Multi-Marker Longitudinal Algorithms Incorporating HE4 and CA125 in Ovarian Cancer Screening of Postmenopausal Women

Aleksandra Gentry-Maharaj; Oleg Blyuss; Andy Ryan; Matthew Burnell; Chloe Karpinskyj; Richard Gunu; Jatinderpal K Kalsi; Anne Dawnay; Ines P Marino; Ranjit Manchanda; Karen Lu; Wei-Lei Yang; John F Timms; Max Parmar; Steven J Skates; Robert C Bast Jr; Ian J Jacobs; Alexey Zaikin; Usha Menon

doi:10.3390/cancers12071931

Multi-Marker Longitudinal Algorithms Incorporating HE4 and CA125 in Ovarian Cancer Screening of Postmenopausal Women

Cancers (Basel). 2020 Jul 17;12(7):1931. doi: 10.3390/cancers12071931.

Authors

Aleksandra Gentry-Maharaj¹, Oleg Blyuss^{2

3}, Andy Ryan^{1

4}, Matthew Burnell¹, Chloe Karpinskyj¹, Richard Gunu⁴, Jatinderpal K Kalsi⁴, Anne Dawnay⁵, Ines P Marino⁶, Ranjit Manchanda^{1

7

8}, Karen Lu⁹, Wei-Lei Yang⁹, John F Timms⁴, Max Parmar¹, Steven J Skates¹⁰, Robert C Bast Jr⁹, Ian J Jacobs^{4

11}, Alexey Zaikin^{3

4

12

13}, Usha Menon¹

Affiliations

¹ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, London WC1V 6LJ, UK.
² School of Physics, Astronomy and Mathematics, University of Hertfordshire, Hatfield AL10 9AB, UK.
³ Department of Paediatrics and Paediatric Infectious Diseases, Sechenov First Moscow State Medical University, Moscow 119991, Russia.
⁴ Department of Women's Cancer, Institute for Women's Health, University College London, London WC1E 6BT, UK.
⁵ Clinical Biochemistry, Barts Health NHS Trust, London E1 8PR, UK.
⁶ Department of Biology and Geology, Physics and Inorganic Chemistry, Universidad Rey Juan Carlos, 28933 Madrid, Spain.
⁷ Wolfson Institute of Preventive Medicine, Barts CRUK Cancer Centre, Queen Mary University of London, London EC1M 6BQ, UK.
⁸ Department of Gynaecological Oncology, St Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK.
⁹ University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹¹ Department of Women's Health, University of New South Wales, Sydney 2052, Australia.
¹² Department of Applied Mathematics, Lobachevsky University of Nyzhniy Novgorod, Nizhniy Novgorod 603105, Russia.
¹³ Department of Mathematics, University College London, London WC1H 0AY, UK.

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.

Keywords: CA125; HE4; MMT; UKCTOCS; ovarian cancer; postmenopausal women; screening.

Abstract

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