Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women

Background: Serum markers are used before pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies. Methods: We conducted a randomized controlled pilot trial to estimate surgical PPV of a -2 of 3 tests positive- screening rule, and to compare use of HE4 as a first-line (Arm 1) versus a second-line (Arm 2) screen, inwomenat high and elevated risk for epithelial ovarian cancer (EOC) at five study sites. Semiannual screening was offered to 208 women ages 25 to 80 years with deleterious BRCA germline mutations and to 834 women ages 35 to 80 years with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women ages 45 to 80 years (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm. Results: Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in 6 women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% confidence interval: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women(26 inArm1 and 11 inArm2).Onthe basis of 12womenwith at least 2 of 3 tests positive (CA125, HE4, or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2. Conclusions: Positive screens were more frequent when HE4 was included in the primary screen. Impact: HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen.