FGFR2 MUTATIONS IN INTERMEDIATE RISK ENDOMETRIAL CANCERS

描述(申请人提供)：子宫内膜癌是美国最常见的妇科恶性肿瘤。2007年将诊断出约39800例新的子宫癌病例，7400名妇女将死于这种疾病。美国是世界上发病率最高的国家之一。幸运的是，大多数患有早期疾病的妇女只需手术(子宫切除术)就可以治愈。子宫内膜癌患者的总体五年存活率估计为80%-85%。尽管治愈率很高，但子宫内膜癌仍然是一种具有临床挑战性的疾病。对于晚期、进展性或复发性疾病的妇女，辅助治疗(放射、激素、化疗或联合治疗)目前还不是很有效。复发后的中位生存期为10个月，复发患者的5年生存率为15%。晚期和复发子宫内膜癌的有效治疗方法仍有待确定。基于对疾病潜在原因的了解，新的生物或靶向治疗有望为患有子宫内膜癌的妇女带来更好的结果。我们最近确定，在大约15%的子宫内膜样癌中存在FGFR2癌基因的激活突变。抗FGFR疗法已经在其他恶性肿瘤的临床试验中，并可能被证明对治疗子宫内膜癌有用。我们建议从妇科肿瘤组协议210分析子宫内膜癌，以更好地了解FGFR2突变的临床意义以及FGFR2激活和DNA错配修复丢失之间的关系，DNA错配修复丢失是大约30%的子宫内膜样癌发生的关键早期事件。提出了两个具体目标：具体目标1：确定FGFR2突变在中高危子宫内膜癌中所起的作用。我们将通过直接测序和对来自GOG-210的550例子宫内膜样癌标本进行靶向突变检测，来评估突变的频率和谱。我们将确定FGFR2突变与临床病理变量的关系，包括无病和总存活率。特异性目标2：确定DNA错配修复缺失与FGFR2突变的关系。我们的初步研究表明，FGFR2突变可能在缺乏DNA错配修复的肿瘤中更为常见。了解哪些途径在癌症中处于失控状态，对于开发生物疗法至关重要。了解FGFR2突变在子宫内膜癌中的临床意义是确定FGFR抑制剂是否对治疗子宫内膜癌患者有用的关键的第一步。公共卫生相关性：我们的合作小组最近发现，成纤维细胞生长因子受体2(FGFR2)受体酪氨酸激酶基因的激活突变在子宫内膜癌中很常见。FGFR2基因产物是一个潜在的治疗靶点，几种具有抗FGFR2活性的生物制品已经在临床试验中。在这项提案中，我们将评估NCI资助的妇科肿瘤组协议书210“子宫内膜癌的分子分期研究”中FGFR2突变的子宫内膜癌。我们将确定突变的频率和谱，以及突变与结果之间的关系。此外，我们将确定FGFR2突变如何与子宫内膜癌的重要临床变量和其他分子异常有关。这些研究是考虑抗FGFR2治疗子宫内膜癌的重要第一步。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in the United States. Approximately 39,800 new cases of cancer of the uterine corpus will be diagnosed and 7,400 women will die of this disease in 2007. The incidence in the United States is among the highest in the world. Fortunately, most women present with early stage disease and surgery alone (hysterectomy) is curative. The overall five-year survival rate for endometrial cancer patients is estimated at 80-85%. Despite the high cure rate, endometrial cancer remains a clinically challenging disease. Adjuvant therapies (radiation, hormonal, chemotherapy, or combinations) for women with advanced stage, progressive or recurrent disease are not very effective at this time. The median survival after recurrence is ten months and the five-year survival for patients who have recurred is <15%. Effective treatments for advanced and recurrent endometrial carcinoma remain to be defined. New biologic or targeted therapies based on an understanding of the underlying causes of disease hold promise for better outcomes for women with endometrial cancer. We recently determined activating mutations in the FGFR2 oncogene are present in approximately 15% of endometrioid endometrial cancers. Anti-FGFR therapeutics are already in clinical trails for other malignancies and may prove useful in the treatment of endometrial cancers. We propose to analyze endometrial cancers from the Gynecologic Oncology Group Protocol 210 to better understand the clinical significance of FGFR2 mutations and the relationship between activation of FGFR2 and loss of DNA mismatch repair, a key early event in the initiation of ~30% of endometrioid endometrial cancers. Two specific aims are proposed: Specific Aim 1: Determine the role FGFR2 mutations play in intermediate and high risk endometrial cancers. We will assess the rate and spectrum of mutations by direct sequencing and test targeted mutation detection in ~550 endometrioid cancer specimens from GOG-210. We will determine the relationship between FGFR2 mutation and clinicopathologic variables including disease-free and overall survival. Specific Aim 2: Determine the relationship between loss of DNA mismatch repair and FGFR2 mutation. Our preliminary studies suggest FGFR2 mutation may be more common in tumors lacking DNA mismatch repair. Understanding what pathways are dysregulated in cancers will be critical to developing biologic therapies. Understanding of the clinical significance of FGFR2 mutations in endometrial cancer is a critical first step towards determining whether FGFR inhibitors could be useful in treating patients with endometrial cancer. PUBLIC HEALTH RELEVANCE: Our collaborative group recently determined activating mutations in the fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinase gene are frequent in uterine endometrial cancers. The FGFR2 gene product is a potential therapeutic target, with several biologics with activity against FGFR2 already in clinical trials. In this proposal we will evaluate endometrial cancers from the NCI-funded Gynecologic Oncology Group Protocol 210 "A molecular staging study of endometrial carcinoma" for mutations in FGFR2. We will determine the frequency and spectrum of mutations and the relationship between mutations and outcome. Furthermore, we will determine how FGFR2 mutations are related to important clinical variables and other molecular abnormalities in endometrial cancers. These studies are an important first step in considering anti-FGFR2 treatments for endometrial cancer.