Clinical trial NCT03597165: Incidental Genomics
Official title: The Health Outcomes, Utility, and Costs of Returning Incidental Genomic Findings
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Cancer
Keywords: Incidental Findings
Genomic Sequencing
Randomized Controlled Trial
Clinical Utility
Personal Utility
Lead sponsor: Unity Health Toronto
Sponsor class: OTHER
First posted: 2018-07-24
Enrollment: 289
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: HEALTH_SERVICES_RESEARCH

Brief summary: 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: 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

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Hospital Anxiety and Depression Scale (HADS)
timeFrame: 2 weeks after return of results
Secondary outcomes:
measure: Impact of Event Scale-Revised (IES-R)
timeFrame: 1 year following return of results.
measure: Multi-Dimensional Impact of Cancer Risk Assessment (MICRA)
timeFrame: 1 year following return of results.
measure: Adapted Behavioral Risk Factor Surveillance System (BRFSS) Questionnaire
timeFrame: 1 year following return of results.
measure: SF-12
timeFrame: 1 year following return of results.
measure: Genetic Self Efficacy (GSE)
timeFrame: 1 year following return of results.
measure: Risk Perception
timeFrame: 1 year following return of results
measure: Qualitative interviews with a subset of patients
timeFrame: 9-12 months following return of results
measure: Qualitative interviews with a subset of practitioners
timeFrame: 9-12 months following return of results
Other outcomes:
measure: Perceived Utility
timeFrame: 1 year following return of results.
measure: Clinical actions triggered by genomic sequencing results
timeFrame: 1 year following return of results.
measure: Impact of genomic sequencing results on reproductive behaviors
timeFrame: 1 year following return of results.
measure: Decisional Conflict Scale (DCS)
timeFrame: 1 year following return of results.
measure: Diagnostic yield
timeFrame: Immediately after sequence analysis.
measure: Health Information National Trends Survey (HINTS) (Adapted)
timeFrame: 1 year following return of results.
measure: Economic impact of GS results
timeFrame: 5 years following return of results.
measure: Costs incurred by participants - survey questions
timeFrame: 1 year following return of results.
measure: Communication of genomic sequencing results to relatives
timeFrame: 1 year following return of results.
measure: Cascade genetic testing among relatives
timeFrame: 1 year following return of results.
measure: Cascade health behaviors among relatives
timeFrame: 1 year following return of results.
measure: Perceptions of uncertainties in genomic sequencing (PUGS) scale
timeFrame: 1 year following return of results.
measure: Tolerance of ambiguity scale
timeFrame: 1 year following return of results.
Locations:
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Toronto
country: Canada
facility: Princess Margret Cancer Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Hospital
state: Ontario
Study officials:
affiliation: St. Michael's Hospital and University of Toronto
name: Yvonne Bombard, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Shickh S, Clausen M, Mighton C, Gutierrez Salazar M, Zakoor KR, Kodida R, Reble E, Elser C, Eisen A, Panchal S, Aronson M, Graham T, Armel SR, Morel CF, Fattouh R, Glogowski E, Schrader KA, Hamilton JG, Offit K, Robson M, Carroll JC, Isaranuwatchai W, Kim RH, Lerner-Ellis J, Thorpe KE, Laupacis A, Bombard Y; Incidental Genomics Study Team. Health outcomes, utility and costs of returning incidental results from genomic sequencing in a Canadian cancer population: protocol for a mixed-methods randomised controlled trial. BMJ Open. 2019 Oct 7;9(10):e031092. doi: 10.1136/bmjopen-2019-031092.