Can ovarian cancer screening work? A secondary analysis of the UK collaborative trial of ovarian cancer screening

Background The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; 2001–2020) showed no reduction in disease mortality in its primary intervention arm using multimodal screening (MMS) with longitudinal Cancer Antigen 125 (CA125) and transvaginal ultrasound. Whether this null result reflects the stop-screen design, screening performance, or ovarian cancer natural history remains unclear. Methods Using individual-level screening and diagnosis data from the MMS arm, we estimated ovarian cancer natural history, focusing on high-grade serous ovarian cancer (HGSC), the most common and lethal subtype. We then simulated trial outcomes under (1) continued screening beyond the trial screening interval and (2) high sensitivity for early-stage detection over an extended time period. Results The estimated window for detecting early-stage HGSC under MMS was <6 months. Continued screening yielded at most a 15% relative mortality reduction. Achieving a ≥20% mortality reduction required extending the detectable early-stage window to 1 year and attaining ≥70% sensitivity during this period. Conclusion Current screening modalities offer a very limited opportunity to intercept HGSC at an early stage. Clinically effective ovarian cancer screening will require first- and second-line tests capable of detecting HGSC substantially earlier in its natural history.