MD Anderson Cancer Center EDRN- Clinical Validation Center for Early Detection of Ovarian Cancer with a multiple marker algorithm

摘要：肿瘤细胞减灭术和联合化疗的进展提高了5年生存率 但在过去两年中，治愈率基本保持不变， 几十年计算机模型表明，早期卵巢癌（I-II期）的检测可以提高卵巢癌的发病率。 治愈10- 30%。在两项主要试验中，采用两阶段策略，用贝叶斯分析法分析CA 125的升高值， 卵巢癌风险算法（ROCA）提示经阴道超声检查和异常成像提示 手术被证明具有足够的特异性，超过10%的阳性预测值（PPV）。在EDRN的支持下， 7，869名健康女性参加了正常风险卵巢癌筛查研究 （NROSS）在美国的11个不同地点进行了46，008次CA 125测定，在过去的21年中。 29例患者接受了17例卵巢癌的手术，其中12例（71%）为早期卵巢癌 I or II.此外，检测到4例早期子宫内膜癌，产生了用于检测癌症的PPV 的72%。不超过2-3个手术将需要检测每个卵巢癌病例。因为CA 125是 仅在80%的上皮性卵巢癌中表达，使用多个 生物标志物。在这个资助周期中，我们已经报道了HE 4，HE 4抗原-自身抗体复合物， 骨桥蛋白显著增强CA 125检测早期（I-II）疾病的敏感性， 开发了一种ROCA 2，包括所有4种生物标志物，并检测到先进的疾病1.4至4.8年前， 罗卡我们发现20-25%的卵巢癌患者抗TP 53自身抗体（AA）水平升高， 癌抗TP 53滴度在CA 125前12个月和诊断前22个月升高， CA 125没有增加。在与弗雷德哈钦森癌症中心的研究人员组成的EDRN联盟中， 亚利桑那州立大学和马萨诸塞州总医院，我们比较了5种抗TP 53自身抗体 分析，发现RAPID分析最敏感。大约28种不同的AA已在一个标准中进行了分析 一组952份血清，以鉴定可在早期疾病中检测到的三种-TP 53、CTAG 1和IL-8， 补体CA 125。在过去的二十年里，我们收集并保存了922份血液和774份组织。 卵巢癌患者初次手术时的样本。在过去的6.5年里， 从NROSS获得18，754份新的血清和血浆样本，并为11名患者提供血清/血浆样本 研究人员测试早期卵巢癌的生物标志物。我们已经发表了23篇同行评审的文章， 评论和评论。一个由36名调查员和工作人员组成的小组将实现3个具体目标：1）进行 NROSS 2试验，使用4-FU确定两阶段卵巢癌筛查策略的特异性和PPV 生物标志物ROCA 2和一组3种自身抗体; 2）评估多种生物标志物用于早期检测 在积极的二次探查手术中疾病的复发或持续;和3）维持和共享血清 和血浆库，以便于评估用于卵巢癌早期检测的新生物标志物。

ABSTRACT: 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%. In two major trials, a two-stage strategy where rising values of CA125 analyzed with a Bayesian Risk of Ovarian Cancer Algorithm (ROCA) prompted transvaginal sonography and abnormal imaging prompted surgery proved sufficiently specific to exceed a positive predictive value (PPV) of 10%. With support of the EDRN, 7,869 apparently healthy women have participated in the Normal Risk Ovarian Cancer Screening Study (NROSS) at 11 different sites in the United States with 46,008 CA125 determinations over the last 21 years. Twenty-nine patients have been referred for operations detecting 17 ovarian cancers with 12 (71%) in early stage I or II. In addition, 4 cases of early stage endometrial cancer were detected, yielding a PPV for detecting cancer of 72%. No more than 2-3 operations will be required to detect each case of ovarian cancer. As CA125 is expressed by only 80% of epithelial ovarian cancers, better sensitivity is likely to be achieved with multiple biomarkers. During this grant cycle we have reported that HE4, HE4 antigen-autoantibody complexes, and osteopontin significantly enhance the sensitivity of CA125 for detecting early stage (I-II) disease and have developed a ROCA2 that includes all 4 biomarkers and detects advanced disease 1.4 to 4.8 years earlier than ROCA. We have found elevated levels of anti-TP53 autoantibodies (AA) in 20-25% of patients with ovarian cancer. Titers of anti-TP53 rise 12 months prior to CA125 and 22 months prior to diagnosis in patients where CA125 does not increase. In an EDRN consortium with investigators from Fred Hutchinson Cancer Center, Arizona State University and the Massachusetts General Hospital, we have compared 5 anti-TP53 autoantibody assays and found the RAPID assay most sensitive. Some 28 different AA have been assayed in a standard panel of 952 sera to identify three - TP53, CTAG1, and IL-8 – that can be detected in early stage disease and complement CA125. Over the last two decades, we have collected and preserved 922 blood and 774 tissue samples at the time of initial surgery in patients with ovarian cancers. During the last 6.5 years we have banked 18,754 new serum and plasma samples from the NROSS and provided serum/plasma samples for 11 investigators to test biomarkers for early stage ovarian cancer. We have published 23 peer reviewed articles, reviews and commentaries. A team of 36 investigators and staff will pursue 3 Specific Aims: 1) to conduct the NROSS2 trial to determine the specificity and PPV of a two-stage ovarian cancer screening strategy using a 4 biomarker ROCA2 and a panel of 3 autoantibodies; 2) to evaluate multiple biomarkers for early detection of recurrence or persistence of disease at positive second look operations; and 3) to maintain and share a serum and plasma bank to facilitate evaluation of novel biomarkers for early detection of ovarian cancer.