Multi-Marker Longitudinal Algorithms Incorporating HE4 and CA125 in Ovarian Cancer Screening of Postmenopausal Women
Abstract
Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 longitudinal algorithm. Women (cases) with invasive tubo-ovarian cancer (WHO 2014) following outcome review with stored annual serum samples donated in the 5 years preceding diagnosis were matched 1:1 to controls (no invasive tubo-ovarian cancer) in terms of the number of annual samples and age at randomisation. Blinded samples were assayed for serum human epididymis protein 4 (HE4), CA72-4 and anti-TP53 autoantibodies. Multimarker method of mean trends (MMT) longitudinal algorithms were developed using the assay results and trial CA125 values on the training set and evaluated in the blinded validation set. The study set comprised of 1363 (2–5 per woman) serial samples from 179 cases and 181 controls. In the validation set, area under the curve (AUC) and sensitivity of longitudinal CA125-MMT algorithm were 0.911 (0.871–0.952) and 90.5% (82.5–98.6%). None of the longitudinal multi-marker algorithms (CA125-HE4, CA125-HE4-CA72-4, CA125-HE4-CA72-4-anti-TP53) performed better or improved on lead-time. Our population study suggests that longitudinal HE4, CA72-4, anti-TP53 autoantibodies adds little value to longitudinal serum CA125 as a first-line test in ovarian cancer screening of postmenopausal women.
Description
The analysis is part of PROMISE, which was funded through Cancer Research UK PRC Programme Grant A12677 and by The Eve Appeal. University College London investigators received support from the National Institute for Health Research University College London Hospitals Biomedical Research Centre and from MRC core funding (MR_UU_12023). UKCTOCS was core funded by the Medical Research Council (G9901012 and G0801228), Cancer Research UK (C1479/A2884), and the Department of Health with additional support from the Eve Appeal. J.F.T. received support from CRUK Early Detection Committee Project Award (C12077/A26223). S.J.S. received additional support from an NCI Early Detection Research Network grant (CA152990). R.C.B. was supported by funds from the Early Detection Research Network (5 U01 CA200462-02) and the MD Anderson Ovarian SPOREs (P50 CA83639 and P50 CA217685), National Cancer Institute, Department of Health and Human Services, the Cancer Prevention Research Institute of Texas (RP101382 and RP160145), Golfer’s Against Cancer, the Mossy Foundation, the Roberson Endowment, National Foundation for Cancer Research, The K Yao Foundation, UT MD Anderson Women’s Moon Shot and generous donations from Stuart and Gaye Lynn Zarrow. A.Z. acknowledges support by MRC grant MR/R02524X/1 and the grant of the Ministry of Education and Science of the Russian Federation Agreement No. 074-02-2018-330.
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