Incidental Genomics

Study Overview
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Brief Summary
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Health care providers (HCP) are increasingly using genomic sequencing (GS) to diagnose diseases and target treatment for patients. However, GS may incidentally reveal inherited risks for thousands of current and future diseases. Guidelines recommend HCP inform patients of incidental GS results. GS is a relatively new technology, raising many questions about its adoption in clinical care, including: What are the psychological harms, health outcomes, clinical utility and economic costs of receiving primary and incidental GS results? We will use a randomized controlled trial (RCT) to evaluate whether patients receiving incidental GS results will report higher levels of distress and more risk reducing behaviors compared to patients receiving GS for their primary indication alone. We will explore the personal utility of GS via in-depth interviews with a subset of patients. Clinical utility for cancer and incidental results will be evaluated through diagnostic yield, clinical actions triggered by GS results and in-depth interviews with a subset of patients and providers. The economic impact will be evaluated in two ways: (a) health service use will be assessed retrospectively using billing records from the Institute of Clinical Evaluative Sciences (ICES); and, (b) participants' personal costs incurred as a result of GS will be assessed via surveys. Participants will be adult cancer patients who have received negative single gene or panel test results and who have been determined by their health care provider to be a candidate for GS.

Detailed Description
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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 behaviors. 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 Evaluate the psychological distress of receiving incidental GS results Evaluate the personal utility and impact of receiving incidental GS results on subsequent risk reduction behaviours. 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. Examine the short-term (1 year) and long-term (5 year) costs associated with genomic sequencing: Costs to the healthcare system. 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.

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

Conditions
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Cancer

Intervention / Treatment
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* Other: Incidental Genomic Sequencing Results
* Other: GS Results for Primary Indications only


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Affected with Cancer Received a negative/inconclusive germline single gene test result for a cancer gene mutation (e.g., BRCA1/2, MLH, MSH, PMS, etc.) in the past two years Or received a negative/inconclusive germline panel test result 18 years old or older Speak and read English Exclusion Criteria: Are in advanced stage cancer (stage 4 /metastatic cancer) Currently in active treatment (chemotherapy, radiation, scheduled surgery) - patients who are on Prophylactic Hormonal Therapy (eg tamoxifen) will be included Received a positive genetic test for a cancer gene mutation (e.g., BRCA1/2, MLH, MSH, PMS, APC, MUTYH, etc.) Have not had single gene germline testing related to their primary cancer condition (e.g., BRCA1/2 for breast/ovarian cancer, MLH, MSH, PMS colorectal cancer, etc.) Previously received genomic sequencing for any reason Currently pregnant or planning on getting pregnant (Including men whose partner is pregnant or planning). Participants who become pregnant over the course of the study will not be excluded. Do not speak or read English Under 18 years of age Have a family member participating in the study Participant in previous study of decision aid (Decision Aid RCT Study or Usability Study).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Incidental Genomic Sequencing Results<br>Patients in Intervention will receive GS results related to primary indication (cancer) and will be offered the option learning their incidental results, categorized into five bins based on a framework by Berg et al. | Other: Incidental Genomic Sequencing Results<br>* Patient will receive GS results related to their primary indication (cancer), as well as the option to learn incidental GS results. Incidental results will be categorized into five bins based on Berg et al.'s framework (medically actionable and pharmacogenetic, common disease SNPs, Mendelian conditions, early-onset brain diseases, and carrier status). In pre-test counseling, patients will have the option to select which bins of incidental results they would like to learn, if any.<br>|
| Active Comparator: Primary Indication only<br>Patients in the control will receive the intervention GS results for Primary Indications only. | Other: GS Results for Primary Indications only<br>* Patients will receive GS results related to the primary indication (cancer) only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hospital Anxiety and Depression Scale (HADS) | Our primary outcome is distress, measured by the Hospital Anxiety & Depression Scale (HADS) using a validated cut-off of >11 on either the anxiety or depression subscale. The Hospital Anxiety and Depression Scale measures clinically significant anxiety and depression. There are two subscales, anxiety (7 items) and depression (7 items). Scores on each subscale range from 0-21, with higher scores indicating worse outcome (higher anxiety or depression). Subscale scores are not combined for a total score. (PMID: 6880820, 25005549) | 2 weeks after return of results | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Impact of Event Scale-Revised (IES-R) | The Impact of Event Scale-Revised (IES-R) is a standardized, validated scale that measures symptoms of traumatic stress. The IES-R comprises of three subscales: Intrusion (8 items), Avoidance (8 items), and Hyperarousal (6 items). The IES-R yields a total score that ranges from 0-88, with higher scores indicating worse outcomes. Scores on the Intrusion subscale range from 0-32, with higher scores indicating worse outcomes. Score on the Avoidance subscale range from 0-32, with higher scores indicating worse outcomes. Scores on the Hyperarousal subscale range from 0-24, with higher scores indicating worse outcomes. (PMID: 23243796) | 1 year following return of results. | 
| Multi-Dimensional Impact of Cancer Risk Assessment (MICRA) | The Multi-Dimensional Impact of Cancer Risk Assessment (MICRA) is a 25-item standardized, validated scale that measures the impact of result disclosure from genetic tests. There are three subscales: Distress (6 items), Uncertainty (9 items) and Positive Experiences (4 items). Total scores range from 0-125, with higher scores indicating worse outcome. Scores on the Distress subscale range from 0-30, with higher scores indicating worse outcome. Scores on the Uncertainty subscale range from 0-45, with higher scores indicating worse outcome. Scores on the Positive Experiences Subscale range from 0-20, with higher scores indicating worse outcomes. (PMID: 12433008) | 1 year following return of results. | 
| Adapted Behavioral Risk Factor Surveillance System (BRFSS) Questionnaire | We will assess the intended use and actual adoption of risk-reducing behaviours and preventative services across all RCT participants using CDC's Behavioural Risk Factor Surveillance System (BRFSS) questionnaire. We have adapted the BFRSS to examine whether the receipt of GS results influences participants' intent to adopt, and actual self-reported adoption of: screening, prophylactic surgery, dietary changes, reduced alcohol intake, increased exercise, adherence/changes to medication, and smoking cessation (beyond those taken due to their cancer diagnosis). Self-reported actual or intended use of these behaviours will be ascertained over the telephone. Higher scores indicate higher uptake of health behaviours. | 1 year following return of results. | 
| SF-12 | The SF-12 scale measures quality of life. The SF-12 has 12 items that address physical and mental functioning. Physical and mental health composite scores range from 0 to 100, with 0 indicating the lowest possible level of health, and 100 indicating the highest possible level of health. | 1 year following return of results. | 
| Genetic Self Efficacy (GSE) | Consistent with the Extended Parallel Process Model (EPPM) which suggests that that higher risk results could motivate individuals to adopt risk-reducing behaviors if they perceive an increased risk of disease, as long as self-efficacy is also high, we will assess genetic self-efficacy using a standardized, validated measure (PMID: 20884465). | 1 year following return of results. | 
| Risk Perception | Consistent with the Extended Parallel Process Model (EPPM) which suggests that that higher risk results could motivate individuals to adopt risk-reducing behaviors if they perceive an increased risk of disease, as long as self-efficacy is also high, we will assess risk perception. Participants will be asked to report their perceived likelihood of developing diseases related to their incidental results. For each disease risk, scores range from 1 to 5, and higher scores indicate higher perceived risk. (PMID: 16969872, 24131974) | 1 year following return of results | 
| Qualitative interviews with a subset of patients | We will use in-depth interviews with patients to provide further insights into the ways in which incidental results impact the quality of life and health outcomes of cancer patients receiving incidental results. Patient interviews will explore: reasons for learning incidental GS results, to whom, how and why results have been communicated, perceived utility and impact of incidental results for personal, familial or life planning. | 9-12 months following return of results | 
| Qualitative interviews with a subset of practitioners | Provider interviews will explore: improvements to patient management and treatment decisions on the basis of their patients' incidental results and their perceptions of the clinical, familial and personal benefits or harms of these results for patients. Interviews will also explore providers' views on any physical or physiological impacts that receipt of incidental results have had on patients. | 9-12 months following return of results | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Incidental Findings, Genomic Sequencing, Randomized Controlled Trial, Clinical Utility, Personal Utility