Incidental Genomics

Titre officiel

The Health Outcomes, Utility, and Costs of Returning Incidental Genomic Findings


Les fournisseurs de soins de santé utilisent de plus en plus le séquençage génomique pour diagnostiquer des maladies et cibler les traitements des patients. Toutefois, le séquençage génomique peut révéler des risques héréditaires associés à des milliers de maladies actuelles et futures. Conformément aux lignes directrices, il est recommandé aux fournisseurs de soins de santé d’aviser les patients des résultats secondaires du séquençage génomique. Le séquençage génomique est une technologie relativement récente, soulevant de nombreuses questions sur son adoption dans le domaine des soins cliniques, y compris : quels sont les préjudices psychologiques, les résultats sur la santé, les bienfaits cliniques et les coûts liés à l’obtention de résultats primaires et secondaires du séquençage génomique? Nous mènerons un essai contrôlé avec répartition aléatoire afin d’évaluer si les patients recevant des résultats secondaires d’un séquençage génomique signalent des niveaux plus élevés de détresse et plus de comportements réduisant le risque que ceux recevant des résultats primaires seulement. Nous explorerons l’utilité personnelle du séquençage génomique au moyen d’entrevues approfondies auprès d’un sous-ensemble de patients. L’utilité clinique pour le cancer et les résultats secondaires seront évalués à l’aide du rendement diagnostique, des actions cliniques prises à la suite des résultats du séquençage génomique et des entrevues en profondeur auprès d’un sous-ensemble de patients et de fournisseurs. Les répercussions économiques seront évaluées de deux façons : (a) l’utilisation des services de santé sera évaluée rétrospectivement à l’aide des dossiers de facturation de l’Institut de recherche en services de santé (IRSS); (b) les coûts personnels des participants découlant du séquençage génomique seront évalués au moyen de sondages. Les participants seront des patients adultes atteints de cancer ayant reçu des résultats négatifs et qui ont été considérés par leur fournisseur de soins de santé comme des candidats pour le séquençage génomique.

Description de l'essai

Primary Outcome:

  • Hospital Anxiety and Depression Scale (HADS)
Secondary Outcome:
  • Impact of Event Scale-Revised (IES-R)
  • Multi-Dimensional Impact of Cancer Risk Assessment (MICRA)
  • Adapted Behavioural Risk Factor Surveillance System (BRFSS) Questionnaire
  • SF-12
  • Genetic Self Efficacy (GSE)
  • Risk Perception
  • Qualitative interviews with a subset of patients
  • Qualitative interviews with a subset of practitioners
Background Genomic sequencing (GS) is considered the 'next step' towards personalized medicine, providing an opportunity to improve the prevention, diagnosis and treatment of disease. Across Canada, clinicians are increasingly using GS to identify treatments and management approaches likely to benefit patients based on molecular makeup, especially in oncology. GS offers increased sensitivity over classic genetic tests. For example, multi-gene sequencing has been shown to increase the sensitivity of identifying clinically actionable mutations in breast cancer patients by 50% to 60% when compared to testing for BRCA1/2 alone. Often breast cancer patients who test negative for BRCA1/2 will be offered GS to identify causative mutations. In addition, GS can also be used to analyze the molecular profile of a patient's tumour (somatic GS) to identify therapeutic targets. However, the process of decoding the genome an individual or their tumour may incidentally reveal information about inherited predispositions to other cancers and diseases, including genetic variants/changes associated with current (undiagnosed) disease, drug response, risk for future diseases and variants of unknown clinical significance. Increasing policy guidance suggests that 'medically actionable' results should be offered to patients undergoing clinical sequencing, with calls to offer additional incidental results based on patient preferences. There is limited evidence on the psychological harms and clinical benefits of returning incidental GS results to patients. Psychological distress: Single-gene and multiplex testing for hereditary cancers, neurological and cardiac disease appears to have minimal psychological impacts. A recent study found that few participants report distress from GS results. However, these findings are based on individuals who agreed to be tested for particular genes, and were prepared through counseling or otherwise to receive these results. This may not translate to incidentally-discovered genetic risk, which individuals did not anticipate or choose to learn a priori. Distress related to receiving incidental GS results remains unknown. Personal utility: Studies suggest that individuals want to learn their GS results because they expect them to offer 'personal utility'. Personal utility is considered an increasingly important precursor of clinical utility, which is believed to offer richer self-knowledge and motivate risk reducing behaviours. Most studies focus on the hypothetical return of incidental GS results, little is known about individuals' actual perceived value of receiving GS results. Health benefits: Single-gene and multiplex testing for low risk single nucleotide polymorphisms (SNPs) and high penetrance susceptibility alleles appears to influence the uptake of diet and medication changes, risk-reducing surgeries and surveillance. However, these findings are based on individuals who requested testing for selected genes, and may not represent individuals who learn incidental results. Clinical Utility: Due to the challenges of applying traditional measures of clinical utility (quality adjusted life years, life years gained) in the context of genomic medicine, an 'intermediate outcome' of utility has emerged based on the 'usefulness and added value to patient management decision making,' of results captured by clinical actions or altered medical recommendations. Preliminary evidence shows GS holds great promise to enable personalized treatments and efficient diagnoses, has demonstrated to facilitate diagnosis in cases of rare diseases with unclear etiology, and strong potential to inform personalized drug therapies compatible with patients' genotypes. The utility of germline GS has largely been examined in limited clinical contexts, such as paediatrics and rare diseases. GS results have been shown to alter clinical management, such as by informing specialist referrals. In a study among a small sample of physicians, providers expressed that while they viewed the current utility of GS as low, they expect it to become more commonplace and more useful in the future. The actual and perceived utility of GS will ultimately determine its clinical implementation, and more evidence in broader clinical settings is needed to inform GS' optimal translation into clinical practice. Economic Analysis: A lack of evidence remains around the costs and cost-effectiveness of GS. Some believe GS has potential to reduce overall healthcare spending by streamlining the diagnostic process enabling tailored treatments, and informing specific prevention efforts. Others, however, believe that GS will increase healthcare expenditures with limited clinical benefits, as sequencing and variant interpretation costs remain high and results may trigger cascades of additional testing and screening procedures. Out-of-pocket costs may be incurred by patients including medications, counseling, and peripheral costs such as lost wages and transportation. Cost-effectiveness studies have predominately been conducted in the context of tumour sequencing for pharmacological applications; the cost-effectiveness of germ-line GS for primary indication has been examined in few clinical contexts. Regarding incidental findings, cost-effectiveness studies have been conducted for fewer than one third of conditions whose disclosure is recommended by the American College of Medical Genetics and Genomics (ACMG). Modelling predicts incidental finding disclosure may be cost-effective for diagnostics but not currently for general population screening. Further investigation into the utility, costs, and cost-effectiveness of GS is necessary to inform health service delivery and funding decisions. Rationale It is unknown whether incidental GS results will be perceived as useful, and whether they motivate the intent or uptake of risk-reducing behaviours. The clinical utility of GS results has not been fully explored, and there is a lack of evidence around cost-effectiveness and costs associated with GS to patients and the healthcare system, which poses a barrier to its clinical implementation. Research Question Do patients receiving incidental GS results experience higher levels of distress and engage in more risk reducing behaviours? What is the diagnostic yield of GS, and how do GS results influence clinical decision making? What are the short-term and long-term costs associated with receiving GS results to patients and the healthcare system? Objectives 1. Evaluate the psychological distress of receiving incidental GS results 2. Evaluate the personal utility and impact of receiving incidental GS results on subsequent risk reduction behaviours. 3. Evaluate the clinical utility of GS: a. Assess the diagnostic yield of GS results: i. Related to primary cancer indication. ii. Medically actionable incidental findings. iii. Incidental findings with implications for reproductive decisions, lifestyle and relatives. b. Explore the nature and extent of clinical activity triggered by primary and incidental GS results (referrals to specialists, laboratory testing, scans and screens, etc.). c. Explore patient and provider perspectives of the perceived and actual clinical utility of primary and incidental GS results. 4. Examine the short-term (1 year) and long-term (5 year) costs associated with genomic sequencing: 1. Costs to the healthcare system. 2. Personal costs. Study procedures Patients will be recruited from familial cancer clinics in the Greater Toronto Area (GTA), consented by a genetic counselor, and randomized. Following randomization, participants in the intervention arm will have the option to select which categories of incidental results they would be willing to receive, with a genetic counselor. Participants' genomes will be sequenced and interpreted. Results will be returned by a genetic counselor. Referrals will be made based on sequencing results. Outcomes will be measured at multiple time points before and after the return of results.

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