Predictors of ovarian failure after chemotherapy in young breast cancer patients

描述(由申请者提供)：这个指导性研究奖将为候选人成为生殖流行病学的独立研究员做好准备。具体地说，这项建议将使首席研究人员能够：1)进行前瞻性队列研究；2)学习遗传学、流行病学和预测建模的方法；3)与多个学科的研究人员合作；以及4)为R01提交的报告收集数据。200多万美国女性是乳腺癌幸存者。大量患有乳腺癌的育龄妇女为研究这一毁灭性疾病和治疗对卵巢老化和生殖的影响提供了独特的机会。准确地描述和预测年轻乳腺癌患者的卵巢功能对幸存者来说是一个重要的问题，因为这涉及到生育、更年期和癌症生存等生殖问题。目前预测化疗后卵巢功能衰竭的因素仅限于年龄和化疗方案。这项建议的目标是确定与辅助化疗后卵巢衰竭相关的显著激素、遗传和卵巢形态测量标记物。建议对绝经前乳腺癌患者进行为期5年的前瞻性队列研究，从诊断到化疗后。我们将检验以下假设：1)。乳腺癌患者化疗前抗苗勒氏激素和抑制素B水平较低，化疗前FSH水平较高者，辅助化疗后发生卵巢功能衰竭的可能性较大。药物代谢酶基因多态性导致环磷酰胺暴露较高的乳腺癌患者在环磷酰胺辅助化疗后发生卵巢功能衰竭的可能性更大；化疗前卵巢体积、直径和有腔卵泡数较小，化疗前后这些指标变化较大的乳腺癌患者发生卵巢衰竭的可能性较大；使用这些目标的变量可以得出一个预测指数，以确定治疗后卵巢衰竭的高危患者。 公共卫生相关性：这项研究将确定荷尔蒙、遗传和卵巢成像标记物来预测化疗后卵巢衰竭。这些工具将帮助年轻的乳腺癌患者和他们的医生做出影响癌症生存和生殖的治疗决定。

DESCRIPTION (provided by applicant): This mentored research award will prepare the candidate to become an independent investigator in reproductive epidemiology. Specifically, this proposal will enable the principal investigator to: 1) conduct a prospective cohort study; 2) learn methods in genetics epidemiology and predictive modeling; 3) collaborate with researchers in multiple disciplines; and 4) gather data for an R01 submission. More than two million American women are breast cancer survivors. The large number of reproductive aged women with breast cancer provides a unique opportunity to study the impact of this devastating disease and treatment on ovarian aging and reproduction. Accurately characterizing and predicting ovarian function in young breast cancer patients is an important issue to survivors because of implications on reproductive issues such as fertility and menopause and cancer survival. Current predictors of ovarian failure after chemotherapy are limited to age and chemotherapy regimen. The goal of this proposal is to identify significant hormonal, genetic and ovarian morphometric markers associated with ovarian failure after adjuvant chemotherapy. A 5-year prospective cohort study of pre-menopausal breast cancer patients, followed from diagnosis to post-chemotherapy, is proposed. We will test the hypotheses that: 1). Breast cancer patients with lower pre-chemotherapy anti-Mullerian hormone and inhibin B levels and higher pre-chemotherapy FSH levels will be more likely to develop ovarian failure after adjuvant chemotherapy; 2). Breast cancer patients with drug metabolizing enzyme polymorphisms resulting in higher cyclophosphamide exposure are more likely to develop ovarian failure after cyclophosphamide-based adjuvant chemotherapy; 3). Breast cancer patients with smaller pre-chemotherapy ovarian volume, diameter and antral follicle count, and larger changes in these measurements pre- and post-chemotherapy are more likely to develop ovarian failure; 4). A predictive index using variables from these aims can be derived to identify patients at high risk for ovarian failure after therapy. PUBLIC HEALTH RELEVANCE: This study will identify hormonal, genetic and ovarian imaging markers to predict ovarian failure after chemotherapy. These tools will assist young breast cancer patients and their physicians in making treatment decisions that would impact cancer survival and reproduction.