Family-based cascade screening in hereditary breast and ovarian cancer: Identification of asymptomatic carriers and a 15-year window for risk reduction.

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Background: The integration of genetic screening into routine care for breast and ovarian cancers (BC and OC) has transformed early detection and the development of targeted medicines. Family-based screening makes it feasible to identify mutation-positive at-risk relatives and adopt measures to prevent the disease. Nonetheless, a significant number of variants of unknown significance (VUS) have been identified, posing challenges in clinical interpretation, which can be mitigated by co-segregation analysis. Although family screening plays an important role, there is a dearth of published data. Methods: A total of 217 family members of 104 mutation-positive probands (86 with LPV/PV and 16 with VUS) were screened using Sanger sequencing or amplicon-based Next Generation Sequencing (NGS). Risks for breast and ovarian cancers were calculated for all the subjects using the BODICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) model. Segregation data analysis was carried out for the reclassification of VUS. Results: A total of 91 (52.6%) family members tested positive for LPV/PVs and 16 (44%) for VUS. Among the 91 mutation-positive individuals, 16 (17.5%) had a diagnosis of malignancy (mean age 47±11 years; median 41 years), while the 75 subjects (82.5%) were asymptomatic at the time of testing, with a significantly younger mean age (32±11 years). Asymptomatic subjects (n=3) chose to undergo risk-reducing surgery at a mean age of 42±9 years. The BOADICEA-based lifetime risk estimates for mutation-positive subjects aged <40, 40–50 and >50 years, for breast cancer were 45%, 36%, and 34% and for ovarian cancer were 23%, 12%, and 6.5%. Three variants of uncertain significance were reclassified as likely benign based on the co-segregation analysis. Conclusions: Family screening is important in identifying high-risk individuals. Based on the study results, the earlier identification of asymptomatic cases offers a significant 15-year prophylactic window for risk reduction considering the risk prediction, mutation-type and family history. Co-segregation analysis using extended family screening would enable reclassification of VUS and further clinical management. To our knowledge, this study represents the largest familial screening cohort reported to date within the Indian population.