The Difference in Contralateral Breast Cancer and Ovarian Cancer risks for BRCA1 Founder Variant (c.5266dup, c.4035del) Carriers with Primary Breast Cancer

Introduction: Previous research has suggested, that primary breast cancer (PBC) and ovarian cancer (OC) risks can be modified by mutation location in BRCA1 gene. In this study we assessed and compared the risks of contralateral breast cancer (CBC) and OC after the event of PBC in carriers of regionally frequent BRCA1 founder pathogenic variants (PV) c.5266dup and c.4035del. Subjects and Methods: In the analysis of CBC and OC risk, 1364 cases with BRCA1 PV and PBC were included. The control group consisted of 11350 consequent unselected and unscreened cases with PBC. The follow-up started at the time of PBC diagnosis and continued till the event of CBC or OC had occurred. The cumulative risks of CBC and OC were calculated using the Kaplan-Meier analysis. Risk factor for developing CBC/OC (age < 40 years) was calculated using cox proportional hazards model. Results: Cumulative 10 years risk of developing CBC was 3.0% in control group, and 20.1% in study group of BRCA1 carriers (log-rank p < 0.001). Cumulative risk of CBC at 10,15 and 20 years was 25.0%, 37.0% and 51.4% in PV c.5266dup subgroup, as opposed to 14.1%, 27.2% and 44.5% in PV c.4035del subgroup (log-rank p = 0.045). Age younger than 40 years at the time of PBC was risk factor for CBC (hazard ratio 2.06, 95% CI 1.83-2.29, p < 0.001). Cumulative risk of developing OC at 10 and 15 years was 1.0% and 1.2% in control group, 10.8% and 16.8% for PV c.5266dup, 13.5% and 30.8% for PV c.4035del. There was difference in OC risks between control group and BRCA1 carriers (log-rank p< 0.001). PV c.4035del showed higher risk of OC, compared to PV c.5266dup, however, this was of borderline statistical significance (log-rank p = 0.057). Age younger than 40 years at the time of PBC was not associated with any difference in future OC risks (hazard ratio 1.03, 95% CI 0.77-1.29, p = 0.23). Conclusion: The data of this study confirms previously established evidence that in cases of PBC the risk of future CBC and OC is increased significantly for BRCA1 carriers in comparison to general unscreened population. Moreover, BRCA1 PV c.5266dup is associated with higher CBC risk and possibly lower OC risk in comparison to BRCA1 PV c.4035del. Age younger than 40 years at diagnosis of PBC is risk factor for CBC, but does not seem to alter the risk of OC.

BRCA1; c.5266dup; c.4035del; founder; CBC; OC; contralateral breast cancer; ovarian cancer