The availability of genetic testing for inherited mutations in BRCA1 and BRCA2 (BRCA1/2) provides potentially valuable information to women at high risk of breast or ovarian cancer. Unfortunately, carriers of inherited mutations in BRCA1/2 have relatively few clinical management options available to reduce their cancer risk. These options include the use of bilateral prophylactic oophorectomy (BPO) to reduce both breast and ovarian cancer risk. However, decisions about the type and timing of this surgery, as well as the use of post-BPO hormone replacement therapy (HRT) are not supported by existing data. Furthermore, BRCA1/2-associated breast tumors appear to have a unique phenotype that may be influenced by exposures such as BPO or HRT use. Thus, while the use of BPO reduces subsequent breast cancer risk in BRCA1/2 mutation carriers, the biological underpinnings of this risk reduction are not clear. In order to address the clinical and biological correlates of breast cancer risk and prevention in BRCA1/2 mutation carriers, we propose the continuation of a cohort study using a sample of BRCA1/2 mutation carriers to evaluate the role of BPO and other hormonal exposures in reducing breast cancer risk. Building on the cohort of nearly 2000 women that comprise the ongoing PROSE (""""""""Prevention and Observation of Surgical Endpoints"""""""") multicenter consortium, we propose a continuation of this research to address the following three specific aims: 1) Evaluate the effect of post-BPO HRT on breast cancer risk reduction; 2) Evaluate whether the timing of BPO with respect to age and reproductive events affects the magnitude of cancer risk reduction; and 3) Evaluate the effect of HRT and BPO on histopathological and biomarker-based characteristics in breast tumor, considering tumors arising from BRCA1 and BRCA2 mutations separately. To achieve these aims, we will study surgical subjects who have undergone BPO, and compare the rate of breast cancer in these women with controls who have no history of BPO. Analyses will be taken to assess the effect of clinically relevant hormonal exposures including BPO, HRT, and reproductive history on breast cancer risk. Furthermore, we will evaluate the biological basis for breast cancer risk and risk reduction associated with these hormonal exposures by characterizing the phenotype of BRCA1/2-associated breast tumors using array-based comparative genome hybridization (aCGH). In completing these aims, we will better understand the role of clinically relevant hormone exposures (i.e., BPO, HRT, reproductive history) on cancer risk, and understand the phenotype of breast tumors in women with these exposures. These studies will motivate future studies of BRCA1/2-associated breast tumor biology, prevention, and treatment. ? ?
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