 18 tests, two or more different sources had issued recommendations, with 67% concordance. Only five tests had Food and Drug Administration approval, and an additional five had clearance. The median time from discovery to recommendation statement was 14.7 years.ConclusionIn general, there were no associations found between translational trajectory and recommendation category.Genet Med 17 6, 431–440.