Official Title
The Health Outcomes, Utility, and Costs of Returning Incidental Genomic Findings
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 behaviours 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.
Trial Description
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.
View this trial on ClinicalTrials.gov
