Predictors of Ovarian Function in Women Treated With Aromatase Inhibitors

描述（由申请人提供）：本K07申请的目的是提供必要的培训和环境，使候选人成为独立的研究者，能够设计，实施和获得高质量的临床和转化研究的资金，重点是乳腺癌的内分泌治疗。在建议的指导期间，职业发展活动将包括（1）完成临床研究设计和统计分析硕士学位（K30计划），以及遗传学，药物基因组学和基因组研究伦理学的额外教学指导，（2）由丹尼尔海斯博士指导（国际公认的乳腺癌治疗和肿瘤标志物分析专家）在设计，执行，和解释与乳腺癌辅助芳香化酶抑制剂（AI）治疗期间卵巢功能预测因子相关的研究，和（3）与乳腺癌药物基因组学联盟和密歇根大学的高级同事在药物基因组学、卵巢储备和绝经过渡方面的实质性合作。候选人提出了一个研究项目，将集中在绝经前妇女与早期乳腺癌谁开发化疗引起的卵巢功能衰竭（CIOF）。这些妇女可能会得到更多的好处，从雌激素剥夺与AI治疗比他莫昔芬，已被证明为绝经后妇女。然而，由于LHRH反馈回路，很大一部分患者在AI治疗期间可能恢复卵巢功能，这将使AI治疗无效。该提案的基石是在CIOF女性中进行AI治疗的前瞻性临床试验。总体目标是使用从研究参与者收集的研究样本和数据，确定AI治疗期间卵巢功能改变的临床适用遗传学、流行病学和生化预测因子。我们假设我们可以预测哪些女性在AI治疗期间将保持绝经后状态，哪些女性很可能恢复卵巢功能。概述的职业发展计划，沿着这个K07应用的指导研究建议，将增加候选人的知识和研究技能，使成功过渡到临床和转化乳腺肿瘤学的独立研究生涯。相关性：美国每年约有20，000名绝经前乳腺癌患者接受化疗和内分泌治疗。芳香化酶抑制剂（AI）治疗可能优于他莫昔芬，但由于卵巢功能恢复的可能性，可能并非对所有患者都安全。在这项提案中，我们将确定那些可以安全接受人工智能治疗的患者，这将使治疗决策更加个性化。

DESCRIPTION (provided by applicant): The purpose of this K07application is to provide the necessary training and environment to prepare the candidate to become an independent investigator, able to design, conduct, and acquire funding for high-quality clinical and translational studies that focus on endocrine therapy for breast cancer. During the proposed mentored period, career development activities will include (1) completion of a Masters Degree in Clinical Research Design and Statistical Analysis (K30 program), as well as additional didactic instruction in genetics, pharmacogenomics, and the ethics of genomic research, (2) mentorship by Dr. Daniel Hayes (an internationally recognized expert in breast cancer treatment and tumor marker analysis) in the design, execution, and interpretation of studies related to predictors of ovarian function during adjuvant aromatase inhibitor(AI) therapy for breast cancer, and (3) substantial collaboration with senior colleagues in the Consortium on Breast Cancer Pharmacogenomics and at the University of Michigan on pharmacogenomics, ovarian reserve, and the menopausal transition. The candidate proposes a research project that will focus on premenopausal women with early stage breast cancer who develop chemotherapy-induced ovarian failure (CIOF). These women likely would derive more benefit from estrogen deprivation with AI therapy than from tamoxifen, as has been demonstrated for postmenopausal women. However, a substantial percentage is likely to recover ovarian function during AI therapy due to LHRH feedback loops, which would render AI therapy ineffective. The cornerstone of this proposal is a prospective clinical trial of AI therapy in women with CIOF. The overall goal is to identify clinically applicable genetic, epidemiologic, and biochemical predictors of alterations of ovarian function during AI therapy using research samples and data collected from study participants. We hypothesize that we can predict which women will remain postmenopausal during AI therapy, and which are highly likely to recover ovarian function. The outlined career development program, along with the mentored research proposal for this K07 application, will augment the candidate's knowledge and research skills to enable the successful transition to an independent research career in clinical and translational breast oncology. RELEVANCE: Each year, approximately 20,000 premenopausal breast cancer patients in the U.S. receive chemotherapy and endocrine therapy. Aromatase inhibitor (AI) therapy may be preferable to tamoxifen, but may not be safe in all patients because of the potential for recovery of ovarian function. In this proposal we will identify those patients who can receive AI therapy safely, which will enable more personalized treatment decisions.