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HE4, Ovarian Cancer Monitoring

HE4, Ovarian Cancer Monitoring

Test Summary

HE4, Ovarian Cancer Monitoring


Clinical Use

  • Monitor for recurrence and disease progression in patients with epithelial ovarian cancer

Clinical Background

Ovarian cancer is the fifth most common cause of cancer-related death among women in the United States, with over 15,500 deaths and 22,280 new cases estimated for 2012.1 CA 125 is currently the serum marker most widely used to monitor therapeutic response and to detect disease recurrence in patients treated for epithelial ovarian cancer.2 The National Comprehensive Cancer Network (NCCN) recommends CA 125 measurement before each treatment cycle for women with elevated pretreatment levels.3 NCCN also recommends CA 125 measurement at each follow-up evaluation if the level was initially elevated.3 CA 125, however, is not elevated in all patients with epithelial ovarian cancer; thus, other markers have been sought.

Human epididymis protein 4 (HE4), a relatively new marker for ovarian carcinoma, is the product of the WFDC2 (HE4) gene that is overexpressed in patients with ovarian carcinoma.4,5 Using an immunoassay, a small study indicated comparable sensitivity for CA 125 and HE4 in postmenopausal women with ovarian cancer.6 A subsequent and larger study confirmed the sensitivity of HE4.7 Another study evaluated the utility of HE4 in the follow-up of 80 patients with ovarian cancer. This study indicated serial HE4 levels correlated with clinical status (progression vs no progression) in 70% (247/354) of the samples.

The HE4 enzyme immunoassay (EIA) used by Quest Diagnostics is FDA cleared as an aid in monitoring recurrence or progressive disease in patients with epithelial ovarian cancer.

Individuals Suitable for Testing

  • Women being treated for epithelial ovarian carcinoma


  • Enzyme immunoassay

  • Analytical sensitivity: 25 pM

  • Reportable range: 25 – 854 pM; if >854, a dilution will be performed and results reported up to
    85,400 pM

  • Aliases: human epididymis protein 4, WFDC2

Interpretive Information

Elevated HE4 levels are associated with ovarian cancer but are not disease-specific (Table 1). A change in HE4 level of 25% is considered significant.8 An increase of this magnitude suggests recurrence or disease progression, while a decrease of this magnitude suggests therapeutic response.

Falsely elevated or depressed values of HE4 may occur in samples containing human anti-mouse antibodies (HAMA). Levels of HE4 within the reference range do not preclude the presence of cancer, nor are elevated results an absolute indication of malignancy; thus, HE4 should not be used for cancer screening. HE4 should not be used for monitoring patients with mucinous or germ cell ovarian cancer.8 Results should be interpreted in conjunction with other clinical and laboratory findings.

Table 1. Distribution of HE4 in Health and Disease8
  Number of
Percent of Subjects
  150 pM 150.1–300 pM 300.1–500 pM >500 pM
Apparently Healthy Women          


76 95 4 0 1


103 94 5 0 1
Malignant Conditions          

Ovarian cancer

127 21 14 16 48

Breast cancer

46 87 9 4 0

Lung cancer

50 58 30 12 0

Endometrial cancer

116 74 13 3 9

Gastrointestinal cancer

56 84 14 0 2
Nonmalignant Conditions          


22 95 5 0 0

Benign gynecologic disease

347 93 5 0 1

Other benign disease

108 76 7 6 10


heart failure

96 78 17 2 3


  1. American Cancer Society. Cancer Facts and Figures.2012. Available at: http://www.cancer.org/Research/
    CancerFactsFigures/index. Accessed October 2, 2012.

  2. Duffy MJ, Bonfrer JM, Kulpa J, et al. CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer. 2005;15:679-691.

  3. NCCN Clinical Practice Guidelines in Oncology®. Ovarian Cancer. V1.2008. Available at: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed February 15, 2008.

  4. Ono K, Tanaka T, Tsunoda T, et al. Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Cancer Res. 2000;60:5007-5011.

  5. Welsh JB, Zarrinkar PP, Sapinoso LM, et al. Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. Proc Natl Acad Sci USA. 2001;98:1176-1181.

  6. Hellström I, Raycraft J, Hayden-Ledbetter M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63:3695-3700.

  7. Moore RG, Brown AK, Miller MC, et al. The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. Gynecol Oncol. 2008;108:402-408.

  8. HE4 EIA [package insert]. Malvern, PA: Fujirebio® Diagnostics, Inc. June, 2008.

Content reviewed 12/2012
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