Breast Cancer Risk Modifiers in BRCA Mutation Carriers

描述（由申请人提供）：BRCA1和BRCA2基因突变携带者的终生乳腺癌风险估计为40-80%。因此，大约20-60%的携带者活到高龄而没有发病，这表明其他基因或个人属性可能会改变携带者的风险。然而，目前人们对这样的个人特征知之甚少。迫切需要确定哪些（如果有的话）可改变的生活方式特征可能会改变携带者患乳腺癌的风险，以帮助她在预防性乳房切除术等预防性选择方面做出理性、知情的选择。我们建议使用从有害BRCA1或BRCA2突变的年轻（年龄< 50岁）病例（N=425）和对照（N=352）携带者中统一收集的数据来评估乳腺癌风险与5个可改变特征之间的关系。这些因素包括：口服避孕药的使用史、诊断前诊断性或治疗性胸部照射史、饮酒、吸烟以及青春期、青年期和中年时期的身体活动模式。我们将重点关注在诊断（病例）或访谈（对照）时年龄在50岁以下的携带者，他们已经参加了国际乳腺癌研究协作家庭登记处（CFRBCS）和纽约、安大略和澳大利亚的临床研究。我们将使用无条件逻辑回归来估计这些属性与乳腺癌风险相关的比值比，同时控制潜在的混杂因素，并使用稳健方差估计器来解释相关携带者属性中存在的任何相关性。这些关于BRCA1或BRCA2突变的大量年轻携带者的可改变特征的数据代表了一种独特的资源，可以提高我们对绝经前高危妇女乳腺癌预防的认识。提出的分析将为这些妇女提供替代乳房切除术作为预防策略的新信息。

DESCRIPTION (provided by applicant): Lifetime breast cancer risks among carriers of mutations of the genes BRCA1 and BRCA2 have been estimated at 40-80%. Thus some 20-60% of carriers live to advanced ages without developing the disease, which suggests that other genes or personal attributes may modify carriers' risks. At present however, title is known about such personal characteristics. There is urgent need to determine which, if any, modifiable lifestyle characteristics may alter a carrier's risk of developing breast cancer, to assist her in making rational, informed choices about such preventive options as prophylactic mastectomy. We propose to use uniformly collected data from young (aged < 50 years) case (N=425) and control (N=352) carriers of deleterious BRCA1 or BRCA2 mutations to evaluate associations between breast cancer risk and five modifiable characteristics. These are: history of oral contraceptive use, history of diagnostic or therapeutic chest irradiation prior to diagnosis, alcohol consumption, cigarette smoking, and physical activity patterns during puberty, young adulthood and middle age. We will focus on carriers under age 50 years at diagnosis (cases) or interview (controls) who have participated in an international Collaborative Family Registry for Breast Cancer Studies (CFRBCS) and in clinical studies in New York, Ontario and Australia. We will use unconditional logistic regression to estimate odds-ratios relating these attributes to breast cancer risk while controlling for potential confounders, and use robust variance estimators to account for any correlation present in attributes of related carriers. These data on modifiable characteristics from a large group of young carriers of BRCA1 or BRCA2 mutations represent a unique resource for advancing our knowledge about breast cancer prevention in premenopausal women at high risk for the disease. The proposed analysis will provide new information on alternatives to mastectomy as a preventive strategy for these women.