Report of Endometrial Cancer in AustralianBRCA1andBRCA2Mutation-Positive Families

Abstract

There is evidence that tamoxifen treatment ofBRCA1andBRCA2carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence thatBRCA1andBRCA2mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC withBRCA1orBRCA2mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater inBRCA1-positive families (35/218 (16%); p = .03) and non-significantly greater inBRCA2-positive families (23/189 (12%); p = .6), compared to high-risk breast cancer families without aBRCA1/2mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses fromBRCA1/2families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed individuals from 57BRCA1/2pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater forBRCA1carriers (hazard ratio = 1.25, 95%CI = 0.65–2.41), andBRCA2carriers (HR = 1.12, 95%CI = 0.51–2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12–15.15; p = 1.7 x 10-6) inBRCA1/2families, with no evidence for interaction between tamoxifen therapy andBRCA1/2genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members fromBRCA1/2families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk withBRCA1/2mutation status alone.