Role of the Sex Hormones and Insulin/IGF-Axes in Endometrial Cancer Recurrence

描述（由申请人提供）：子宫内膜癌是美国女性最常见的妇科恶性肿瘤，每年有超过39,000例新病例。II期或更高阶段的子宫内膜癌在30%以上的病例中复发，大多数复发病例导致死亡。然而，关于子宫内膜癌复发的生物学因素知之甚少。我们推断，许多与子宫内膜癌初始发展相关的相同危险因素也可能代表复发的危险因素（例如，通过刺激残余肿瘤和癌前细胞的生长）。子宫内膜样腺癌（最常见的子宫内膜癌）的两个最强的危险因素是雌激素暴露和肥胖。事实上，高雌激素水平在肥胖的绝经后妇女中很常见，并且被认为部分解释了肥胖与ea的关系。高胰岛素血症在肥胖患者中也很常见，我们最近在妇女健康倡议（WHI）中进行的前瞻性研究发现，在控制了雌激素后，具有促丝分裂/抗凋亡活性的胰岛素与EA发生风险显著相关（风险比，最高至最低四分位数= 2.33;1.13-4.82）。我们还研究了胰岛素样生长因子- i （IGF-I）。igf - 1与胰岛素序列同源，具有有丝分裂性。然而，子宫和血清igf - 1水平受到不同机制的调节，它们是否相关尚不清楚。因此，值得注意的是，我们发现EA与血清中游离IGF-I水平呈反比关系，结果与大多数先前的横断面研究一致，并且可以反映血清中已知的IGF-I抗炎活性。这种间接影响与血清和子宫igf - 1水平或活性之间几乎没有相关性是一致的，这种可能性需要进一步研究。确定胰岛素、igf轴和性激素在EA复发中的作用具有重要的临床意义。首先，它可以提供一种将EA区分为预后亚类别的方法（例如，将患者分类为更积极或更少的治疗），其次，提高对这些致瘤途径的理解可能会导致新的治疗方法。因此，在妇科肿瘤组（GOG）的合作下，我们提出了第一个关于胰岛素、IGF和性激素轴及其与II-IV期EA复发关系的大型前瞻性研究。受试者将包括在GOG-0210中纳入的所有815例II-IV期EA，这是一项在治疗前纳入的子宫内膜癌患者的研究。预计超过170例ii至iv期EA病例会复发。预处理标本将用于解决以下目标。研究EA复发与以下因素的关系：(i)空腹血清胰岛素、总和游离IGF-I、IGF-II、IGFBP-1和-3、雌二醇、雌酮、孕酮和性激素结合球蛋白（SHBG）水平；（ii）肿瘤中IGF-I、IGF-II、IGFBP-1和-3 mRNA的表达（基于RT-PCR），以及胰岛素受体、IGF-I受体、雌激素受体、孕酮受体的表达（基于免疫组织化学）。最后，我们将（iii）测量患有和未患癌症的女性血清和组织IGF-I、IGF-II、IGFBP-1和-3的相关性。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in US women, with more than 39,000 new cases each year. Stage II or higher endometrial cancers recur in more than 30% of cases, and most recurrent cases result in death. However, little is known regarding the biologic factors that underlie endometrial cancer recurrence. We reason that many of the same risk factors associated with the initial development of endometrial cancer may also represent risk factors for recurrence (e.g., by stimulating the growth of residual tumor and pre-cancerous cells). Two of the strongest risk factors for endometrioid adenocarcinoma (EA), the most common form of endometrial cancer, are estrogen exposure and obesity. In fact, high estrogen levels are common in obese postmenopausal women, and are thought to partly explain the obesity-EA relationship. Hyperinsulinemia is also common in obese patients, and our recent prospective study in the Women's Health Initiative (WHI) found that insulin - which has mitogenic/anti-apoptotic activity - was significantly associated with risk of incident EA (hazard ratio, highest to lowest quartile = 2.33; 1.13-4.82), after controlling for estradiol. We also studied insulin-like growth factor-I (IGF-I). IGF-I shares sequence homology with insulin and is mitogenic. However, uterine and serum IGF-I levels are regulated by different mechanisms, and it is not known whether they are at all correlated. It is notable, therefore, that we found an inverse relation of EA with free IGF- I levels in serum, results that are in keeping with most prior cross-sectional studies, and could reflect the known anti-inflammatory activity of IGF-I in serum. An indirect effect such as this is consistent with there being little correlation between serum and uterine IGF-I levels or activity, a possibility that requires further study. Determining the role of insulin, the IGF-axis and sex hormones in EA recurrence has important clinical implications. First, it could provide a means of differentiating EA into prognostic subcategories (e.g., to triage patients into more or less aggressive therapy), and second, improved understanding of these tumorigenic pathways could lead to novel therapeutic approaches. Therefore, in collaboration with the Gynecologic Oncology Group (GOG), we propose the first large prospective study of the insulin, IGF and sex hormone axes and their associations with recurrence of stage II-IV EA. Subjects will include all of the 815 stage II-IV EA expected to be enrolled in GOG-0210, a study of endometrial cancer patients enrolled prior to treatment. More than 170 of the stage II-IV EA cases are expected to recur. Pretreatment specimens will be used to address the following aims. To study the associations of EA recurrence with: (i) fasting serum levels of insulin, total and free IGF-I, IGF-II, IGFBP-1 and -3, estradiol, estrone, progesterone and sex hormone binding globulin (SHBG); (ii) tumor expression of IGF-I, IGF-II, IGFBP-1 and -3 mRNA (based on RT-PCR), and of the insulin receptor, IGF-I receptor, estrogen receptor, progesterone receptor (based on immuno-histochemistry). Lastly, we will (iii) measure the correlations of serum and tissue IGF-I, IGF-II, IGFBP-1 and -3 in women with and without cancer. PUBLIC HEALTH RELEVANCE: Endometrial cancer is the most common gynecologic malignancy in women, and higher stage endometrial cancer is associated with high rates of recurrence and subsequent death. The proposed application will investigate the prognostic value of both serologic and tissue levels of sex hormones and insulin/IGF axis components in relation to endometrial cancer recurrence. The study will be conducted in a large, prospective cohort study of endometrial cancer (GOG-0210).