HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm

Abstract

Background:Recently, a Risk of Ovarian Malignancy Algorithm (ROMA) utilising human epididymis secretory protein 4 (HE4) and CA125 successfully classified patients as presenting a high or low risk for epithelial ovarian cancer (EOC). We validated this algorithm in an independent prospective study.Methods:Women with a pelvic mass, who were scheduled to have surgery, were enrolled in a prospective study. Preoperative serum levels of HE4 and CA125 were measured in 389 patients. The performance of each of the markers, as well as that of ROMA, was analysed.Results:When all malignant tumours were included, ROMA (receiver operator characteristic (ROC)-area under curve (AUC)=0.898) and HE4 (ROC-AUC)=0.857) did not perform significantly better than CA125 alone (ROC–AUC=0.877). Using a cutoff for ROMA of 12.5% for pre-menopausal patients, the test had a sensitivity of 67.5% and a specificity of 87.9%. With a cutoff of 14.4% for post-menopausal patients, the test had a sensitivity of 90.8% and a specificity of 66.3%. For EOC vs benign disease, the ROC–AUC of ROMA increased to 0.913 and for invasive EOC vs benign disease to 0.957.Conclusion:This independent validation study demonstrated similar performance indices to those recently published. However, in this study, HE4 and ROMA did not increase the detection of malignant disease compared with CA125 alone. Although the initial reports were promising, measurement of HE4 serum levels does not contribute to the diagnosis of ovarian cancer.

Tissue CA125 and HE4 Gene Expression Levels Offer Superior Accuracy in Discriminating Benign from Malignant Pelvic Masses

“…Our results are somewhat consistent with those of previous studies (Hellström et al, 2003;Moore et al, 2008;Huhtinen et al, 2009;Montagnana et al, 2009;Moore et al, 2009;Moore et al, 2010;Nolen et al, 2010;Bandiera et al, 2011;Molina et al, 2011;Park et al, 2011;Van Gorp et al, 2011;Karlsen et al, 2012;Park et al, 2012), which reported that serum CA125 and HE4 levels were significantly higher in ovarian cancer women than those in benign ovarian tumor women and in healthy women. In accordance with previous observations , our results showed that serum CA125 and HE4 levels were found to be related to FIGO stage with higher concentrations in late stages (stage III/IV) than in early stages (stage I/II).…”

“…There may be several explanations for the heterogeneity observed among previous studies, and in our opinion, the most intriguing are the differences in the study design, study population, demographic characteristics of patients, ovarian cancer prevalence, sample size, control group (healthy women or women with benign diseases), methods of measuring serum CA125 or HE4 levels (ELISA or chemiluminescent microparticle immunoassay) and cutoff values of CA125/HE4 assays (manufacturer or clinical practice). Furthermore, several studies did not take into account the effect of the uneven distribution of patients in pre-and post-menopausal status, histological subtypes and FIGO stages when interpreting the results of CA125 and HE4 measurements (Moore et al, 2009;Moore et al, 2010;Kim et al, 2011;Montagnana et al, 2011;Ruggeri et al, 2011;Van Gorp et al, 2011). Overall, each of these points theoretically represent a source of heterogeneity among studies likely influencing the markers' diagnostic performances.…”

“…Although several studies have reported that ROMA yielded a better diagnostic accuracy than either marker alone (Moore et al, 2008;Moore et al, 2009;Bandiera et al, 2011;Molina et al, 2011;Moore et al, 2011;Li et al, 2012;Ortiz-Muñoz et al, 2014;Fujiwara et al, 2015), other studies failed to demonstrate its superiority over CA125 or HE4 alone for assessing the risk of ovarian cancer (Montagnana et al, 2011;Van Gorp et al, 2011;Wang et al, 2014).…”

“…Although several meta-analyses have reported that HE4 had a better performance than CA125 for the diagnosis of ovarian cancer (Yu et al, 2012;Ferraro et al, 2013;Yang et al, 2013;Zhen et al, 2104), in other studies (Montagnana et al, 2009;Partheen et al, 2011;Van Gorp et al, 2011), it has been indicated that HE4 is not superior to CA125 in differentiating benign ovarian masses from malignant ovarian tumors.…”

Urinary Concentrations of Human Epidydimis Secretory Protein 4 (He4) in The Diagnosis of Ovarian Cancer: A Case-Control Study

“…Similarly, women with borderline ovarian tumors have lower serum HE4 concentrations than patients with invasive ovarian cancer. No differences have been identified in serum concentrations of HE4 in patients with various degrees of morphological grade ovarian cancers (van Gorp et al, 2011). Hellström et al demonstrated that the combination of HE4 and CA125 assay provides higher ovarian cancer diagnostic sensitivity and specificity than each biomarker alone (Hellström et al, 2003).…”