Background Identifying mutation-carrying relatives of patients with hereditary cancer syndromes via cascade testing is an underused first step in primary cancer prevention. A feasibility study of facilitated genetic testing of at-risk relatives of patients with a known pathogenic mutation demonstrated encouraging uptake of cascade testing.
Primary objective Our primary objective is to compare the proportion of genetic testing of identified first-degree relatives of probands with a confirmed BRCA1/2 mutation randomized to a facilitated cascade testing strategy versus standard of care, proband-mediated, information sharing.
Study hypothesis We hypothesize that facilitated cascade testing will drive significantly higher uptake of genetic testing than the standard of care.
Trial design The FaCT (Facilitated Cascade Testing) trial is a prospective multi-institutional randomized study comparing the efficacy of a multicomponent facilitated cascade testing intervention with the standard of care. Patients with a known BRCA1/2 mutation (probands) cared for at participating sites will be randomized. Probands randomized to the standard of care group will be instructed to share a family letter with their first-degree relatives and encourage them to complete genetic testing. First-degree relatives of probands randomized to the intervention arm will receive engagement strategies with a patient navigator, an educational video, and accessible genetic testing services.
Major inclusion/exclusion criteria Adult participants who are first-degree relatives of a patient with a BRCA1/2 mutation and have not had prior genetic testing will be included.
Primary endpoint Analyses will assess the proportion of first-degree relatives identified by the proband who complete genetic testing by 6 months in the intervention arm versus the control arm.
Sample size One hundred and fifty probands with a BRCA1/2 mutation will be randomized. Each proband is expected to provide an average of 3 relatives, for an expected 450 participants.
Estimated dates for completing accrual and presenting results January 2024.
Trial registration NCT04613440
- ovarian cancer
- BRCA1 protein
- BRCA2 protein
Data availability statement
No data are available.
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Pathogenic variants in breast cancer susceptibility gene 1 (BRCA1) or gene 2 (BRCA2) mutations are implicated in approximately 20% of high-grade ovarian cancers1 2 and 15% of familial breast cancer cases.3 Despite the clinical significance of these pathogenic variants, population-level screening strategies are underused and only 10–20% of all BRCA1/2 carriers in the United States have been identified.4–6 Beyond the therapeutic and prognostic implications for patients with cancer, identification of inherited mutations provides a unique opportunity to diagnose affected family members. The process of testing at-risk relatives is known as cascade testing. It has the potential to identify high-risk individuals who, in the absence of surveillance, screening, and risk-reducing surgery, may develop and succumb to a hereditary cancer.5 7 Despite the potential power of cascade testing, as a medical community, we have yet to successfully implement this strategy or realize its benefits.
Studies have demonstrated that probands share their genetic testing results with approximately 80% of their first-degree relatives, but rates of cascade testing are more modest.8–12 The reasons for this gap have not been fully elucidated in the literature, though lack of access to genetic services, socioeconomic factors, lack of health insurance coverage, and poor communication, probably contribute to limited use of genetic services related to cancer.8 13–19 Moreover, the medical system has relied on affected patients to carry the burden of organizing cascade testing for their relatives. This may be particularly problematic for patients with cancer undergoing arduous therapy. Unsurprisingly, the proportion of cancer-related cascade testing has been estimated to be less than 30%.8–12 Studies that challenged the status quo and employed direct contact of family members by the medical team have yielded the highest cascade testing rates.20–22 In a pilot study, a strategy of facilitated cascade testing that used telephone genetic counseling and mailed saliva testing resulted in uptake of genetic testing by 58% of at-risk relatives. This single institution pilot study, however, was limited by lack of a control arm and long-term health-related and quality of life follow-up.
The goal of this multicenter prospective randomized control trial is to investigate facilitated cascade testing versus standard of care proband-mediated information sharing and to assess the long-term consequences of cascade testing. We hypothesize that facilitated cascade testing for cancer-associated germline pathogenic variants with telephone genetic counseling and mailed saliva kit testing will drive significantly higher uptake of genetic testing than proband-mediated testing.
METHODS AND ANALYSIS
This multi-institutional prospective randomized controlled trial will compare the efficacy of a multicomponent facilitated cascade testing intervention to the standard of care. Enrolled patients (probands) with known BRCA1/2 pathogenic variants receiving care at one of the participating institutions will be randomly assigned to the intervention arm or the standard of care arm (Figure 1). The intervention is the facilitated cascade testing pathway. It includes the following: (1) the genetics team will work with proband to collect demographic, socioeconomic, and medical history and to identify first-degree relatives through creation of a pedigree; (2) the genetics team will contact relatives to confirm eligibility, obtain consent, and collect demographic, socioeconomic, and medical history; (3) the genetics team will send a link to a short educational video explaining the importance and implications of genetic testing and an email link to the study’s website hosted by the genetic testing laboratory; (4) relatives will access the online portal to order a genetic test free of charge; (5) relatives will receive a genetic testing saliva kit by mail with a self-addressed return envelope and instructions on saliva sample collection; (6) relatives will undergo telephone genetic counseling for disclosure of genetic testing results and review of guideline-based recommendations for cancer preventative strategies.
In the standard of care arm, the genetics team will work with the proband to collect demographic, socioeconomic, and medical history and to identify first-degree relatives through creation of a pedigree. All information regarding genetic testing will flow from the proband to their first-degree relatives, as occurs in standard clinical practice. Probands will be instructed to share a family letter (providing information on the familial mutation) with their first-degree relatives and encourage them to complete genetic testing. The family letter will also contain information on how to obtain free genetic testing through the study, if the relatives desire to undergo testing. The genetics team will contact relatives to confirm eligibility, obtain consent, and collect demographic, socioeconomic, and medical history.
The study team will follow-up with relatives at 6, 12, and 18 months after consent. At each check-in, relatives be will asked whether or not they underwent genetic testing. The study schema is outlined in Figure 2.
All surveys will be distributed to participants at 6, 12, and 18 months after consent. Relatives from both groups found to have BRCA1/2 pathogenic variants will be followed up to determine if they completed cancer risk-reducing surveillance or surgery based on the National Comprehensive Cancer Network guidelines.23
All relatives who undergo testing will be asked to complete validated instruments, the Satisfaction with Decision Scale24 and the Multidimensional Impact of Cancer Risk Assessment questionnaire to assess for distress following testing.25
Relatives who elect not to undergo genetic testing will complete a validated instrument26 27 to assess perceived benefits and risks of genetic testing (eg, attitudes), evaluate self-efficacy, and the reasons 'to test' or 'not to test'. They will also complete the Satisfaction with Decision Scale to assess their satisfaction with their decision about genetic testing.24
The FaCT trial is a non-commercial trial that does not receive any support from the industry. All trial related expenses (regulatory services, statistics, electronic database, and data quality monitoring) are covered by research grants.
Patients (probands) are eligible for the study if they are at least 18 years old and diagnosed with a deleterious (pathogenic) variant in BRCA1, or BRCA2 (that is included on testing panel provided by the clinical genetic testing laboratory) within the preceding 12 months. Probands must also be receiving care at one of the academic medical institutions participating in the study. Eligible relatives are first-degree relatives (son, daughter, full brother, full sister, mother, father) of the proband who are ≥18 years of age, at risk for carrying the familial pathogenic variant, who have not had prior cancer genetic testing, and are aware of the proband’s pathogenic mutation. These relatives will be identified jointly by the proband and the genetics team, and their inclusion in the study is contingent on the proband’s permission to contact them.
The primary endpoint is the proportion of genetic testing by 6 months among first-degree relatives who were identified by the proband (and with whom contact was authorized) in each study arm. Exploratory endpoints include the rates of positive genetic testing in each group, risk-reducing procedures and surveillance among those with positive genetic test results in each group, distress, uncertainty, and positive experiences associated with cascade genetic testing using the Multidimensional Impact of Cancer Risk Assessment survey and the Satisfaction with Decision Scale. We also plan to describe potential covariate associations (eg, sociodemographic and clinical factors, correlations with proband risk-reducing behaviors, etc), where distributions allow, and facilitators of and barriers to cascade testing.
Probands will be recruited from the participating institutions and randomized 1:1 either to the intervention or to the control arm via Research Electronic Data Capture (REDCap).28 Randomization will be stratified by number of first-degree relatives, cancer diagnosis (cancer or no cancer), and months from proband BRCA test result (≤6 months vs >6 months).
One hundred and fifty probands will be recruited and randomized 1:1 either to the intervention or to the control arm. We expect to enroll two or three relatives for each proband. We conservatively assume that the intervention will be less effective in relatives of probands without a diagnosis of cancer, and therefore enrollment of relatives related to probands without cancer will be limited to 20% of the total sample size. We will compare the proportion of identified relatives who completed genetic testing between the intervention and the control arms with a two-sided Cochran-Mantel-Haenszel test adjusted for intra-proband correlation.29 30
We conservatively assume that the intervention in relatives of probands without a diagnosis of cancer will be half as effective as that of probands with cancer. Furthermore, we expect the OR for uptake to be 2.25 within each stratum. Therefore power was calculated for 60% uptake in relatives related to probands with cancer and who were randomized to the intervention, 40% uptake in relatives related to probands with cancer and who were randomized to standard of care; 30% uptake in relatives related to probands without cancer and who were randomized to the intervention, and 16% uptake in relatives related to probands without cancer and who were randomized to standard of care. The power for detecting this difference when conducting a two-sided Cochran-Mantel-Haenszel test adjusted for intra-proband correlation with a 10% type I error ranges from 0.84 to 0.93 as intra-proband correlation ranges from 0.1 to 0.5 when there are two relatives per proband. Power increases as the number of relatives per proband increases. Sample size was calculated using PASS 13.
Descriptive statistics will be calculated for all secondary aims along with 95% confidence intervals. All statistical testing and calculation of confidence intervals will adjust for intra-proband correlation. Specifically, we will calculate the proportion of positive genetic test results by study arm. Among those who test positive for BRCA1/2, we will calculate the proportion of relatives who participate in risk-reducing procedures, as well as the proportion by type of risk-reducing procedure—that is, active surveillance or surgery. We will also examine whether there are any sociodemographic and clinical factors that are independently associated with participation in risk-reducing behaviors. This will be completed through the use of models that also include a term for intervention and stratum. However, no hypothesis testing will be completed, only 95% confidence intervals, because of the expected low number of relatives who have a positive genetic test. Multidimensional Impact of Cancer Risk Assessment and Satisfaction with Decision Scale scores will be compared using either two-sample t-tests or Wilcoxon rank-sum tests adjusted for clustering. We will use time-to-event methods, such as Kaplan-Meier graphs, log-rank tests, and proportional hazards models, to examine the association between time to BRCA1/2 testing and demographic/baseline clinical values. If we find that any relatives were diagnosed with cancer or died prior to getting genetic testing, we will use competing risks models with cancer diagnosis and death as competing events. Facilitators and barriers of cascade testing, as reported by probands and first-degree relatives, will be categorized, tallied, and reported.
The launch of the Precision Medicine Initiative in 2015 was based on the potential of genomic information to individualize medical treatment for each patient. Cascade genetic testing, or the process of familial diffusion of genomic risk information, represents a powerful application of precision medicine. When an individual (proband) is found to carry a cancer-associated germline pathogenic variant, the information should be shared with at-risk relatives, particularly first-degree relatives, who have a 50% likelihood of carrying the same pathogenic variant. This process of cascade testing enables genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention, and risk-reducing surgery, which reduces morbidity and prevents mortality in this high-risk population.13 31 32 A study modeling large-scale implementation of facilitated cascade testing20 found that if 70% of all relatives were tested, all individuals with pathogenic variants in 18 cancer susceptibility genes in the United States would be diagnosed in less than 10 years.7 Given its potential in primary cancer prevention, cascade testing has been designated by the Centers for Disease Control and Prevention (CDC) as a tier 1 genomic application for hereditary breast and ovarian cancer.33
However, the promise of genomics as a tool for cancer prevention has yet to be realized. Even as the price of genetic testing has plummeted,5 31 efforts to alleviate barriers to cascade testing have not been broadly implemented. Studies have demonstrated that probands share their genetic testing results with over 80% of their first-degree relatives,34–36 indicating that the cascade testing 'bottleneck' may represent a breakdown in communication about complex information and resultant lack of understanding among family members.37 A qualitative study of 131 subjects belonging to 14 families described proband-mediated transfer of information as 'highly defective' as less than half of the relatives knew the risk of having a pathogenic variant, and only a third understood the preventive implications of identifying one. Early studies focused on healthcare team outreach to probands in the form of telephone calls and letters, but have demonstrated inconsistent results.11 38 39 For example, a study using mailed letters to 591 relatives showed that the proportion of recipients seeking further information was no higher than 34%.11 Hodgson and colleagues randomized 95 probands to a telephone genetic counseling intervention versus control and found that there was no difference in the proportion of relatives who made contact with genetic services (25.6% vs 20.9%). Importantly, these studies demonstrate that interventions focused at the level of the proband, have not effectively led to increased cascade testing or contact with genetic services,11 39 even when free genetic testing was offered .38
Recent studies focusing on healthcare team outreach at the level of the relatives have yielded more encouraging results.20 21 40 Evans and colleagues demonstrated that direct offering of cascade testing to relatives of probands with a BRCA1 mutation led to an uptake of 56% over 10 years.21 In a study from Trinidad, 77 of 125 identified at-risk relatives were invited to participate in an education session, after which all participants consented to be tested for the familial mutation.40 Finally, a strategy of facilitated cascade testing that used telephone genetic counseling and mailed saliva testing kits resulted in testing for 58% of at-risk relatives without negative quality-of-life implications.20 To date, however, there have been no randomized controlled trials of facilitated cascade testing focused on at-risk relatives versus standard of care. The FaCT trial is the first multi-institutional randomized controlled trial of a facilitated strategy of cascade testing compared with standard of care, proband-mediated, information sharing. Traditionally, the medical system has relied on affected patients to carry the burden of organizing cascade testing for their relatives. We hypothesize that a shift in the current paradigm, transferring this role to the medical team, could make a cascade testing program more successful.
Data availability statement
No data are available.
Collaborators Brandelyn N Pitcher.
Contributors All authors have reviewed the manuscript.
Funding This work was supported by grants from the National Institutes of Health National Cancer Institute (JAR-H: K08 CA234333; RN, KHL, DLU, and JAR-H: P30 48CA016672; KHL: 5T32 CA101642), and National Center for Advancing Translational Sciences (AM: KL2TR001874; MKF:KL2TR002385). The funding sources were not involved in the development of the research hypothesis, study design, data analysis, or manuscript writing.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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