A Pooled Analysis to Identify New Ovarian Cancer Risk Factors

描述（由申请人提供）：卵巢癌是妇女中第八大最常见的癌症，是妇女癌症相关死亡的第五大最常见原因，也是妇科癌症死亡的主要原因。1年和5年生存率分别只有76%和45%，这主要是由于大多数妇女在诊断时处于晚期。虽然口服避孕药（OCs）形式的外源性激素显然与上皮性卵巢癌（卵巢癌）的风险降低有关，但使用外源性激素的另一种主要形式，即绝经期激素治疗（HT）的情况不太清楚。我们最近的研究表明，虽然雌激素治疗（ET）的使用时间明显与卵巢癌的风险增加有关，但雌激素加黄体酮治疗（EPT）的风险在统计学上显著低于ET。这一观察结果揭示了有关卵巢癌病因的基本问题：如果黄体酮可以改善雌激素的一些风险诱导特性，那么更大的黄体酮剂量有什么影响？剂量计划是否重要？如果黄体酮确实可以阻断雌激素对卵巢癌风险的影响这可能表明OCs和怀孕的机制，两者都比正常的黄体酮暴露量高，降低风险不是通过阻断排卵，而是通过增加黄体酮暴露量。同样相关的是，这些影响是否基于肿瘤的组织学亚型、最近使用或其他风险因素（如肥胖）的存在而有所不同。这些问题需要回答。除了HT，还有其他一些疑似/已知的危险因素需要进一步随访：子宫内膜异位症、不孕症和子宫切除术。卵巢癌风险与这些暴露的特定参数（如子宫内膜异位症的发生时间、不孕症的原因、子宫切除术的时间）、相关的环境修饰因素（如卵巢癌使用史）和肿瘤特征之间的关系需要解决。从历史上看，这些分析是非常困难的，因为单独的研究没有足够的动力，但卵巢癌协会联盟（OCAC）的成员已经认识到需要合作，汇集数据来解决这些问题。来自世界各地的15个研究小组已经同意提供超过13,000例卵巢癌病例和17,000例健康对照的数据，以全面解决激素疗法、子宫内膜异位症、不孕症和子宫切除术与卵巢癌风险的作用，从而阐明该疾病的病因。重要的是，由于OCAC的基础设施已经建立，调查人员有合作的记录，因此这项工作可以高效和经济地进行。公共卫生相关性：卵巢癌是妇女第八大最常见癌症，是妇女癌症相关死亡的第五大最常见原因，也是妇科癌症死亡的主要原因；1年和5年的存活率分别只有微不足道的76%和45%。我们将对现有数据进行汇总分析，使用来自世界各地15个小组的数据，涉及13000多例卵巢癌病例和17000名健康妇女，以回答有关卵巢癌风险的问题，以及以下感兴趣的暴露：更年期激素治疗、子宫内膜异位症、不孕症和子宫切除术。该项目将提供对卵巢癌的更好了解，这对于确定有风险的妇女和改善被诊断患有这种疾病的妇女的结局至关重要。

DESCRIPTION (provided by applicant): Ovarian cancer is the eighth most common cancer in women, the fifth most common cause of cancer-related death in women and the leading cause of gynecological cancer death. One- and five-year survival is only 76% and 45%, respectively, primarily due to the late stage at diagnosis for most women. While it is clear that exogenous hormones in the form of oral contraceptives (OCs) are associated with decreased risk of epithelial ovarian cancer (ovarian cancer), the situation with the other major form of exogenous hormone use, namely, menopausal hormone therapy (HT) is less clear. We have recently shown that while duration of estrogen therapy (ET) use is clearly associated with increased risk of ovarian cancer, estrogen plus progestin therapy (EPT) is associated with a statistically significant lower risk than ET. This observation brings to light fundamental questions with regard to the etiology of ovarian cancer: If a progestin can ameliorate some of the risk-inducing properties of estrogen, what effect does a larger progestin dose have and does dose scheduling matter? And, if it is true that progestins can block the effect of estrogen on ovarian cancer risk it might suggest that the mechanism through which both OCs and pregnancy, both of which create higher than normal exposure to progestins, decrease risk is not through blocking ovulation, but rather through the increased progestin exposure. Also relevant is whether these effects differ based on histological subtype of the tumor, recency of use, or presence of other risk factors such as obesity. These questions need to be answered. In addition to HT, there are several additional suspected/known risk factors which are in need of further follow-up: endometriosis, infertility and hysterectomy. The relationship between risk of ovarian cancer and specific parameters of these exposures (e.g., timing of endometriosis, reasons for infertility, timing of hysterectomy), environmental modifiers of the association (e.g., history of OC use), and tumor characteristics needs to be addressed. Historically these would have been very difficult analyses to undertake because individual studies are not adequately powered, but members of the Ovarian Cancer Association Consortium (OCAC) have recognized the need to work collaboratively to pool data to address such questions. Fifteen groups from around the world have agreed to contribute data on more than 13,000 ovarian cancer cases and 17,000 healthy controls to comprehensively address the role of HT, endometriosis, infertility and hysterectomy with ovarian cancer risk in order to shed light on the etiology of the disease. Importantly, because the infrastructure of the OCAC has already been established and the investigators have a track record of working together this work can be conducted efficiently and cost-effectively. PUBLIC HEALTH RELEVANCE: Ovarian cancer is the eighth most common cancer in women, the fifth most common cause of cancer-related death in women and the leading cause of gynecological cancer death; one- and five-year survival is a paltry 76% and 45%, respectively. We will conduct pooled analyses of existing data using data from 15 groups from around on the world on more than 13,000 ovarian cancer cases and 17,000 healthy women to answer questions about risk of ovarian cancer and the following exposures of interest: menopausal hormone therapy, endometriosis, infertility and hysterectomy. Gaining a better understanding of ovarian cancer, which this project will provide, is critical to identifying women at risk and for improving the outcome for women who are diagnosed with this disease.