Human epididymal protein 4 (HE4) is a novel biomarker and a promising prognostic factor in ovarian cancer patients

Purpose of investigation: The aim of this work was to compare serum concentrations of HE4 in patients with benign and malignant epithelial tumors and to determine the association of preoperative concentrations of HE4 with some clinicopathologic factors. Methods. We enrolled 94 patients, including 39 females with freshly diagnosed ovarian cancer. HE4 concentrations were measured with ELISA HE4 ETA assay from Fujirebio Diagnostics. Results. Serum concentrations of HE4 differed significantly in patients with ovarian cancer (324.1 pM) compared with benign epithelial tumors (26.1 pM; p < 000.1). There was also a significant difference between HE4 concentrations at diagnosis of ovarian cancer (324.1 pM) and in patients with complete clinical remission (23.3 pM; p < 0.0001). Patients with poorly differentiated tumors had significantly higher concentrations of HE4. Preoperative HE4 levels were higher in patients in whom relapse was noted and who died before the end of the two-year follow-up period. Conclusion. On the basis of these findings and reports in the literature it appears likely that HE4 can complement CA125 in the monitoring of therapy in ovarian cancer and may also serve for prognostication.

[1] Rosen D., Wang L., Atkinson J., Yu Y., Lu K., Diamandis et al.: “Potential markers that complement expression of CA 125 in epithelial ovarian cancer”. Gynecol. Oncol., 2005, 99, 267.

[2] Hellstrom I., Heagerty P., Swisher E., Liu P., Jaffar J., Agnew K. et al.: “Detection of the HE 4 protein in urine as biomarker for ovarian neoplasms”. Cancer Letters, 2010, 296, 43.

[3] Moore R.G., Jabre-Raughley M., Brown A.K., Robison K.M., Miller M.C., Allard W.J. et al.: “Comparison of a novel multiple marker assay vs the risk of malignancy index for the prediction of epithelial ovarian cancer in patients with a pelvic mass”. Am. J. Obstet. Gynecol., 2010, 203, 1.

[4] Havrilesky L., Whitehead C., Rubatt J., Cheek R., Groeckle J., He Q. et al.: “Evaluation of biomarker panels for early stage ovarian cancer detection and monitoring for disease recurrence”. Gynecol. Oncol., 2008, 110, 374.

[5] Moore R.G., McMeekin D.S., Brown A.K., DiSilvestro P., Miller M.C., Allard W.J. et al.: “A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass”. Gynecol. Oncol., 2009, 112, 40.

[6] Kirchhoff C., Habben I., Ivell R., Krull N.: “A major human epididymis- specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors”. Biol. Reprod., 45, 350.

[7] Galgano M., Hampton G., Frierson H. Jr.: “Comprehensive analysis of HE 4 expression in normal and malignant human tissues”. Mod. Path., 2006, 19, 847.

[8] Drapkin R., Horsten H., Lin Y., Mok S., Crum Ch., Welch W. et al.: “Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas”. Cancer Res., 2005, 65, 2162.

[9] Gorp T., Cadron I., Despierre E., Daemen A., Leunen K., Amant F. et al.: “HE 4 and CA 125 as diagnostic test in ovarian cancer: prospective validation of the risk of ovarian malignancy algorithm”. Br. J. Cancer, 2011, 104, 863.

[10] Lowe K.A., Shah C., Wallace E., Anderson G., Paley P., McIntosh M. et al.: “Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy postmenopausal women at high-risk for ovarian cancer”. Cancer Epidemiol. Biomarkers Prev., 2008, 17, 2480.

[11] Hellstrom I., Raycraft J., Hayden-Ledbetter M., Ledbetter J.A., Schummer M., McIntosh M. et al.: “The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma”. Cancer Res., 2003, 63, 3695.

[12] Shah Ch., Lowe K., Paley P., Wallace E., Anderson G., McIntosh M.: “Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4 and CA 125”. Cancer Epidemiol Biomarkers Prev., 2009, 18, 1365.

[13] Kobel M., Kalloger S., Boyd N., McKinney S., Mehl E., Palmer Ch. et al.: “Ovarian carcinoma subtypes are different diseases: implications for biomarker studies”. PLoS Medicine, 2008, 5, 1749.

[14] Duffy M.J., Bonfrer J.M., Kulpa J., Rustin G.J., Soletormos G., Tuxen M.K., Zwirner M.: “CA 125 in ovarian cancer: European Group on Tumor Markers”. Int. J. Gynecol. Cancer, 2005, 15, 679.

[15] Medeiros L.R., Rosa D.D., da Rosa M.I., Bozzetti M.C.: “Accurancy of CA 125 level in the diagnosis of ovarian tumors : a quantitative systematic review”. Eur. J. Obstet. Gynecol. Reprod. Biol., 2009, 142, 99.

[16] Huhtinen K., Suvitie P., Hiissa J., Junnila J., Huvila J., Kujari: “Serum HE4 concentration differentiates malignant ovarian tumors from ovarian endometriotic cysts”. Br. J. Cancer, 2009, 100, 1315.

[17] Anastasi E., Granato T., Coppa A., Manganaro L., Giannini G., Comploj S.: “HE4 in the differential diagnosis of pelvic mass: a case report”. Int. J. Mol. Sci., 2011, 12, 627.

[18] Anastasi E., Granato T., Marchei G.G., Viggiani V., Colaprisca B., Comploj S. et al.: “Ovarian tumor marker HE 4 is differently expressed during the phases of the menstrual cycle in healthy young women”. Tumor Biol., 2010, 31, 411.

[19] Wang S., Dong L., Li H., Wang M.: “The application of HE 4 in diagnosis of gynaecological pelvic malignant tumor”. Clin. Oncol. Cancer Res., 2009, 6, 72.

[20] Anderson G., McIntosh M., Barnett M., Goodman G., Thorpe J., Bergan.: “Assessing lead time of selected ovarian cancer biomarkers: a nested case control study”. J. Natl. Cancer Inst., 2010, 102, 26.

[21] Andersen R., Goff B., Lowe K., Scholler N., Bergan L., Drescher Ch. et al.: “Use of a symptom index, CA 125 and HE4 to predict ovarian cancer”. Gynecol. Oncol., 2010, 116, 378.

[22] Anastasi E., Marchei G., Viggiani V., Gennarini G., Frati L., Reale M.: “HE4: a new potential early biomarker for the recurrence of ovarian cancer”. Tumor Biol., 2010, 31, 113.

[23] Paek J., Lee S.H., Yim G.W., Lee M., Kim Y.J., Nam E.J. et al.: “Prognostic significance of human epidydimis protein 4 in epithelial ovarian cancer”. Eur. J. Gynecol. Obstet. Reprod. Biol., 2011, in press.

[24] Steffensen K.D., Waldstrom M., Brandslund I., Jakobsen A.: “Prognostic impact of prechemotherapy serum levels of HER2, CA 125, and HE4 in ovarian cancer patients”. Int. J. Gynecol. Cancer, 2011, 21, 1040.

[25] Yamashita S., Tokuishi K., Hashimoto T., Moroga T., Kamei M., Ono K. et al.: “Prognostic significance of HE 4 expression in pulmonary adenocarcinoma”. Tumour Biol., 2011, 32, 265.