Acceptability and Usability of the Family Gene Toolkit for Swiss and Korean Families Harboring BRCA1/BRAC2 Pathogenic Variants: A Web-Based Platform for Cascade Genetic Testing.

The study adapted the Family Gene Toolkit and developed a customized web application for Swiss and Korean families harboring BRCA1 or BRCA2 pathogenic variants to support family communication of genetic testing results and promote cascade genetic testing among at-risk relatives. In the first step, narrative data from 68 women with BRCA1/BRCA2 pathogenic variants and clinician feedback informed a culturally sensitive adaptation of the content consistent with current risk management guidelines. In the second step, the Information Technology team developed the functions and the interface of the web application that will host the intervention. In the third step, a new sample of 18 women from families harboring BRCA1/BRCA2 pathogenic variants tested the acceptability and usability of the intervention using "think-aloud" interviews and a questionnaire. Participants expressed high levels of satisfaction with the intervention. They provided positive feedback for the information regarding active coping, strategies to enhance family communication, interactive elements, and illustrative stories. They reported that the information was useful and the web application was easy to navigate. Findings suggest that the Family Gene Toolkit is well-designed and can increase rates of cascade testing among at-risk relatives. Its efficacy will be tested in a subsequent randomized trial.

Cohort profile: population-based cohorts of patients with colorectal cancer and of their relatives in Geneva, Switzerland.

PURPOSE: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide. Variability between patients in prognosis and treatment response is partially explained by traditional clinicopathological factors. We established a large population-based cohort of patients with CRC and their first-degree and second-degree relatives registered in the Canton of Geneva, to evaluate the role of family history and tumour biomarkers on patient outcomes. PARTICIPANTS: The cohort includes all patients with CRC diagnosed between 1985 and 2013. Detailed information on patient and tumour characteristics, treatment and outcomes were extracted from the Geneva Cancer Registry database, completed by medical records review and linkage with administrative and oncogenetics databases. Next-generation tissue microarrays were constructed from tissue samples of the primary tumour. A prospective follow-up of the cohort is realised annually to collect data on outcomes. First-degree and second-degree relatives of patients are identified through linkage with the Cantonal Population Office database and information about cancer among relatives is retrieved from the Geneva Cancer Registry database. The cohort of relatives is updated annually. FINDINGS TO DATE: The cohort includes 5499 patients (4244 patients with colon cancer and 1255 patients with rectal cancer). The great majority of patients were diagnosed because of occurrence of symptoms and almost half of the cases were diagnosed with an advanced disease. At the end of 2019, 337 local recurrences, 1143 distant recurrences and 4035 deaths were reported. At the same date, the cohort of first-degree relatives included 344 fathers, 538 mothers, 3485 children and 375 siblings. Among them, we identified 28 fathers, 31 mothers, 18 siblings and 53 children who had a diagnosis of CRC. FUTURE PLANS: The cohort will be used for long-term studies of CRC epidemiology with focus on clinicopathological factors and molecular markers. These data will be correlated with the most up-to-date follow-up data.

Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort.

Cascade screening for Tier 1 cancer genetic conditions is a significant public health intervention because it identifies untested relatives of individuals known to carry pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). The Swiss CASCADE is a family-based, open-ended cohort, including carriers of HBOC- and LS-associated pathogenic variants and their relatives. This paper describes rates of cascade screening in relatives from HBOC- and LS- harboring families, examines carriers' preferences for communication of testing results, and describes theory-based predictors of intention to invite relatives to a cascade screening program. Information has been provided by 304 index cases and 115 relatives recruited from September 2017 to December 2021. On average, 10 relatives per index case were potentially eligible for cascade screening. Approximately 65% of respondents wanted to invite relatives to the cohort, and approximately 50% indicated a preference for patient-mediated communication of testing results, possibly with the assistance of digital technology. Intention to invite relatives was higher for first- compared to second- and third-degree relatives, but was not different between syndromes or based on relatives' gender. The family environment and carrying pathogenic variants predicts intention to invite relatives. Information helps optimize delivery of tailored genetic services.

A population-based cohort of young women diagnosed with breast cancer in Geneva, Switzerland.

PURPOSE: Breast cancer is the most frequently diagnosed cancer among women worldwide. Despite the fact that breast cancer is more frequent after fifty years of age, breast cancer among young women has recently drawn particular attention due to an increase in incidence in several western countries. With the exception of individuals with a high genetic risk, breast cancer occurring in younger women remains poorly understood. This project aims at investigating the patient, tumour and treatment characteristics as well as the long-term health outcomes of these women by evaluating numerous variables that were collected from their pathology and medical files, including the social environment, family history, fertility and pregnancy. PARTICIPANTS: We constituted a population-based cohort from the Geneva Cancer Registry of 1586 patients with breast cancer who were aged less than 46 years at the time of diagnosis. FINDINGS TO DATE: Breast cancer was diagnosed before the age of 35 years in 225 women (14.2%), between 35 and 39 years of age in 368 women (23.2%) and between 40 and 45 years of age in 993 women (62.6%). Most of the patients were diagnosed with luminal A or luminal B molecular subtypes (32.8 and 37.5%, respectively), stage I or II tumours (75.2%), and estrogen (74.8%) and progesterone (67.5%) positive receptors. During the study period, 16.7% of these women developed loco-regional recurrences and 25.4% developed distant metastases; the majority (66.3%) did not have a recurrence. Regarding mortality, 474 (29.9%) women died during the study period, 347 (73.2%) from breast cancer. FUTURE PLANS: The results of this study will help filling the knowledge gap about treatment of young breast cancer patients and having a child after breast cancer, and will provide clinicians and public health professionals' with additional information to improve quality of care and decrease the impact of breast cancer in young women.

Impact of obesity on diagnosis and treatment of breast cancer.

In this population-based study, we evaluated the impact of obesity on presentation, diagnosis and treatment of breast cancer. Among all women diagnosed with invasive breast cancer in the canton Geneva (Switzerland) between 2003 and 2005, we identified those with information on body mass index (BMI) and categorized them into normal/underweight (BMI <25 kg/m(2)), overweight (BMI > or =-<30 kg/m(2)) and obese (BMI > or =30 kg/m(2)) women. Using multivariate logistic regression, we compared tumour, diagnosis and treatment characteristics between groups. Obese women presented significantly more often with stage III-IV disease (adjusted odds ratio [OR(adj)]: 1.8, 95% CI: 1.0-3.3). Tumours > or =1 cm and pN2-N3 lymph nodes were significantly more often impalpable in obese than in normal/underweight patients (OR(adj) 2.4, [1.1-5.3] and OR(adj) 5.1, [1.0-25.4], respectively). Obese women were less likely to have undergone ultrasound (OR(adj) 0.5, [0.3-0.9]) and MRI (OR(adj) 0.3, [0.1-0.6]) and were at increased risk of prolonged hospital stay (OR(adj) 4.7, [2.0-10.9]). This study finds important diagnostic and therapeutic differences between obese and lean women, which may impair survival of obese women with breast cancer. Specific strategies are needed to optimize the care of obese women with or at risk of breast cancer.

Twenty-three novel BRCA1 and BRCA2 sequence variations identified in a cohort of Swiss breast and ovarian cancer families.

BRCA1 and BRCA2 are the major genes predisposing to breast-ovarian cancer (i.e., breast or ovarian cancer or both). Since 1994, hundreds of distinct germline alterations have been reported in these two genes. Besides pathogenic mutations resulting in loss of function of the protein, an increased number of variants of unknown clinical significance have been described. In a cohort of 350 Swiss breast-ovarian cancer families, the systematic search for BRCA1/BRCA2 germline mutations was carried out using denaturating high-performance liquid chromatography as the first screening procedure. The screening strategy resulted in the identification of 23 alterations not previously reported: 9 in BRCA1 and 14 in BRCA2. By using the available tools to assign a functional role to newly identified sequence variations, 5 (22%) of these were classified as new disease-causing mutations, 5 (22%) were classified as benign polymorphisms, and the remaining 13 (56%) alterations were considered as unclassified variants. These data illustrate the major challenge for clinical oncologists currently facing the interpretation of alterations identified in BRCA1 or BRCA2. The key points are to classify these genetic variations as pathogenic mutations, benign polymorphisms, or variants of unknown clinical significance and to adequately use this information for the management of high-risk individuals and their families.