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.

NARRATIVE When ovarian cancer is diagnosed at an early stage, combination surgery and chemotherapy can cure 90% of women with disease contained in the ovary (stage I) and 70% with disease limited to the pelvis (stage II), but when disease has spread further, cure slips to 20% or less. Our group has shown that annual measurement of CA125 followed by ultrasound, and surgery, if indicated, can detect early stage (I, II) disease in 71% of patients with no more than two-three operations for each case detected, but a multi-marker algorithm is likely to be required to impact mortality. Our Clinical Validation Center will continue to collaborate and to provide specimens to EDRN BCCs and test whether annual measurement of four blood tests detects early stage cases in >70% of cases with an acceptable number of benign ovarian lesions.