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Healthy carriers of BRCA1/2 pathogenic variants (PVs) may benefit from risk-reducing measures of proven efficacy. The main approach to identify these individuals is cascade testing, and strategies to support this complex process are under investigation. In Italy, cascade testing has received little attention; therefore, we analyzed the uptake and characteristics of BRCA1/2 cascade testing in families diagnosed with HBOC between 2017 and 2019 at two Italian genetics centers. All blood relatives aged 18 years or older at September 2022 and who could be involved in the first step of cascade testing (i.e., all the living relatives closest to the proband) were included. In addition to first-degree relatives, individuals who were second-, third- or fourth-degree relatives were included if the closest relative(s) was/were deceased. Overall, 213 families were included (103, Genoa; 110, Bologna). Most probands were women affected by breast and/or ovarian cancer (86.4%, Genoa; 84.5%, Bologna), and the branch segregating the PV was known/suspected in 62% of families (62.1%, Genoa; 60.9%, Bologna). Overall, the uptake of cascade testing was 22.8% (25.8%, Genoa; 19.9%, Bologna; OR = 0.59: 95%CI 0.43-0.82). It was strongly associated with female gender (OR = 3.31, 95%CI 2.38-4.59), age ≤ 70 years (< 30 years OR = 3.48, 95%CI 1.85-6.56; 30-70 years OR = 3.08, 95%CI 2.01-4.71), first-degree relationship with the proband (OR = 16.61, 95%CI 10.50-26.28) and segregation of the PV in both the maternal (OR = 2.54, 95%CI 1.72-3.75) and the paternal branch (OR = 4.62, 95%CI 3.09-6.91). These real-world data may be important to inform the design and implementation of strategies aimed at improving the uptake of HBOC cascade testing in Italy., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Hereditary breast and ovarian cancer has long been established to affect a considerable number of patients and their families. By identifying those at risk ideally before they have been diagnosed with breast and/or ovarian cancer, access to preventive measures, intensified screening and special therapeutic options can be obtained, and thus, prognosis can be altered beneficially. Therefore, a standardized screening and counseling process has been established in Germany under the aegis of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). As one of these specialized clinics, the HBOC-Center at Charité offers genetic counseling as well as genetic analysis based on the GC-HBOC standards. This analysis aims first at depicting this process from screening through counseling to genetic analysis as well as the patient collective and second at correlating the results of genetic analysis performed. Thus, real-world data from an HBOC-Center with a substantial patient collective and a high frequency of pathogenic variants in various genes shall be presented., Methods: The data of 2531 people having been counseled at the HBOC-Center at Charité in 2016 and 2017 were analyzed in terms of patient and family history as well as pathogenic variants detected during genetic analysis with the TruRisk ® gene panel when genetic analysis was conducted. This standardized analysis is compiled and regularly adjusted by the GC-HBOC. The following genes were included at time of research: BRCA1, BRCA2, ATM, CDH1, CHEK2, PALB2, RAD51C, RAD51D, NBN, and TP53., Results: Genetic analysis was conducted in 59.8% of all cases meeting the criteria for genetic analysis and 286 pathogenic variants were detected among 278 (30.3%) counselees tested using the TruRisk ® gene panel. These were primarily found in the genes BRCA1 (44.8%) and BRCA2 (28.3%) but also in CHEK2 (12.2%), ATM (5.6%) and PALB2 (3.5%). The highest prevalence of pathogenic variants was seen among the families with both ovarian and breast cancer (50.5%), followed by families with ovarian cancer only (43.2%) and families with breast cancer only (35.6%)-these differences are statistically significant (p < 0.001). Considering breast cancer subtypes, the highest rate of pathogenic variants was detected among patients with triple-negative breast cancer (40.7%) and among patients who had had been diagnosed with triple-negative breast cancer before the age of 40 (53.4%)-both observations proved to be statistically significant (p = 0.003 and p = 0.001)., Conclusion: Genetic counseling and analysis provide the foundation in the prevention and therapy of hereditary breast and ovarian cancer. The rate of pathogenic variants detected is associated with family history as well as breast cancer subtype and age at diagnosis, and can reach considerable dimensions. Therefore, a standardized process of identification, genetic counseling and genetic analysis deems mandatory., (© 2022. The Author(s).)