Randomized Controlled Trial Using Novel Markers to Predict Malignancy in Elevated Risk Women

Nicole Urban, ScD - Fred Hutchinson Cancer Research Center
Beth Karlan, MD - Cedars Sinai Medical Center

Early detection, a key to improved outcomes for women with ovarian cancer, is a major focus of our research program. During the previous funding period we worked to recommend a set of markers and an algorithm that can be used in a clinical trial for ovarian cancer screening to prevent ovarian cancer from escaping early detection. Achievement of this goal required the development of a novel statistical model to identify promising markers, as well as the evaluation of several currently existing and novel markers using serum specimens from three separate studies for ovarian cancer screening.

To date, project investigators have successfully developed two algorithms that have been described in several publications (see list below). The first, the Parametric Empirical Bayes (PEB) Method, is used to screen for cancer using markers measured over time and tailors the screening decision rule to the individual woman. The second combines theoretical and practical work to characterize (1) the optimal method to combine two markers, and (2) a practical way to estimate this combination. Both algorithms have been employed to evaluate the performance of several ovarian cancer biomarker candidates.

The most promising of these markers is HE4, identified and developed by our group during our first SPORE funding cycle. We are now poised to evaluate HE4 in a prospective, randomized controlled trial (RCT). We will use an epithelial ovarian cancer risk model incorporating serum markers and other risk factors along with conventional pedigree and mutation data to select women for screening. For the prospective evaluation of HE4 we have assembled a team of experienced clinical investigators at four clinical sites including Beth Karlan, MD at Cedars-Sinai Medical Center (CSMC) in Los Angeles, Paula Hillard, MD at Stanford in Palo Alto, Pam Paley, MD at Swedish Cancer Institute (SCI) in Seattle, Melanie Palomares, MD at City of Hope (COH) in Duarte, California and Mary Daly, MD, PhD at Fox Chase Cancer Center (FCCC) in Philadelphia, Pennsylvania.

We will conduct a Phase I trial to compare two multimodal screening strategies. The first strategy (Arm 1) uses both CA125 and HE4 in a first-line screen to select women for imaging. The second strategy (Arm 2) uses CA125 alone as a first-line screen to select women for imaging and HE4 testing. Because CA125 and HE4 exhibit greater variability among women than within a woman over time, the parametric empirical Bayes (PEB) longitudinal algorithm will be used to interpret rise in either marker as a signal of disease in first-line screens (3). Surgical consult will be indicated if any 2 of the 3 modalities is positive. Three additional experimental markers will also be measured but will not be acted upon in the absence of compelling evidence in their favor. If one or more equally promising new markers emerges prior to or during the period of the study, those markers will be measured and, if evidence is sufficiently compelling, added as a first- or second-line screen.

Women aged 25-80 will be eligible for semi-annual screening if they have a documented deleterious mutation in BRCA1 or BRCA2. Women aged 35-80 will be eligible for semi-annual screening if they have another mutation or a pedigree suggestive of inherited susceptibility. Women aged 45-80 will be eligible for annual screening if they have serum marker levels or other risk factors conferring elevated risk. Although this is a RCT, as a Phase I trial it is intended to assess safety and feasibility. We will test the null hypotheses that the two screening strategies do not differ with respect to compliance with the screening protocol, surgical procedures performed per cancer detected, and cancer worry among women experiencing false positives.

For more information about participation in this study, please click here.

The study protocol is summarized in this PDF document.

For additional details about this trial, please visit

Other Research

Project 1
Project 2
Project 3
Project 4
Project 5
Clinical Core
Informatics Core
Specimen Core
Leadership Core

Project 1 Publications

1. Lowe KA, Andersen MR, Urban N, Paley P, Dresher CW, Goff BA. The temporal stability of the Symptom Index among women at high-risk for ovarian cancer. Gynecol Oncol. 2009 Aug;114(2):225-30. PMCID: PMC2736546

2. Shah CA, Lowe KA, Paley P, Wallace E, Anderson GL, McIntosh MW, Andersen MR, Scholler N, Bergan LA, Thorpe JD, Urban N, Drescher CW. Influence of Ovarian Cancer Risk Status on the Diagnostic Performance of the Serum Biomarkers Mesothelin, HE4, and CA125. Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1365-72. PMCID: PMC2714056

3. Lowe K, Shah C, Wallace E, Anderson G, Paley P, McIntosh M, Andersen M, Scholler N, Bergan L, Thorpe J, Urban N, Drescher C. Effects of Personal Characteristics on Serum CA125, Mesothelin, and HE4 Levels in Healthy Post-menopausal Women at High-Risk for Ovarian Cancer. Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2480-7. PMCID: PMC2632599

4. Andersen MR, Goff B, Lowe K, Scholler N, Bergan L, Urban N. Combining a symptoms index with CA125 to improve detection of ovarian cancer. Cancer. 2008 Aug 1;113(3):484-9. PMCID: PMC2734274

5. Palmer C, Duan X, Hawley S, Scholler N, Thorpe JD, Sahota RA, Wong MQ, Wray A, Bergan L, Drescher CW, McIntosh M, Brown P, Nelson B, Urban N. Systematic evaluation of candidate blood markers for detecting ovarian cancer. PLOS ONE. 2008 Jul 9;3(7):e2633. PMCID: PMC2440813

6. Urban N, Drescher C. Potential and limitations in early diagnosis of ovarian cancer. Advances in Experimental Medicine and Biology. 2008;622:3-14.

7. Pavelka JC, Li AJ, Karlan BY. Hereditary ovarian cancer--assessing risk and prevention strategies. Obstet Gynecol Clin North Am. 2007 Dec;34(4):651-65, vii-viii.

8. Scholler N, Urban N. CA125 in ovarian cancer. Biomarkers in Medicine. 2007 Dec;1(4):513-523.

9. Andersen M, Drescher C, Zheng Y, Bowen D, Wilson S, Young A, McIntosh M, Mahony B, Lowe K, Urban N. Changes in cancer worry associated with participation in ovarian cancer screening. Psycho-oncology. 2007; 16(9): 814-20.

10. Scholler N, Crawford M, Sato A, Drescher CW, O'Briant KC, Kiviat N, Anderson GL, Urban N. Bead-Based ELISA for Validation of Ovarian Cancer Early Detection Markers. Clin Cancer Res. 2006 Apr 1;12(7):2117-24.

11. Urban N, Drescher C. Current and future developments in screening for ovarian cancer. Women's Health. 2006; 2(5): 733-42.

12. Hellstrom I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M, Drescher C, Urban N, Hellstrom KE. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003 Jul 1;63(13):3695-700.

13. McIntosh MW, Urban N. A parametric empirical Bayes method for cancer screening using longitudinal observations of a biomarker. Biostatistics. 2003; 4:27-40.

14. McIntosh M, Urban N, Karlan B. Generating Longitudinal Screening Algorithms Using Novel Biomarkers for Disease. Cancer Epidemiol Biomarkers Prev. 2002 Feb1,;11(2):159-66.

15. Etzioni R, Urban N, Ramsey S, McIntosh M, Schwartz S, Reid B, Radich J, Anderson G, Hartwell L. The case for early detection. Nature Reviews Cancer. 2003; 3(4): 243-52.

16. Scholler N, Fu N, Yang Y, Ye Z, Goodman G, Hellstrom K, Hellstrom I. Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. Proc Natl Acad Sci U S A. 1999; 96(20): 11531-6.