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

 描述（由申请人提供）：细胞减灭术和联合化疗的进展提高了上皮性卵巢癌患者的5年生存率，但在过去20年中治愈率基本保持不变。计算机模型表明，早期（I-II）卵巢癌的检测可以提高10- 30%的治愈率。在一小部分CA 125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志物测量，然后进行TVS，已证明比单独使用任何一种方式更特异，更敏感。使用这种策略，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，只需3次手术即可检测出每例卵巢癌。在过去的13年里，我们的研究小组在4,904名绝经后妇女中进行了NROSS研究，这些妇女具有卵巢癌的平均风险。CA 125的年度测定值已通过Skates博士开发的卵巢癌风险算法（ROCA）进行分析。如果风险没有改变，妇女在一年内返回;如果它显着增加，进行TVS并将参与者转诊给妇科肿瘤学家;如果风险是中等的，则在3个月内重复CA 125。已经进行了15次手术，以检测10种卵巢癌。2例为交界性肿瘤，8例为浸润性肿瘤，其中8例（80%）为I期或II期。NROSS试验利用了由美国7个研究中心组成的协调良好的网络，在该网络中按照标准操作方案采集、处理和储存了22，981份血液样本。来自MDACC的术前标本已从502名卵巢癌妇女和737名良性疾病妇女中储存。这为评估新的生物标志物提供了宝贵的资源。由于CA 125仅在80%的上皮性卵巢癌中表达，因此需要额外的生物标志物来优化灵敏度。我们的研究小组发现，在UKCTOCS试验的样本中，HE 4和CA72.4可以检测到CA 125遗漏的16%的病例。肿瘤相关抗原的自身抗体显示出更大的前景。在常规诊断时，在20-25%的CA 125正常的患者中发现了针对TP 53的自身抗体水平升高。抗TP 53滴度在CA 125前13.5个月（平均值）和诊断前33个月（平均值）升高，而CA 125未升高的患者。目前，我们正在开发一种新的ROCA，其中包含CA 125，HE 4，CA72.4和抗TP 53自身抗体数据。一个由27名研究者组成的多学科团队将追求以下具体目标：1）进行筛选试验，以确定4种生物标志物ROCA（包括CA 125、HE 4、CA 72.4和抗TP 53自身抗体）在两阶段策略中的特异性和阳性预测值，用于早期检测处于平均疾病风险的绝经后妇女的卵巢癌; 2）维护和共享血清和血浆库，以促进对早期检测的新型生物标志物的评估; 3）与EDRN的其他中心合作，以评估用于卵巢癌早期检测的其他生物标志物。

 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.