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

摘要：细胞减灭术和联合化疗的进展提高了5年生存率。 在上皮性卵巢癌患者中，但治愈率在过去两年基本保持不变 几十年。计算机模型表明，在早期(I-II)发现卵巢癌可以提高卵巢癌的发生率 治愈率为10%-30%。在两个主要试验中，采用两阶段策略，其中CA125的值上升用贝叶斯分析 卵巢癌风险算法(ROCA)提示经阴道超声检查和异常成像提示 手术证明具有足够的特异性，超过了10%的阳性预测值(PPV)。在EDRN的支持下， 7869名表面健康的妇女参加了正常风险卵巢癌筛查研究 (NRoss)在过去21年中，在美国11个不同的地点进行了46,008次CA125测定。 29例患者转诊手术发现17例卵巢癌，其中12例(71%)处于早期 I或II。此外，4例早期子宫内膜癌被检测到，产生了用于检测癌症的PPV 72%。每个卵巢癌病例的检测需要不超过2-3次手术。和CA125一样 只有80%的上皮性卵巢癌表达，更好的敏感性可能是通过多次 生物标志物。在这个赠款周期中，我们已经报告了HE4、HE4抗原-自身抗体复合体，以及 骨桥蛋白显著提高CA125检测早期(I-II)疾病的敏感性 开发了一种ROCA2，它包括所有4个生物标记物，并在1.4至4.8年前检测到晚期疾病 罗卡。我们发现20-25%的卵巢疾病患者抗TP53自身抗体(AA)水平升高 癌症。在CA125前12个月和诊断前22个月的患者中，抗TP53滴度上升 CA125不增加。在EDRN与弗雷德·哈钦森癌症中心的研究人员组成的财团中， 亚利桑那州立大学和马萨诸塞州总医院，我们已经比较了5种抗TP53自身抗体 检测发现，快速检测最敏感。在一个标准中检测了大约28种不同的AA 由952份血清组成的小组，以确定三种-TP53，CTAG1和IL-8-在早期疾病和 补体CA125。在过去的二十年里，我们收集和保存了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，我们一直在 来自NROSS的18,754个新的血清和血浆样本，并为11个国家提供了血清/血浆样本 研究人员测试早期卵巢癌的生物标记物。我们发表了23篇同行评议的文章， 评论和评论。一个由36名调查人员和工作人员组成的团队将追求3个具体目标：1)进行 NROSS2试验确定卵巢癌两阶段筛查策略的特异性和PPV 生物标记物ROCA2和一组3种自身抗体；2)评估多个生物标记物早期检测 在积极的二次检查手术中疾病复发或持续；以及3)维持和共享血清 和血浆库，以促进对卵巢癌早期检测的新生物标志物的评估。

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.