Risk of contralateral breast cancer and ovarian cancer in BRCA1 founder mutation (5382insC or 4154delA) carriers with primary breast cancer

Background: Current scientific evidence suggests that BRCA1/2 mutant phenotypic characteristics depend on specific site of mutation in gene. The objective of this study is to estimate the risk of new cancer events, (metachronous contralateral breast cancer (CBC) and ovarian cancer (OC)) in BRCA1 mutation carriers with primary breast cancer in population of Latvia, dominated by two founder mutation types. Secondary goal is to verify the risk reduction associated with contralateral prophylactic mastectomy (CPM) and bilateral prophylactic salpingo-ophorectomy (BPSO) procedures.
Patients and Methods: In this retrospective observational cohort study we selected women with BRCA1 gene mutation (5382insC or 4154delA) who had treatment for primary unilateral breast cancer in stage 1 to 3. Information regarding BRCA1 mutation was obtained from RSU Oncology Institute database (Latvia). Primary study endpoints were CBC and OC. Data about new cancer events was obtained from national oncology register (eveseliba. gov.lv). Information about CPM procedures was obtained from Pauls Stradins Hospital database. Risk of cancer events was calculated using Kaplan-Meier and Log-rank type analysis.
Results: Between February 1980 and September 2019, 178 patients were enrolled in study. Mean age at primary breast cancer diagnosis was 46.5 (±1.7, 95% CI) years. Total of 128 (71.9%) subjects had mutation “5382insC” and 50 (28.1%) subjects had mutation “4157delA” At median follow up of 11.9 (IQR 10.1–13.6) years, 27 (15.2%) subjects developed CBC. Mean time to CBC was 10.7(±3.2, 95% CI) years. Cumulative risk of CBC at 10 years was 21.5%. Total of 25 (14.0%) subjects developed ovarian cancer at mean age of 55.2 (±3.9, 95% CI) years. 10 years cumulative risk for developing ovarian cancer was 15.6%. CPM procedure was performed in 31 cases, mostly synchronous with primary cancer operation. Mean follow-up of this subgroup was 3.8 (±1.0, 95% CI) years. None of patients who had CPM developed CBC. BPSO was performed in 40 subjects, with mean follow-up time of 8.2 (±2.7, 95%CI) years, there were no cases of ovarian cancer in this subgroup. In subgroup without CPM (N = 147), 10 years cumulative risk of CBC was 25.6% and in subgroup without BPSO (N = 138), 10 year cumulative risk of OC was 19.7% In multivariate analysis of CBC/OC risk, there was no significant statistical difference between two types of mutations.
Conclusion: Carriers of BRCA1 mutations 5382insC or 4157delA and primary breast cancer have high risk of CBC and OC. Prophylactic procedures should be strongly encouraged in this group. The risk of CBC and OC in this BRCA1 founder population is relatively comparable to other non-founder/mixed BRCA1 populations.