Biomaker, Carbohydrate antigen125, HE4, Human epididymis protein 4, Ovarian cancer
Citation Information :
Singh S, Jyala NS, Kumar U, Kumari R. Serum Human Epididymus Protein-4 (HE4) as a Biomarker in Ovarian Cancer and its Comparison with CA-125 in Benign and Malignant Cases. Indian J Med Biochem 2019; 23 (2):242-246.
Introduction: Ovarian cancer is the third leading site of cancer among women in India. 70% of ovarian cancers are diagnosed with advanced disease leading to high fatality rate. Human epididymis protein 4 (HE4), also known as WAP four disulphide core 2 (WFDC2), is a novel protein and is one of the more promising biomarkers for improving diagnostic performance in ovarian cancer detection.
Aim: To evaluate a new tumor marker, HE4, in comparison with CA-125 in diagnosis of ovarian cancer and benign gynecological diseases.
Material and Methods: Pre-operative serum HE4 and CA-125 were determined in 146 patients with benign gynecologic diseases and 100 patients with malignant gynecologic cancers (64 were epithelial ovarian cancers patients). HE4 and CA-125 cutoffs were 140 pmol/L and 35 kU/L, respectively. Sandwich Elisa, biotin-labelled antibody kit was used for HE4.
Results: HE4 demonstrated better specificity than CA 125 in benign gynecologic disease patients, with abnormal concentrations in 1.3% and 33.6% , respectively. A significantly higher area under the ROC curve was obtained with HE4 than with CA 125 in the differential diagnosis of gynecologic diseases (0.875 vs 0.723; p=0.0001). Both markers were clearly related to stage (HE4:p=0.004; CA-125: p=0.001).) and histopathological type (HE4: p =0.003 and CA-125:p =0.009 in serous papillary ovarian cancer).
Conclusion: HE4 has significantly higher diagnostic specificity than CA 125, and the combination of CA-125 and HE4 improved the detection of ovarian cancer in all stages and histological types. HE4 use may be important in the differential diagnosis of ovarian cancer.
Three year report of population based cancer registries 2012-2014: Incidence, distribution, trends in incidence rates and projections of burden of cancer . [Internet]. Bengaluru, India: national Centre for Disease Informatics and Research, National Cncer Registry Programme, and Indian Council of Medical research [cited 2016 May 2016]. Available from: http://www.ncrpindia.org/ALL_NCRP_REPORTS/PBCR_REPORT_2012_2014/ALL_CONTENT/Printed _Version.htm
National Institutes of Health. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Statistical summaries: cancer stat fact sheets (ovary) and cancer statistics review (CSR), 1975-2013. http:// seer.cancer.gov/statistics/summaries.html.
Clarke-Pearson DL. Clinical practice. Screening for ovarian cancer. N Engl J Med. 2009;361(2):170-177.
Jelovac D, Armstrong DK. Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin. 2011;61(3):183-203.
American Cancer Society. Ovarian cancer. 2014. http://www.cancer. org/acs/groups/cid/documents/webcontent/003130-pdf.pdf. Accessed March 8, 2016.
Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124(1):1-5. .
Bast RC Jr, Badgwell D, Lu Z, Marquez R, Rosen D, Liu J, et al. New tumor markers: CA-125 and beyond. Int J Gynecol Cancer 2005;15(Suppl 3): 274–281.
Sturgeon CM, Duffy MJ, Stenman UH, Lilja H, Brunner N, Chan DW, et al. National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem 2008;54:e11–79.
Moore RG, McMeekin DS, Brown AK, DiSilvestro P, Miller MC, Allard WJ, et al. A novel multiple marker bioassay utilizing HE4 and CA-125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol 2009;112:40–6.
Duffy MJ, Bonfrer JM, Kulpa J, Rustin GJ, Soletormos G, Torre GC, et al. CA-125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer 2005;15:679 –691.
Anastasi E, Granato T, Marchei GG, Viggiani V, Colaprisca B, Comploj S, et al. Ovarian tumor marker HE4 is differently expressed during the phases of the menstrual cycle in healthy young women. Tumour Biol 2010;31:411–415.
Moore RG, Jabre-Raughley M, Brown AK, Robison KM, Miller MC, Allard WJ, 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;203:228.
Nolen B, Velikokhatnaya L, Marrangoni A, De Geest K, Lomakin A, Bast RC Jr, Lokshin A. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol 2010;117:440–445.
Bingle L, Singleton V, Bingle CD. The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Oncogene 2002;21:2768–2773.
Galgano MT, Hampton GM, Frierson HF Jr. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol 2006; 19:847–853.
Drapkin R, von Horsten HH, Lin Y, Mok SC, Crum CP, Welch WR, Hecht JL. Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res 2005;65:2162–2169.
Montagnana M, Lippi G, Danese E, Franchi M, Guidi GC. Usefulness of serum HE4 in endometriotic cysts. Br J Cancer 2009;101:548.
van Dalen A, Favier J, Hallensleben E, Burges A, Stieber P, de Bruijn HW, et al. Significance of serum CA-125 and TPS antigen levels for determination of overall survival after three chemotherapy courses in ovarian cancer patients during long-term follow-up. Eur J Gynaecol Oncol 2009; 30:609 –615.
Molina R, Auge JM, Bosch X, Escudero JM, Vinolas N, Marrades R, et al. Usefulness of serum tumor markers, including progastrin-releasing peptide, in patients with lung cancer: correlation with histology. Tumour Biol 2009;30:121–129.
Hellstrom I, Heagerty PJ, Swisher EM, Liu P, Jaffar J, Agnew K, Hellstrom KE. Detection of the HE4 protein in urine as a biomarker for ovarian neoplasms. Cancer Lett 2010;296:43– 48.
Karlsen NS, Karlsen MA, Høgdall CK, Høgdall EV. HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors: a systematic review. Cancer Epidemiol Biomarkers Prev. 2014 ;23:2285-2295
Park Y, Kim Y, Lee EY, Lee JH, Kim HS. Reference ranges for HE4 and CA-125 in a large Asian population by automated assays and diagnostic performances for ovarian cancer. Int J Cancer. 2012;130:1136-1144
Anastasi E, Marchei GG, Viggiani V, Gennarini G, Frati L, Reale MG. HE4: a new potential early biomarker for the recurrence of ovarian cancer. Tumour Biol 2010;31:113–119.
Huhtinen K, Suvitie P, Hiissa J, Junnila J, Huvila J, Kujari H, et al. Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts. Br J Cancer 2009;100: 1315–1319.
Goff BA, Agnew K, Neradilek MB, Gray HJ, Liao JB, Urban RR . Combining a symptom index, CA-125 and HE4 (triple screen) to detect ovarian cancer in women with a pelvic mass. Gynecol Oncol. 2017;147:291-295
Yuan T, Li Y. Human Epididymis Protein 4 as a Potential Biomarker of Chronic Kidney Disease in Female Patients With Normal Ovarian Function. Lab Med. 2017;48:238-243.
Jose ME, Jose MA, Xavier F, Aureli T, Jaume P, Rafael M. Comparison of Serum Human Epididymis Protein 4 with Cancer Antigen 125 as a Tumor Marker in Patients with Malignant and Nonmalignant Diseases. Clin Chemistry 2011; 57:1534–1544.
Leung F, Bernardini MQ, Brown MD, Zheng Y, Molina R, Bast RC Jr, Davis G et al. Validation of a Novel Biomarker Panel for the Detection of Ovarian Cancer. Cancer Epidemiol Biomarkers Prev. 2016 ;25:1333-1340
Hellstrom I, Hellstrom KE. SMRP and HE4 as biomarkers for ovarian carcinoma when used alone and in combination with CA-125 and/or each other. Adv Exp Med Biol 2008;622:15–21.