Background: Hereditary cancer predisposition syndromes are responsible for approximately 5–10% of all diagnosed cancer cases. In order to identify individuals at risk in a cost-efficient manner, family members of individuals carrying pathogenic alterations are tested only for the specific variant that was identified in their carrier relative. The purpose of this study was to investigate the clinical use and implementation of cascade family testing (CFT) in families of breast cancer patients with pathogenic/likely pathogenic variants (PVs/LPVs) in cancer-related predisposition genes. Methods: Germline sequencing was carried out with NGS technology using a 52-gene panel, and cascade testing was performed by Sanger sequencing or MLPA. Results: In a cohort of 1785 breast cancer patients (families), 20.3% were found to have PVs/LPVs. Specifically, 52.2%, 25.1%, and 22.7% of patients had positive findings in high-, intermediate-, and low-penetrance breast cancer susceptibility genes, respectively. Although CFT was recommended to all families, only 117 families (32.3%) agreed to proceed with genetic testing. Among the first-degree relatives who underwent CFT, 70.3% were female, and 108 of 121 (89.3%) were cancer free. Additionally, 42.7%, 36.7%, and 20.6% were offspring, siblings, and parents of the subject, respectively. Our data suggest that CFT was mostly undertaken (104/117, 88.8%) in families with positive findings in high-risk genes. Conclusions: Cascade family testing can be a powerful tool for primary cancer prevention by identifying at-risk family members. It is of utmost importance to implement genetic counseling approaches leading to increased awareness and communication of genetic testing results.

Breast cancer (BC) is the most prominent tumor type among women, accounting for 32% of newly diagnosed cancer cases. BC risk factors include inherited germline pathogenic gene variants and family history of disease. However, the etiology of the disease remains occult in most cases. Therefore, in the absence of high-risk factors, a polygenic basis has been suggested to contribute to susceptibility. This information is utilized to calculate the Polygenic Risk Score (PRS) which is indicative of BC risk. This study aimed to evaluate retrospectively the clinical usefulness of PRS integration in BC risk calculation, utilizing a group of patients who have already been diagnosed with BC. The study comprised 105 breast cancer patients with hereditary genetic analysis results obtained by NGS. The selection included all testing results: high-risk gene-positive, intermediate/low-risk gene-positive, and negative. PRS results were obtained from an external laboratory (Allelica). PRS-based BC risk was computed both with and without considering additional risk factors, including gene status and family history. A significantly different PRS percentile distribution consistent with higher BC risk was observed in our cohort compared to the general population. Higher PRS-based BC risks were detected in younger patients and in those with FH of cancers. Among patients with a pathogenic germline variant detected, reduced PRS values were observed, while the BC risk was mainly determined by a monogenic etiology. Upon comprehensive analysis encompassing FH, gene status, and PRS, it was determined that 41.90% (44/105) of the patients demonstrated an elevated susceptibility for BC. Moreover, 63.63% of the patients with FH of BC and without an inherited pathogenic genetic variant detected showed increased BC risk by incorporating the PRS result. Our results indicate a major utility of PRS calculation in women with FH in the absence of a monogenic etiology detected by NGS. By combining high-risk strategies, such as inherited disease analysis, with low-risk screening strategies, such as FH and PRS, breast cancer risk stratification can be improved. This would facilitate the development of more effective preventive measures and optimize the allocation of healthcare resources.

Background: Risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) are established strategies for women carrying pathogenic or likely pathogenic (P/LP) variants in high-risk cancer susceptibility genes. However, real-world uptake remains variable and is influenced by clinical, demographic, and psychosocial factors. This study evaluated adherence to guideline-recommended surgical risk-reduction strategies following positive genetic testing. Materials and Methods: We conducted a retrospective observational study of 13,069 women who underwent hereditary cancer testing using a multigene next-generation sequencing panel between 2020 and 2025. Among them, 1,255 carriers of P/LP variants in genes with established recommendations for RRM and/or RRSO were identified. Physician-reported questionnaires were available for 203 individuals and captured data on counseling, acceptance, and implementation of risk-reducing surgery. Genes were grouped according to NCCN guideline recommendations: (i) BRCA1/2; (ii) PALB2, PTEN, TP53; and (iii) BRIP1, RAD51C, RAD51D. Results: Of the 203 women, 83% had a personal history of cancer. Overall, 83.7% were offered at least one risk-reducing intervention, with 64.9% accepting. RRM was more frequently discussed in higher breast cancer–risk genes, while RRSO discussion varied by gene group; these differences were statistically significant. Acceptance rates were moderate for RRM but consistently high for RRSO across groups. Younger age and advanced-stage disease were key factors limiting uptake or discussion, and 22 patients postponed surgery despite initial agreement. Conclusions: In this real-world cohort, physician counseling largely aligned with gene-specific guidelines, and acceptance of risk-reducing surgery was high once discussed, particularly for RRSO. However, uptake was influenced by age, disease stage, and clinical context. These findings highlight the importance of early genetic testing and multidisciplinary counseling to optimize timely decision-making and improve adherence to preventive strategies.