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Randomized Controlled Trial
. 2025 Feb:112:105554.
doi: 10.1016/j.ebiom.2024.105554. Epub 2025 Jan 13.

Estimating the ovarian cancer CA-125 preclinical detectable phase, in-vivo tumour doubling time, and window for detection in early stage: an exploratory analysis of UKCTOCS

Jacob S Bedia  1 , Ian J Jacobs  2 , Andy Ryan  3 , Aleksandra Gentry-Maharaj  4 , Matthew Burnell  3 , Naveena Singh  5 , Ranjit Manchanda  6 , Jatinderpal K Kalsi  7 , Anne Dawnay  8 , Lesley Fallowfield  9 , Alistair J McGuire  10 , Stuart Campbell  11 , Mahesh K B Parmar  3 , Usha Menon  3 , Steven J Skates  12
Affiliations
Randomized Controlled Trial

Estimating the ovarian cancer CA-125 preclinical detectable phase, in-vivo tumour doubling time, and window for detection in early stage: an exploratory analysis of UKCTOCS

Jacob S Bedia et al. EBioMedicine. 2025 Feb.

Abstract

Background: The ovarian cancer (OC) preclinical detectable phase (PCDP), defined as the interval during which cancer is detectable prior to clinical diagnosis, remains poorly characterised. We report exploratory analyses from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Methods: In UKCTOCS between Apr-2001 and Sep-2005, 101,314 postmenopausal women were randomised to no screening (NS) and 50,625 to annual multimodal screening (MMS) (until Dec-2011) using serum CA-125 interpreted by the Risk of Ovarian Cancer Algorithm (ROCA). All provided a baseline blood sample. Women with invasive epithelial OC diagnosed between randomisation and trial censorship (Dec-2014) in the MMS and NS arms with two or more CA-125 measurements, including one within two years of diagnosis were included. OC-free women (2:1 to cases) from the MMS arm provided information on baseline CA-125 distribution. CA-125 measurements were obtained from MMS results, secondary analysis of baseline samples, and medical records. PCDP duration and in-vivo tumour doubling time were estimated using the change-point model underlying ROCA. Early-stage (Stage I and II) PCDP was estimated from a Bayesian model for the probability of early stage given a CA-125 measurement.

Findings: Of 541 women (2371 CA-125 measurements) with high-grade serous cancer (HGSC), 93% (504/541) secreted CA-125 into the circulation. Median CA-125 PCDP duration for clinically-diagnosed HGSC was 15.2 (IQR 13.1-16.9, 95% IPR 9.6-21.8) months, of which 11.9 (IQR 10.5-13.1, 95% IPR 7.5-16.5) months was in early stage. The median HGSC in-vivo tumour doubling time for cancers secreting CA-125 was 2.9 (IQR 2.3-3.7, 95% IPR 1.5-7.6) months.

Interpretation: We report a comprehensive characterisation of the OC CA-125 PCDP. The 12-month window for early-stage detection and short tumour doubling time of HGSC provide a benchmark for researchers evaluating novel screening approaches including need to reduce diagnostic workup interval. Equally the findings provide urgent impetus for clinicians to reduce intervals from presentation to treatment onset.

Funding: NCI Early Detection Research Network, Concord (MA) Detect Ovarian Cancer Early Fund, MRC Clinical Trials Unit at UCL Core Funding.

Keywords: Biomarker; Blood; CA-125 antigen; Carcinoma; Early detection of cancer∗; Early diagnosis; Epidemiology; Longitudinal studies; Mass screening; Natural history of cancer; Ovarian epithelial∗; Ovarian neoplasms∗; Preclinical detectable phase; Preclinical history of cancer; UKCTOCS.

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Conflict of interest statement

Declaration of interests UM had stock ownership, awarded by University College London (UCL) until October, 2021, in Abcodia, which holds the licence for risk of ovarian cancer algorithm (ROCA). UM and MKBP have received grants and AG-M, AR, and MB have been funded by grants from the Medical Research Council (MRC), Cancer Research UK, the National Institute for Health Research (NIHR), and The Eve Appeal. UM and AG-M have also received grants from the Australian National Health and Medical Research Council (NHMRC), MRC Proximity to Discovery Industrial Connectivity Award, and Innovate UK Grant. UM and AG-M report research collaboration contracts with iLOF (intelligent Lab on Fiber), Micronoma, Imperial College London, Dana Farber Cancer Institute (DFCI), QIMR Berghofer Medical Research Institute, Mercy Bioanalytics, and University of Innsbruck. UM additionally reports research collaboration contracts with RNA Guardian and DFCI. UM holds patent number EP10178345.4 for Breast Cancer Diagnostics. UM received an honorarium for a lecture from the New York Obstetrical Society (USA), and was reimbursed for travel and accommodations by New York Obstetrical Society. UM has also been a member of Tina's Wish Scientific Advisory Board (USA) and Research Advisory Panel, Yorkshire Cancer Research (UK). She has been a member of International Alliance for Cancer Early Detection (ACED); data monitoring committee for the mixed COVID-19 vaccines study in India; Trial Steering Committee, NOVEL; Trial Steering Committee, PROTECTOR. AG-M is a member of ACED Gynaecological Cancer Working Group and is ACED codirector Research Domain Trials. MKBP was an Associate Member of the EME funding committee while the project was active. SJS co-developed ROCA in 1995, which was patented by Massachusetts General Hospital, MA, USA, and Queen Mary University of London, London, UK, and is owned by these universities (the patent has expired). Massachusetts General Hospital and Queen Mary University of London granted a licence for the ROCA to Abcodia in 2014. SJS reports stock options from SISCAPA Assay Technologies for participation on a board. SJS received grants and JSB has been funded from the US National Cancer Institute. SJS additionally reports funding from Concord (MA) Detect Ovarian Cancer Early Fund and Mercy Bioanalytics. SJS participated in clinical and scientific advisory boards for Mercy BioAnalytics, SISCAPA Assay Technologies, and Guardant Health (for which he was paid consulting fees). IJJ reports grants from Eve Appeal Charity, MRC, Cancer Research UK, and NIHR during the conduct of the study. IJJ co-developed the ROCA in 1995. Massachusetts General Hospital and Queen Mary University of London granted a licence for the ROCA to Abcodia in 2014. IJJ was non-executive director, shareholder, and consultant to Abcodia and has rights to royalties from sales of the ROCA. IJJ founded (in 1985), was a trustee of (2012–14), and is now an Emeritus trustee (2015–present) of The Eve Appeal, one of the funding agencies for UKCTOCS. LF reports MRC funding for the psychosocial group of the UKCTOCS study 2001–13, paid to University of Sussex. AJM was a member of NIHR Health Technology Assessment and Efficacy and Mechanism Evaluation editorial board (2012–22). RM reports funding from The Eve Appeal, Rosetrees Charity, Barts Charity, Yorkshire Cancer Research, Ovacure, British Gynaecological Cancer Society, AstraZeneca, North East London Cancer Alliance, and GSK. RM reports consulting fees from Everything Genetics Limited. NS received honoraria from AstraZeneca–MSD and GSK for participation in advisory boards. All other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Diagram of cases diagnosed with invasive epithelial ovarian cancer in the multimodal and no screening arms of UKCTOCS and selection for analysis. Participants are grouped based on their estimated Risk of Ovarian Cancer as CA-125 secreting if risk is greater than 1 in 2000 and non-CA-125 secreting if their risk is less than 1 in 2000. Risk of ovarian cancer is computed using all available CA-125 levels. Cases diagnosed in the multimodal screening arm after screening concluded on 31-Dec-2011 are defined as clinically diagnosed. MMS = multimodal screening, NS = no screening, HGSC = high grade serous cancer.
Fig. 2
Fig. 2
Observed and estimated CA-125 secretion profiles for five ovarian cancer histotypes. a) Schematic of CA-125 secretion showing parameters estimated by the model underlying the Risk of Ovarian Cancer Algorithm (ROCA). Each blue diamond is a CA-125 measurement for that participant. The CA-125 scale is logarithmic, with a linear increase in the graph corresponding to an exponential increase in CA-125, equivalent to CA-125 doubling in a fixed period. The time for CA-125 to double estimates the tumour doubling time. The preclinical detectable phase duration starts when CA-125 levels increase above the participant's baseline and ends at diagnosis. b) Examples of CA-125 secreting and non-CA-125 secreting tumours from the multimodal screening arm for five ovarian cancer histotypes, with an overlay of the CA-125 profile estimated by the model underlying ROCA. PCDP = preclinical detectable phase.
Fig. 3
Fig. 3
High-grade serous cancer tumour doubling time and preclinical detectable phase duration. a) Histogram of tumour doubling times for 504 high grade serous tumours secreting CA-125. b) Histogram comparing preclinical detectable phase durations for 143 CA-125 secreting cases detected by screening and 335 CA-125 secreting cases that were clinically diagnosed.
Fig. 4
Fig. 4
CA-125 at diagnosis in clinically-diagnosed, early and late-stage high-grade serous cancer and probability of early-stage disease. a) Normalised density of CA-125 on the day of diagnosis for 38 early stage and 297 late-stage, clinically diagnosed cases. b) Curve showing probability of early-stage high grade serous cancer at 1000 CA-125 levels equally spaced on the log scale ranging from 10 U/ml to 100,000 U/ml. Shaded region denotes 95% interval.
See this image and copyright information in PMC

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