Prof. Dr. Maria Katapodi

In Hereditary Breast and Ovarian Cancer (HBOC) syndrome, communication of genetic test results with relatives is essential to cascade genetic screening. Cascade genetic screening is a sequential process of identifying and testing blood relatives of a known mutation carrier to determine if they also carry the pathogenic variant, in order to propose preventive and other clinical management options that reduce morbidity and mortality. However, according to Swiss and Korean privacy laws, individuals identified with the pathogenic variant have the sole responsibility to share information about test results and health implication to relatives. Empirical evidence suggests that up to 50% of biological relatives are unaware of relevant genetic information, suggesting that potential benefits of genetic testing are not communicated effectively. Thus, interventions designed to help probands effectively communicate with relatives are critical for better management of hereditary cancer risk.

Technology could play a significant role in facilitating communication and genetic education within HBOC families. Given the lack of well-developed digital health tools to assist individuals with genetic predisposition to cancer effectively communicate genetic information to their relatives, the study aims to develop a modern, scalable, mobile friendly digital health solution for Swiss and Korean HBOC families. The digital health solution will be based on the Family Gene Toolkit (FGT), a web-based intervention designed to enhance communication of genetic test results within HBOC families that has been successfully tested for acceptability, usability, and participant satisfaction.

The study will also expand an existing research infrastructure developed in Switzerland, to enable future collaborative projects between Switzerland and Korea in this field. The Specific Aims of the project are: 1) Develop a digital health solution to support the communication of cancer predisposition among HBOC families, based on linguistic and cultural adaptation methods of the Family Gene Toolkit for the Swiss and Korean population 2) Develop the K-CASCADE research infrastructure in Korea by expanding an existing research infrastructure developed by the CASCADE Consortium in Switzerland 3) Evaluate the efficacy of the aforementioned digital solution on psychological distress and communication of genetic test results, as well as knowledge of cancer genetics, coping, decision making and quality of life 4) Explore the reach, effectiveness, adoption, implementation, and maintenance of the aforementioned digital solution.

The content for the digital health solution will be based on the FGT with linguistic adaptation to Korean, German, French and Italian, and will be made available for web and mobile access. Aim 1 will be achieved through focus groups in each country to better identify cultural context with 20 -24 HBOC mutation carriers and relatives and 6-10 healthcare providers involved in genetic services (counseling and testing).

For Aim 2 , K-CASCADE, a Korean database of HBOC families (mutation carriers and relatives) will be created based on the Swiss CASCADE Consortium database, creating a lasting research infrastructure that will facilitate future collaboration, including the possibility to apply machine learning algorithms for prediction of breast and ovarian cancer risk.

For Aim 3, feasibility and efficacy of the digital health solution against the comparison intervention will be assessed in a randomized trial, with a sample of 104 HBOC mutation carriers (52 in each study arm).

Aim 4 will be achieved with survey and interview data collected from participating HBOC families and healthcare providers during all phases of the study. Dissemination strategies will also be generated to ensure sustainable use of the digital health solution. Adapting existing interventions, rather than developing new ones, takes advantage of previous valid experiences without duplicating efforts.

Adaptation and implementation of culturally sensitive, digital health interventions that can facilitate communication processes within the family and enhance understanding of genetic cancer risk are extremely timely and relevant, given the expansion of genetic testing technology, the falling costs of genetic testing, and the increased pressure for integration of genetic knowledge in routine clinical care. The study would be one of the first resource-effective international research platforms to develop digital health solutions that can be scaled to large patient numbers and can be used in routine practice.

Background: Breast, colorectal, ovarian, and endometrial cancers constitute approximately 30% of newly diagnosed cancer cases in Switzerland, affecting more than 12,000 individuals annually. Hundreds of these patients are likely to carry germline pathogenic variants associated with hereditary breast ovarian cancer (HBOC) or Lynch syndrome (LS). Genetic services (counseling and testing) for hereditary susceptibility to cancer can prevent many cancer diagnoses and deaths through early identification and risk management. Objective: Cascade screening is the systematic identification and testing of relatives of a known mutation carrier. It determines whether asymptomatic relatives also carry the known variant, needing management options to reduce future harmful outcomes.

Specific aims of the CASCADE study are to (1) survey index cases with HBOC or LS from clinic-based genetic testing records and determine their current cancer status and surveillance practices, needs for coordination of medical care, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to serve as advocates for cancer genetic services to blood relatives, (2) survey first- and second-degree relatives and first-cousins identified from pedigrees or family history records of HBOC and LS index cases and determine their current cancer and mutation status, cancer surveillance practices, needs for coordination of medical care, barriers and facilitators to using cancer genetic services, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to participate in a study designed to increase use of cancer genetic services, and (3) explore the influence of patient-provider communication about genetic cancer risk on patient-family communication and the acceptability of a family-based communication, coping, and decision support intervention with focus group(s) of mutation carriers and relatives.

Methods: CASCADE is a longitudinal study using surveys (online or paper/pencil) and focus groups, designed to elicit factors that enhance cascade genetic testing for HBOC and LS in Switzerland. Repeated observations are the optimal way for assessing these outcomes. Focus groups will examine barriers in patient-provider and patient-family communication, and the acceptability of a family-based communication, coping, and decision-support intervention. The survey will be developed in English, translated into three languages (German, French, and Italian), and back-translated into English, except for scales with validated versions in these languages.

Results: Descriptive analyses will include calculating means, standard deviations, frequencies, and percentages of variables and participant descriptors. Bivariate analyses (Pearson correlations, chi-square test for differences in proportions, and t test for differences in means) will assess associations between demographics and clinical characteristics. Regression analyses will incorporate generalized estimating equations for pairing index cases with their relatives and explore whether predictors are in direct, mediating, or moderating relationship to an outcome.

Focus group data will be transcribed verbatim and analyzed for common themes. Conclusions: Robust evidence from basic science and descriptive population-based studies in Switzerland support the necessity of cascade screening for genetic predisposition to HBOC and LS. CASCADE is designed to address translation of this knowledge into public health interventions. Trial Registration: ClinicalTrials.gov NCT03124212; https://clinicaltrials.gov/ct2/show/NCT03124212 (Archived by WebCite at http://www.webcitation.org/6tKZnNDBt)