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The Prognostic and Predictive Value of Combined HE4 and CA-125 in Ovarian Cancer Patients
  1. Karina Dahl Steffensen, MD, PhD*,,
  2. Marianne Waldstrøm, MD,
  3. Ivan Brandslund, MD, DMSc,
  4. Max Petzold, PhD§ and
  5. Anders Jakobsen, MD, DMSc*,
  1. *Departments of Oncology,
  2. Departments of Pathology, and
  3. Departments of Clinical Biochemistry, Vejle Hospital, Vejle,
  4. Departments of Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark;
  5. §Departments of Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; and
  6. Departments of Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
  1. Address correspondence and reprint requests to Karina Dahl Steffensen, MD, PhD, Department of Oncology, Vejle Hospital, Kabbeltoft 25, DK-7100 Vejle, Denmark. E-mail:


Objective A risk-of-ovarian-malignancy algorithm (ROMA) based on human epididymis protein 4 (HE4) and CA-125 has been reported to categorize women with a pelvic mass into high or low risk of ovarian malignancy. Originally, the ROMA score was developed for diagnostic purposes and the clinical application of HE4 for other purposes such as a predictor of survival or platinum resistance has not been extensively investigated. The objective of the present study was to evaluate the prognostic importance of prechemotherapy combined levels of HE4 and CA-125 and prediction of platinum resistance. Furthermore, we wanted to investigate the dynamics of the markers during treatment.

Materials and Methods Serum from 137 patients with newly diagnosed serous ovarian cancer was analyzed for CA-125 and HE4 using ELISAs in a training data set. Patients with high levels (upper third percentiles) of both HE4 and CA-125 were classified as high-risk patients. Data were validated in an independent data set of an additional 94 patients. HE4 and CA-125 were also analyzed at all cycles of subsequent chemotherapy.

Results The combined score of HE4 and CA-125 was highly predictive of both progression-free and overall survival in univariate as well as multivariate survival analysis. Values in the upper third percentiles (66th) were significantly associated with decreased progression-free and overall survival in both the training and in the validation set (P < 0.05 in all analyses).

The positive predictive value in relation to platinum resistance was higher for the combination of markers than for the markers individually. The positive predictive values were 64.3% and 60.7% for combined CA-125/HE4 in the training and validation sets, respectively.

Conclusions The combination of HE4 and CA-125 levels at baseline just before initiation of chemotherapy was significantly associated with decreased progression-free and overall survival and to some extent with platinum resistance.

  • Ovarian cancer
  • HE4
  • CA-125
  • ROMA
  • Prognostic factor
  • Platinum resistance

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  • The study was supported by the Danish Gynecological Cancer Database, which contributed with delivery of clinical data. The study was supported by grants from Vejle Hospital and The Cancer Foundation.

  • The authors declare no conflicts of interest.

  • Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (

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