No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting

Gynecol Oncol. 2011 Jun 1;121(3):487-91. doi: 10.1016/j.ygyno.2011.02.022. Epub 2011 Mar 21.


Objective: About 70% of epithelial ovarian cancer patients (EOC) are diagnosed at advanced stage with a five-year survival rate of only 30%. Whilst CA125 detects peritoneally-spread disease, it has limited sensitivity for early cancers, many of which are potentially curable.

Methods: We compared the new commercially available tumor marker HE4 with CA125 individually, in combination, within the risk of malignancy index (RMI) and the newly defined risk of malignancy algorithm (ROMA). Our prospectively-collected cohort of 160 patients consisted of healthy controls, benign diseases, and borderline tumors/adenocarcinomas of ovarian, tubal, peritoneal and endometrial origin. HE4 and CA125 were measured in serum using standardized ELISA.

Results: Both markers showed similar diagnostic performance in the detection of EOC at clinically defined thresholds (CA125 35U/ml; HE4 70pM) but HE4 was not elevated in endometriosis. Comparison of non-malignant diagnoses (n=71) versus early stage ovarian and tubal cancers (n=19) revealed that HE4 and ROMA displayed the best diagnostic performance (AUC 0.86/0.87, specificity 85.9%/87.3% and sensitivity 78.9%/78.9%, respectively). Whilst RMICA125 detects peritoneal cancer better than all other models (AUC 0.99, specificity 97.2%, sensitivity 80.0%), there is no other detection benefit from RMI compared to HE4 alone or included in ROMA.

Conclusions: The major advantage of HE4 lies in its specificity and improved detection of borderline tumors and early stage ovarian and tubal cancers. HE4 is superior to CA125 with or without RMI and ROMA indices. However, we see no benefit from combining both markers in clinical practice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / blood*
  • CA-125 Antigen / blood*
  • Carcinoma, Ovarian Epithelial
  • Cohort Studies
  • Enzyme-Linked Immunosorbent Assay
  • Epididymal Secretory Proteins / analysis*
  • Female
  • Humans
  • Membrane Proteins / blood*
  • Middle Aged
  • Neoplasms, Glandular and Epithelial / blood
  • Neoplasms, Glandular and Epithelial / diagnosis
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / blood
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / pathology
  • Sensitivity and Specificity
  • beta-Defensins


  • Biomarkers, Tumor
  • CA-125 Antigen
  • DEFB126 protein, human
  • Epididymal Secretory Proteins
  • MUC16 protein, human
  • Membrane Proteins
  • beta-Defensins