Prophytactic surgery in carriers of BRCA 1/2 mutations

BRCA 1/2 突变携带者的预防性手术

• 批准号: 7498412
• 负责人: TIMOTHY R REBBECK
• 金额: $ 71.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498412
• 关键词: Ablation; Address; Affect; Age; Androgen Receptor; Applications Grants; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Bilateral; Bilateral oophorectomy; Biological; Biological Factors; Biological Markers; Breast; Characteristics; Clinical; Clinical Management; Cohort Studies; Contraceptive Usage; Data; Diagnosis; End Point; Estrogens; Evaluation; Event; Funding; Future; General Population; Genes; Genetic screening method; Goals; Grant; High Risk Woman; Hormonal; Hormone replacement therapy; Hormones; Hot flushes; Inherited; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Menopausal hot flushes; Methods; Mutation; NCOA3 gene; Operative Surgical Procedures; Osteoporosis; Ovarian hormone; Ovariectomy; Pathway interactions; Personal Satisfaction; Phenotype; Placement; Premature Menopause; Prevention; Progesterone; Progesterone Receptors; Quality of life; Rate; Recording of previous events; Relative (related person); Reproductive History; Research; Research Design; Research Personnel; Resources; Risk; Risk Assessment; Risk Reduction; Role; Sampling; Sleep Disorders; Survival Analysis; Time; Tumor Biology; Tumor Markers; Woman; analytical method; base; cancer risk; carcinogenesis; child bearing; clinically relevant; cohort; comparative genomic hybridization; improved; insight; malignant breast neoplasm; mutation carrier; programs; prophylactic; prospective; reproductive; response; steroid hormone metabolism; therapy duration; tumor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：BRCA1 和 BRCA2 (BRCA1/2) 遗传突变基因检测的可用性为乳腺癌或卵巢癌高风险女性提供了潜在有价值的信息。不幸的是，BRCA1/2 遗传突变携带者可用于降低癌症风险的临床治疗选择相对较少。这些选择包括使用双侧预防性卵巢切除术 (BPO) 来降低乳腺癌和卵巢癌的风险。然而，现有数据并不支持有关手术类型和时机的决定，以及 BPO 后激素替代疗法 (HRT) 的使用。此外，BRCA1/2 相关乳腺肿瘤似乎具有独特的表型，可能会受到 BPO 或 HRT 使用等暴露的影响。因此，虽然 BPO 的使用降低了 BRCA1/2 突变携带者随后患乳腺癌的风险，但这种风险降低的生物学基础尚不清楚。为了解决 BRCA1/2 突变携带者乳腺癌风险和预防的临床和生物学相关性，我们建议继续使用 BRCA1/2 突变携带者样本进行队列研究，以评估 BPO 和其他激素暴露在乳腺癌中的作用。降低患乳腺癌的风险。正在开展的 PROSE（“手术终点的预防和观察”）多中心联盟由近 2000 名女性组成，在此基础上，我们建议继续开展这项研究，以实现以下三个具体目标： 1) 评估 BPO 后的效果HRT 降低乳腺癌风险； 2) 评估 BPO 相对于年龄和生殖事件的时机是否影响癌症风险降低的程度； 3) 分别考虑由 BRCA1 和 BRCA2 突变引起的肿瘤，评估 HRT 和 BPO 对乳腺肿瘤组织病理学和基于生物标志物特征的影响。为了实现这些目标，我们将研究接受过 BPO 的手术受试者，并将这些女性与没有 BPO 病史的对照女性的乳腺癌发病率进行比较。将进行分析以评估临床相关激素暴露（包括 BPO、HRT 和生育史）对乳腺癌风险的影响。此外，我们将通过使用基于芯片的比较基因组杂交 (aCGH) 表征 BRCA1/2 相关乳腺肿瘤的表型，评估乳腺癌风险和与这些激素暴露相关的风险降低的生物学基础。在完成这些目标的过程中，我们将更好地了解临床相关激素暴露（即 BPO、HRT、生殖史）对癌症风险的作用，并了解具有这些暴露的女性乳腺肿瘤的表型。这些研究将推动未来 BRCA1/2 相关乳腺肿瘤生物学、预防和治疗的研究。