Risk-stratified CA125 screening integrating CA125 trajectories, trajectory-specific progression and transvaginal ultrasound for ovarian cancer

Cancer antigen 125 (CA125) is widely used for screening ovarian cancer (OC), yet its effectiveness remains debated. Potential factors may include ineffective cut-off value for CA125 in screening, as well as a lack of consideration for CA125 trajectories and trajectory-specific progression. Based on data from multiple rounds of CA125 tests and transvaginal ultrasound (TVU) examinations conducted on 28,456 women in the PLCO Trial, time-dependent receiver-operating-characteristic curves (ROCs) and area-under-the-curves (tdAUCs) analyses were employed to identify the optimal CA125 cut-off values for OC screening. Participants were categorized into four CA125 trajectories: stable negative CA125 (CA125 ), loss of positive CA125 (CA125 ), stable positive CA125 (CA125 ), and gain of positive CA125 (CA125 ). The associations between different CA125 trajectories, trajectory-specific progression indicators, and OC risk were explored. The effectiveness of risk-stratified CA125 screening, incorporating CA125 trajectories, trajectory-specific progression, and TVU, was evaluated using hazard ratio and 95% confidence intervals [HR (95%CIs)], with adjustments for potential confounders. After a median follow-up of 14.8 years for OC incidence and 23.8 years for OC mortality, 250 OC cases and 218 OC deaths were identified. The tdAUC for 10-year OC incidence with CA125 was 0.663, with an optimal cut-off value of 13.00 U/ml. Trajectory analyses showed that both CA125 and CA125 were significantly associated with increased risks of OC incidence [HRs (95%CIs): 2.00(1.47-2.73) and 3.06(2.25-4.16)] and mortality [HRs (95%CIs):1.58(1.13-2.21) and 2.60(1.87-3.62)] compared to CA125 . Trajectory-specific progression analyses identified relative velocity as the optimal progression indicators for both CA125 and CA125 (tdAUCs: 0.712 and 0.767), with optimal cut-off values of 9% and 32% per year, respectively. Positive progression was associated with significantly increased risks of OC incidence [HRs (95%CI): 7.26(4.00-13.17) and 3.83(1.96-7.51) CA125 and CA125 ] and mortality [HRs (95%CI): 8.03(4.15-15.56) and 6.04(2.78-13.14)] compared to negative progression. Optimized risk-stratified CA125 screening, which integrated CA125 trajectories, trajectory-specific progression, and TVU, reduced missed OC by 3.6% and improved accuracy compared to traditional screening methods. Incorporating CA125 trajectories and trajectory-specific progression into screening protocols enhances the identificatio