Joan Scott

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 Recommendations: The 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.Rationale: Genetic 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 Validity: The EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high.Clinical Validity: After 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 Utility: The 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 Issues: CRC 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.

Managing Incidental Findings and Research Results in Genomic Research Involving Biobanks and Archived Data Sets

Biobanks and archived data sets collecting samples and data have become crucial engines of genetic and genomic research. Unresolved, however, is what responsibilities biobanks should shoulder to manage incidental findings and individual research results of potential health, reproductive, or personal importance to individual contributors (using “biobank” here to refer both to collections of samples and collections of data). This article reports recommendations from a 2-year project funded by the National Institutes of Health. We analyze the responsibilities involved in managing the return of incidental findings and individual research results in a biobank research system (primary research or collection sites, the biobank itself, and secondary research sites). We suggest that biobanks shoulder significant responsibility for seeing that the biobank research system addresses the return question explicitly. When reidentification of individual contributors is possible, the biobank should work to enable the biobank research system to discharge four core responsibilities to (1) clarify the criteria for evaluating findings and the roster of returnable findings, (2) analyze a particular finding in relation to this, (3) reidentify the individual contributor, and (4) recontact the contributor to offer the finding. We suggest that findings that are analytically valid, reveal an established and substantial risk of a serious health condition, and are clinically actionable should generally be offered to consenting contributors. This article specifies 10 concrete recommendations, addressing new biobanks as well as those already in existence.Genet Med 2012:14(4):361–384

Public Expectations for Return of Results from Large-Cohort Genetic Research

The National Institutes of Health and other federal health agencies are considering establishing a national biobank to study the roles of genes and environment in human health. A preliminary public engagement study was conducted to assess public attitudes and concerns about the proposed biobank, including the expectations for return of individual research results. A total of 141 adults of different ages, incomes, genders, ethnicities, and races participated in 16 focus groups in six locations across the country. Focus group participants voiced a strong desire to be able to access individual research results. Recognizing the wide range of possible research results from a large cohort study, they repeatedly and spontaneously suggested that cohort study participants be given ongoing choices as to which results they received.

Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors

This statement summarizes the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommendations regarding CYP450 genetic testing in adult patients beginning treatment with selective serotonin reuptake inhibitors (SSRIs), and the supporting scientific evidence. EGAPP is a project developed by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice in the United States. A key goal of the EGAPP Working Group is to develop conclusions and recommendations regarding clinical genomic applications and to establish clear linkage to the supporting scientific evidence. The Working Group members are nonfederal experts in genetics, laboratory medicine, and clinical epidemiology convened to establish methods and processes; set priorities for review topics; participate in technical expert panels for commissioned evidence reviews; publish recommendations; and provide guidance and feedback on other project activities.Summary of 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.Rationale: The EGAPP Working Group found no evidence linking testing for CYP450 to clinical outcomes in adults treated with SSRIs. While some studies of a single SSRI dose in healthy patients report an association between genotypic CYP450 drug metabolizer status and circulating SSRI levels, this association was not supported by studies of patients receiving ongoing SSRI treatment. Further, CYP450 genotypes are not consistently associated with the patient outcomes of interest, including clinical response to SSRI treatment or adverse events as a result of treatment. No evidence was available showing that the results of CYP450 testing influenced SSRI choice or dose and improved patient outcomes, or was useful in medical, personal, or public health decision-making. In the absence of evidence supporting clinical utility, it is not known if potential benefits from CYP450 testing will outweigh potential harms. Potential harms may include increased cost without impact on clinical decision making or improvement in patient outcomes, less effective treatment with SSRI drugs, or inappropriate use of genotype information in the management of other drugs metabolized by CYP450 enzymes.

Public preferences regarding the return of individual genetic research results: findings from a qualitative focus group study

Purpose:People are interested in receiving their individual research results in exchange for participating in genetic research. However, it is unclear whether the public understands the nature and limitations of these results and whether they would want information with unknown clinical utility.Methods:We conducted 10 focus groups in three US cities to examine the types of results people would want and the perceived value of different types of individual research results.Results:Nearly all focus group participants said they would want at least some individual research results returned. Priority was placed on results that are well understood. Less important to participants were the magnitude of the risk conferred and actionability of the result. In addition to helping treat or prevent disease, participants identified several other potential health-related and personal reasons for wanting individual research results. Many believed that researchers have an obligation to return individual research results. Although most people would prefer to receive as much information as possible, many would accept the return of a limited set of results.Conclusion:Participants understood the nuances and limitations of individual research results. Researchers deciding the value of returning a given result should consider using a broader definition of clinical utility as well as the possible personal utility of the information.Genet Med 2012:14(4):451–457

Risky Business: Risk Perception and the Use of Medical Services among Customers of DTC Personal Genetic Testing

Direct-to-consumer genetic testing has generated speculation about how customers will interpret results and how these interpretations will influence healthcare use and behavior; however, few empirical data on these topics exist. We conducted an online survey of DTC customers of 23andMe, deCODEme, and Navigenics to begin to address these questions. Random samples of U.S. DTC customers were invited to participate. Survey topics included demographics, perceptions of two sample DTC results, and health behaviors following DTC testing. Of 3,167 DTC customers invited, 33% (n = 1,048) completed the survey. Forty-three percent of respondents had sought additional information about a health condition tested; 28% had discussed their results with a healthcare professional; and 9% had followed up with additional lab tests. Sixteen percent of respondents had changed a medication or supplement regimen, and one-third said they were being more careful about their diet. Many of these health-related behaviors were significantly associated with responses to a question that asked how participants would perceive their colon cancer risk (as low, moderate, or high) if they received a test result showing an 11% lifetime risk, as compared to 5% risk in the general population. Respondents who would consider themselves to be at high risk for colon cancer were significantly more likely to have sought information about a disease (p = 0.03), discussed results with a physician (p = 0.05), changed their diet (p = 0.02), and started exercising more (p = 0.01). Participants’ personal health contexts—including personal and family history of disease and quality of self-perceived health—were also associated with health-related behaviors after testing. Subjective interpretations of genetic risk data and personal context appear to be related to health behaviors among DTC customers. Sharing DTC test results with healthcare professionals may add perceived utility to the tests.

Public Perspectives on Informed Consent for Biobanking

The National Institutes of Health and other federal health agencies are considering establishing a national biobank to study the roles of genes and environment in health. We assessed the publics attitudes toward the proposed biobank, including preferences for providing informed consent. Sixteen focus groups were conducted, and themes arising from the focus groups were tested in a large, representative survey (n=4659) of the general population. Our research demonstrates that when considering participating in a genomic biobank, individuals want ongoing choices and control over access to their samples and information.

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

Summary of Recommendations: The 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.Rationale: The 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 Validity: Some 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 Validity: The 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 Utility: The 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 Issues: The EWG reviewed economic studies that used modeling to predict potential effects of using gene profiling, and judged the evidence inadequate.

Recommendations from the EGAPP working group: Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?

Summary of Recommendations: The 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).Rationale: The 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 Validity: The 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 Validity: The 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 Utility: The 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 Issues: Addressing 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.

New Models for Large Prospective Studies: Is There a Better Way?

Large prospective cohort studies are critical for identifying etiologic factors for disease, but they require substantial long-term research investment. Such studies can be conducted as multisite consortia of academic medical centers, combinations of smaller ongoing studies, or a single large site such as a dominant regional health-care provider. Still another strategy relies upon centralized conduct of most or all aspects, recruiting through multiple temporary assessment centers. This is the approach used by a large-scale national resource in the United Kingdom known as the “UK Biobank,” which completed recruitment/examination of 503,000 participants between 2007 and 2010 within budget and ahead of schedule. A key lesson from UK Biobank and similar studies is that large studies are not simply small studies made large but, rather, require fundamentally different approaches in which “process” expertise is as important as scientific rigor. Embedding recruitment in a structure that facilitates outcome determination, utilizing comprehensive and flexible information technology, automating biospecimen processing, ensuring broad consent, and establishing essentially autonomous leadership with appropriate oversight are all critical to success. Whether and how these approaches may be transportable to the United States remain to be explored, but their success in studies such as UK Biobank makes a compelling case for such explorations to begin.