We propose to conduct a randomized controlled trial (RCT) to compare safety, feasibility and positive predictive value (PPV) of two ovarian cancer screening strategies, one using CA125 and HE4 together as a first-line screen, the other introducing HE4 as a second-line screen. Women aged 35-80 will be eligible if they are at elevated risk based on a documented mutation in BRCA1 or BRCA2 or a pedigree suggestive of inherited susceptibility;800 such women will be enrolled and screened semi-annually. Women aged 50-80 will be eligible if they have elevated risk based on a previously developed OvCaRisk model;400 such women will be enrolled and screened annually. We will interpret serum markers using the previously developed parametric empirical Bayes (PEB) longitudinal algorithm (above a threshold corresponding to 90%, 95% or 99% specificity) to take advantage of rise in a marker as a signal of disease, a phenomenon that has been well documented. We will target a positive predictive value of 10% in both arms, corresponding to a ratio of 10 surgeries per cancer detected.
In Aim 1 we will document protocol-indicated surgical procedures and malignancies detected in order to rule out a ratio of surgeries to malignancies greater than 20.
In Aim 2 we will document compliance with first- and second-line screens and test the null hypothesis that compliance does not differ between the two arms.
In Aim 3 we will document effects on health-related quality of life (HRQOL) and test the null hypotheses that 1) effects on HRQOL do not differ between the two arms and 2) effects on cancer worry do not differ between women who do and do not experience a false-positive first-line screen. Our goal is that the results of this RCT together with results of ongoing large efficacy trials will lead to clinical implementation of screening using novel markers within 5 years. We have partnered with Abbott Diagnostics and the Canary Foundation to accelerate translation. Four clinical centers (Swedish Medical Cancer, Cedars-Sinai, Stanford and City of Hope) will participate, and participation will be offered to all Ovarian SPORE institutions. Data will also support analyses ofthe cost- effectiveness of screening using each strategy, and estimation of the costs of conducting a full-scale efficacy trial should such a trial be required in the future.

Public Health Relevance

This project will introduce HE4 as an early detection and diagnostic marker for the first time in a prospective clinical trial. We will denhonstrate and evaluate better strategies than are currently used for screening high- risk women. Clinical implementation may follow without the need for another large trial, by combining data from this study with reports from ongoing efficacy trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA083636-15
Application #
8523015
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$138,833
Indirect Cost
$41,441
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Wang, Yifan; Krais, John J; Bernhardy, Andrea J et al. (2016) RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance. J Clin Invest 126:3145-57
Norquist, Barbara M; Harrell, Maria I; Brady, Mark F et al. (2016) Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol 2:482-90
Yu-Rice, Yi; Edassery, Seby L; Urban, Nicole et al. (2016) Selenium Binding Protein 1 autoantibodies in ovarian disorders and ovarian cancer. Reproduction :
Yumul, Roma; Richter, Maximilian; Lu, Zhuo-Zhuang et al. (2016) Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models. Hum Gene Ther 27:325-37
Wang, Yifan; Bernhardy, Andrea J; Cruz, Cristina et al. (2016) The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin. Cancer Res 76:2778-90
Andersen, M Robyn; Thorpe, Jason; Buist, Diana S M et al. (2016) Cancer Risk Awareness and Concern among Women with a Family History of Breast or Ovarian Cancer. Behav Med 42:18-28
Buas, Matthew F; Gu, Haiwei; Djukovic, Danijel et al. (2016) Identification of novel candidate plasma metabolite biomarkers for distinguishing serous ovarian carcinoma and benign serous ovarian tumors. Gynecol Oncol 140:138-44
Elias, Kevin M; Emori, Megan M; Westerling, Thomas et al. (2016) Epigenetic remodeling regulates transcriptional changes between ovarian cancer and benign precursors. JCI Insight 1:
Gregory, Mark T; Bertout, Jessica A; Ericson, Nolan G et al. (2016) Targeted single molecule mutation detection with massively parallel sequencing. Nucleic Acids Res 44:e22
Bernards, Sarah S; Norquist, Barbara M; Harrell, Maria I et al. (2016) Genetic characterization of early onset ovarian carcinoma. Gynecol Oncol 140:221-5

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