Prof. Dr. Maria Katapodi

CASCADE is a Swiss, multicenter, family-based, open-ended, prospective cohort established in 2017 by contacting individuals with pathogenic variants (PV) associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) and their biological relatives. The cohort includes individuals with PV who are either affected or unaffected by cancer, relatives without the familial PV (true negatives), and relatives who did not have genetic testing (cascade screening). Self-administered questionnaires collect information on epidemiological factors (e.g., cancer status) and risk management behaviors (e.g., risk reducing surgeries) approximately 18-24 months apart.

Since the initiation of the cohort we have examined rates of cascade screening among relatives and family communication of genetic risk (CASCADE I); and guideline-concordant cancer surveillance and risk reducing practices (CASCADE II). CASCADE III will focus on individuals from HBOC and LS families whose cancer surveillance and risk management behaviors do not correspond to the expectations of the healthcare system (discordant behaviors). We hypothesize that discordant behaviors may be related to the characteristics of the healthcare system and/or its responses to the needs of these individuals.

CASCADE III will: Aim 1: Examine the influence of individual domain clusters (e.g., cancer status), interpersonal domain clusters (e.g., partner status), and healthcare system domain clusters (e.g., provider specialty) on cancer risk management behaviors, and explore how changes in these clusters impact changes in risk management. Aim 1 will be addressed with two (additional) questionnaires approximately 24 months apart. Combined data will cover a period of close to 10 years and 6 data collection points for participants who have been in the cohort since its initiation - currently 461 carriers of pathogenic variants (index cases and relatives), and 86 untested or ‘true negative’ individuals. Newly-identified carriers and their biological relatives will also be recruited. Risk management behaviors will be analyzed longitudinally, in light of the trajectory of the person, using survival analyses.

Aim 2: Explore decision-making processes and the perceived role of providers and the healthcare system among individuals from HBOC and LS families with discordant cancer surveillance, risk management, and genetic testing behaviors. Aim 2 will be addressed with questionnaire and narrative data. Subgroups of individuals with discordant risk management behaviors (e.g., female, over 45 years old, without risk-reducing salpingo-oophorectomy) will be invited to participate either in in-depth interviews or in focus groups. Data will be analyzed with thematic analysis.

Aim 3: Design improvements in the healthcare system based on risk-stratified “survivorship care” models for families harboring HBOC or LS pathogenic variants. Aim 3 will be addressed with a Delphi survey of a panel with international and national experts and patient representatives. The panel will explore models of risk-stratified survivorship care for HBOC and LS families. Delphi methodology is based on the principle that decisions of an expert panel are more accurate than those of unstructured groups, given adequate diversity and representativeness of panel members.

The research network "Responsible Digital Society" is involved in a variety of ways to strengthen the promotion of interdisciplinary exchange and cooperative research in the field of digital transformation.

In the area of research, the network creates forums for regular scientific exchange and supports the coordination of interdisciplinary research proposals. In the area of promoting young researchers, the network organizes summer and winter schools for them. In the area of networking, the network promotes regular exchanges with industrial partners in the region. In the area of outreach, the network strengthens the public dialogue by organizing colloquia and panel discussions on digitization with guests from various disciplines.

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)