MD Anderson Cancer Center EDRN- CVC for Early Detection of Ovarian Cancer

 描述(申请人提供)：细胞减少性手术和联合化疗的进展提高了上皮性卵巢癌患者的5年存活率，但治愈率在过去20年中基本保持不变。计算机模型表明，在早期(I-II)发现卵巢癌可以将治愈率提高10%-30%。在一小部分CA125升高的绝经后妇女中，随着时间的推移，连续使用血清生物标记物，然后使用TVS，已经证明比单独使用这两种方法都更特异和更敏感。使用这一策略，英国卵巢癌筛查合作试验(UKCTOCS)和美国正常风险卵巢癌筛查研究(NRoss)表明，检测出每个卵巢癌病例只需要3次手术。在过去的13年里，我们团队对4904名患有卵巢癌的绝经后妇女进行了nRoss研究。每年的CA125测定已经通过由Skates博士开发的卵巢癌风险算法(ROCA)进行了分析。如果风险没有变化，女性会在一年内回归；如果风险显著增加，就会进行TVS，并将参与者转介给妇科肿瘤医生；如果风险为中度，则在3个月内重复CA125。已经进行了15次手术来检测10例卵巢癌。两个是交界性肿瘤，8个是侵袭性肿瘤，其中8个(80%)处于I或II期。nRoss试验利用了一个由美国7个地点组成的协调良好的网络，这些地点已经按照标准操作规程获取、处理和存储了22981个血液样本。MDACC的术前样本来自502名卵巢癌患者和737名良性疾病患者。这为评价新的生物标志物提供了宝贵的资源。由于CA125只在80%的上皮性卵巢癌中表达，因此需要额外的生物标记物来优化敏感性。我们的团队发现，在UKCTOCS试验的样本中，HE4和CA72.4可以检测到CA125遗漏的16%的病例。抗肿瘤相关抗原的自身抗体显示出更大的希望。在常规诊断时CA125正常的患者中，有20%-25%的患者发现针对TP53的自身抗体水平升高。在CA125无升高的患者中，抗TP53抗体滴度在CA125前13.5个月(平均值)和确诊前33个月(平均值)升高。目前，我们正在开发一种新的ROCA，它融合了CA125、HE4、CA72.4和抗TP53自身抗体的数据。一个由27名研究人员组成的多学科团队将追求以下具体目标：1)进行一项筛查试验，以确定CA125、HE4、CA72.4和抗TP53自身抗体等4种生物标记物ROCA在两阶段策略中的特异性和阳性预测价值，以早期发现卵巢癌；2)维护和共享一个血清和血浆库，以便于对新的生物标记物进行早期检测；3)与EDRN的其他中心合作，评估更多用于卵巢癌早期检测的生物标记物。

 DESCRIPTION (provided by applicant): Advances in cytoreductive surgery and combination chemotherapy have improved 5-year survival in patients with epithelial ovarian cancer, but the rate of cure remains essentially unchanged over the last two decades. Computer models suggest that detection of ovarian cancer in early stage (I-II) could improve rates of cure by 10-30%. Sequential use of serum biomarkers measured over time followed by TVS in a small fraction of postmenopausal women with rising CA125 has proven more specific and more sensitive than either modality used alone. Using this strategy, the United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) and the Normal Risk Ovarian Cancer Screening Study (NROSS) in the United States have shown that only 3 operations are required to detect each case of ovarian cancer. Over the last 13 years, our group has conducted the NROSS study in 4,904 postmenopausal women at average risk for ovarian cancer. Annual determinations of CA125 have been analyzed by the Risk of Ovarian Cancer Algorithm (ROCA) developed by Dr. Skates. If the risk does not change, women return in a year; if it increases markedly, TVS is performed and participants are referred to a gynecologic oncologist; if the risk is intermediate CA125 is repeated in 3 months. Fifteen operations have been performed to detect 10 ovarian cancers. Two were borderline tumors and 8 were invasive with 8 of the 10 (80%) in Stage I or II. The NROSS trial has utilized a well-coordinated network of 7 sites in the United States where 22,981 blood samples have been obtained, processed and stored with standard operating protocols. Pre-operative specimens from MDACC have been banked from 502 women with ovarian cancer and 737 with benign disease. This has provided a valuable resource for evaluating new biomarkers. As CA125 is expressed by only 80% of epithelial ovarian cancers, additional biomarkers will be required to optimize sensitivity. Our group has found that HE4 and CA72.4 can detect 16% of the cases missed by CA125 in samples from the UKCTOCS trial. Autoantibodies to tumor associated antigens have shown even greater promise. Elevated levels of autoantibodies against TP53 have been found in 20-25% of patients with normal CA125 at the time of conventional diagnosis. Titers of anti-TP53 rise 13.5 months (mean) prior to CA125 and 33 months (mean) prior to diagnosis in patients who present without an increase in CA125. At present we are developing a new ROCA that incorporates CA125, HE4, CA72.4 and anti-TP53 autoantibody data. A multidisciplinary team of 27 investigators will pursue the following Specific Aims: 1) to conduct a screening trial to determine the specificity and positive predictive value for a 4 biomarker ROCA including CA125, HE4, CA72.4 and anti-TP53 autoantibodies in a two stage strategy for early detection of ovarian cancer in postmenopausal women at average risk for the disease; 2) to maintain and share a serum and plasma bank to facilitate evaluation of novel biomarkers for early detection; 3) to collaborate with other Centers in the EDRN to evaluate additional biomarkers for early detection of ovarian cancer.