FGFR2 MUTATIONS IN INTERMEDIATE RISK ENDOMETRIAL CANCERS

描述（由申请人提供）：子宫内膜癌是美国最常见的妇科恶性肿瘤。2007年，将诊断出大约39 800例新的子宫癌病例，7 400名妇女将死于这种疾病。美国的发病率是世界上最高的。幸运的是，大多数患有早期疾病的妇女单独手术（子宫切除术）是可以治愈的。子宫内膜癌患者的总体五年生存率估计为80-85%。尽管治愈率很高，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）此时不是很有效。复发后的中位生存期为10个月，复发患者的5年生存率<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理解，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，大约15%的子宫内膜样子宫内膜癌中存在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，可能被证明对子宫内膜癌的治疗有用。我们建议分析妇科肿瘤学小组协议210中的子宫内膜癌，以更好地了解FGFR2突变的临床意义以及FGFR2激活与DNA错配修复缺失之间的关系，DNA错配修复缺失是约30%子宫内膜样子宫内膜癌发生的关键早期事件。具体目标1：确定FGFR2突变在中高危子宫内膜癌中的作用。我们将通过直接测序和测试靶向突变检测来评估GOG-210约550个子宫内膜样癌样本的突变率和谱。我们将确定FGFR2突变与临床病理变量（包括无病生存和总生存）之间的关系。特异性目标2：确定DNA错配修复缺失与FGFR2突变之间的关系。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常见。了解癌症中哪些通路失调对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抑制剂是否可用于治疗子宫内膜癌患者的关键的第一步。公共卫生相关性：我们的合作小组最近确定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活性的生物制剂已经进入临床试验。在本提案中，我们将评估nci资助的妇科肿瘤学小组协议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频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中的重要临床变量和其他分子异常相关。这些研究是考虑抗fgfr2治疗子宫内膜癌的重要的第一步。

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.