Mini-Review Article

Is HE4 Superior over CA-125 in the Follow-up of Patients with Epithelial Ovarian Cancer?

Author(s): Khalid El Bairi*, Said Afqir and Mariam Amrani

Volume 21, Issue 10, 2020

Page: [1026 - 1033] Pages: 8

DOI: 10.2174/1389450121666200425211732

Price: $65

Abstract

Notwithstanding important advances in the treatment of epithelial ovarian cancer (EOC), this disease is still a leading cause of global high mortality from gynecological malignancies. Recurrence in EOC is inevitable and it is responsible for poor survival rates. There is a critical need for novel effective biomarkers with improved accuracy compared to the standard carbohydrate antigen-125 (CA-125) for follow-up. The human epididymis protein 4 (HE4) is used for early detection of EOC (ROMA algorithm) as well as for predicting optimal cytoreduction after neoadjuvant chemotherapy and survival outcomes. Notably, the emerging HE4 is a promising prognostic biomarker that has displayed better accuracy in various recent studies for detecting recurrent disease. In this mini-review, we discussed the potential of HE4 as an accurate predictor of EOC recurrence.

Keywords: HE4, prognostic biomarkers, ovarian cancer, recurrence, follow-up, survival.

Graphical Abstract
[1]
Webb PM, Jordan SJ. Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol 2017; 41: 3-14.
[http://dx.doi.org/10.1016/j.bpobgyn.2016.08.006] [PMID: 27743768]
[2]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[3]
Yang WL, Lu Z, Bast RC Jr. The role of biomarkers in the management of epithelial ovarian cancer. Expert Rev Mol Diagn 2017; 17(6): 577-91.
[http://dx.doi.org/10.1080/14737159.2017.1326820] [PMID: 28468520]
[4]
El Bairi K, Kandhro AH, Gouri A, et al. Emerging diagnostic, prognostic and therapeutic biomarkers for ovarian cancer. Cell Oncol (Dordr) 2017a; 40(2): 105-18.
[http://dx.doi.org/10.1007/s13402-016-0309-1] [PMID: 27981507]
[5]
Qiao N, Li H. The value of mesothelin in the diagnosis and follow-up of surgically treated ovarian cancer. Eur J Gynaecol Oncol 2013; 34(2): 163-5.
[PMID: 23781590]
[6]
Cheng X, Zhang L, Chen Y, Qing C. Circulating cell-free DNA and circulating tumor cells, the “liquid biopsies” in ovarian cancer. J Ovarian Res 2017; 10(1): 75.
[http://dx.doi.org/10.1186/s13048-017-0369-5] [PMID: 29132396]
[7]
Lycke M, Kristjansdottir B, Sundfeldt K. A multicenter clinical trial validating the performance of HE4, CA125, risk of ovarian malignancy algorithm and risk of malignancy index. Gynecol Oncol 2018; 151(1): 159-65.
[http://dx.doi.org/10.1016/j.ygyno.2018.08.025] [PMID: 30149898]
[8]
Zapardiel I, Gorostidi M, Ravaggi A, Allende MT, Silveira M, Macuks R. Utility of human epididymis protein 4 serum marker for the detection of adnexal malignancy: a multicentric prospective study. Eur J Cancer Prev 2017; 26(4): 346-50.
[http://dx.doi.org/10.1097/CEJ.0000000000000259] [PMID: 27116243]
[9]
Mi D, Zhang Y. Prognostic value of serum HE4 in patients with advanced ovarian, fallopian tube, and peritoneal carcinoma. Arch Gynecol Obstet 2020; 301(3): 779-85.
[http://dx.doi.org/10.1007/s00404-020-05447-z] [PMID: 32034508]
[10]
Romagnolo C, Leon AE, Fabricio ASC, et al. HE4, CA125 and risk of ovarian malignancy algorithm (ROMA) as diagnostic tools for ovarian cancer in patients with a pelvic mass: An Italian multicenter study. Gynecol Oncol 2016; 141(2): 303-11.
[http://dx.doi.org/10.1016/j.ygyno.2016.01.016] [PMID: 26801941]
[11]
Chhikara N, Saraswat M, Tomar AK, Dey S, Singh S, Yadav S. Human epididymis protein-4 (HE-4): a novel cross-class protease inhibitor. PLoS One 2012; 7(11) e47672
[http://dx.doi.org/10.1371/journal.pone.0047672] [PMID: 23139753]
[12]
Galgano MT, Hampton GM, Frierson HF Jr. Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol 2006; 19(6): 847-53.
[http://dx.doi.org/10.1038/modpathol.3800612] [PMID: 16607372]
[13]
Zhu L, Zhuang H, Wang H, et al. Overexpression of HE4 (human epididymis protein 4) enhances proliferation, invasion and metastasis of ovarian cancer. Oncotarget 2016; 7(1): 729-44.
[http://dx.doi.org/10.18632/oncotarget.6327] [PMID: 26575020]
[14]
Uhlen M, Zhang C, Lee S, et al. A pathology atlas of the human cancer transcriptome. Science 2017; 357(6352) eaan2507
[http://dx.doi.org/10.1126/science.aan2507] [PMID: 28818916]
[15]
Gyorffy B, Lánczky A, Szállási Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer 2012; 19(2): 197-208.
[http://dx.doi.org/10.1530/ERC-11-0329] [PMID: 22277193]
[16]
Fekete JT, Győrffy B. ROCplot.org: Validating predictive biomarkers of chemotherapy/hormonal therapy/anti-HER2 therapy using transcriptomic data of 3,104 breast cancer patients. Int J Cancer 2019; 145(11): 3140-51.
[http://dx.doi.org/10.1002/ijc.32369] [PMID: 31020993]
[17]
Bingle L, Cross SS, High AS, et al. WFDC2 (HE4): a potential role in the innate immunity of the oral cavity and respiratory tract and the development of adenocarcinomas of the lung. Respir Res 2006; 7(1): 61.
[http://dx.doi.org/10.1186/1465-9921-7-61] [PMID: 16600032]
[18]
Orfanelli T, Jayaram A, Doulaveris G, Forney LJ, Ledger WJ, Witkin SS. Human epididymis protein 4 and secretory leukocyte protease inhibitor in vaginal fluid: relation to vaginal components and bacterial composition. Reprod Sci 2014; 21(4): 538-42.
[http://dx.doi.org/10.1177/1933719113503416] [PMID: 24023032]
[19]
Moore RG, Hill EK, Horan T, et al. HE4 (WFDC2) gene overexpression promotes ovarian tumor growth. Sci Rep 2014; 4: 3574.
[http://dx.doi.org/10.1038/srep03574] [PMID: 24389815]
[20]
James NE, Chichester C, Ribeiro JR. Beyond the Biomarker: Understanding the Diverse Roles of Human Epididymis Protein 4 in the Pathogenesis of Epithelial Ovarian Cancer. Front Oncol 2018; 8: 124.
[http://dx.doi.org/10.3389/fonc.2018.00124] [PMID: 29740539]
[21]
Lu R, Sun X, Xiao R, Zhou L, Gao X, Guo L. Human epididymis protein 4 (HE4) plays a key role in ovarian cancer cell adhesion and motility. Biochem Biophys Res Commun 2012; 419(2): 274-80.
[http://dx.doi.org/10.1016/j.bbrc.2012.02.008] [PMID: 22342977]
[22]
Zhuang H, Tan M, Liu J, et al. Human epididymis protein 4 in association with Annexin II promotes invasion and metastasis of ovarian cancer cells. Mol Cancer 2014; 13: 243.
[http://dx.doi.org/10.1186/1476-4598-13-243] [PMID: 25362534]
[23]
Qu W, Li J, Duan P, et al. Physiopathological factors affecting the diagnostic value of serum HE4-test for gynecologic malignancies. Expert Rev Mol Diagn 2016; 16(12): 1271-82.
[http://dx.doi.org/10.1080/14737159.2016.1251317] [PMID: 27784171]
[24]
Schummer M, Ng WV, Bumgarner RE, et al. Comparative hybridization of an array of 21,500 ovarian cDNAs for the discovery of genes overexpressed in ovarian carcinomas. Gene 1999; 238(2): 375-85.
[http://dx.doi.org/10.1016/S0378-1119(99)00342-X] [PMID: 10570965]
[25]
Georgakopoulos P, Mehmood S, Akalin A, Shroyer KR. Immunohistochemical localization of HE4 in benign, borderline, and malignant lesions of the ovary. Int J Gynecol Pathol 2012; 31(6): 517-23.
[http://dx.doi.org/10.1097/PGP.0b013e31824fe269] [PMID: 23018214]
[26]
Drapkin R, von Horsten HH, Lin Y, et al. Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res 2005; 65(6): 2162-9.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-3924] [PMID: 15781627]
[27]
Lee S, Choi S, Lee Y, Chung D, Hong S, Park N. Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer. J Obstet Gynaecol Res 2017; 43(1): 220-7.
[http://dx.doi.org/10.1111/jog.13181] [PMID: 27862665]
[28]
Wang H, Zhu L, Gao J, Hu Z, Lin B. Promotive role of recombinant HE4 protein in proliferation and carboplatin resistance in ovarian cancer cells. Oncol Rep 2015; 33(1): 403-12.
[http://dx.doi.org/10.3892/or.2014.3549] [PMID: 25354091]
[29]
El Bairi K, Amrani M, Kandhro AH, Afqir S. Prediction of therapy response in ovarian cancer: Where are we now? Crit Rev Clin Lab Sci 2017b; 54(4): 233-66.
[http://dx.doi.org/10.1080/10408363.2017.1313190] [PMID: 28443762]
[30]
Ribeiro JR, Schorl C, Yano N, et al. HE4 promotes collateral resistance to cisplatin and paclitaxel in ovarian cancer cells. J Ovarian Res 2016; 9(1): 28.
[http://dx.doi.org/10.1186/s13048-016-0240-0] [PMID: 27184254]
[31]
Braicu EI, Fotopoulou C, Van Gorp T, et al. Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: results from the OVCAD study. Gynecol Oncol 2013; 128(2): 245-51.
[http://dx.doi.org/10.1016/j.ygyno.2012.11.023] [PMID: 23178313]
[32]
Shen Y, Li L. Serum HE4 superior to CA125 in predicting poorer surgical outcome of epithelial ovarian cancer. Tumour Biol 2016; 37(11): 14765-72.
[http://dx.doi.org/10.1007/s13277-016-5335-0] [PMID: 27629144]
[33]
Aarenstrup Karlsen M, Høgdall C, Nedergaard L, et al. HE4 as a predictor of adjuvant chemotherapy resistance and survival in patients with epithelial ovarian cancer. APMIS 2016; 124(12): 1038-45.
[http://dx.doi.org/10.1111/apm.12625] [PMID: 27859687]
[34]
Scaletta G, Plotti F, Luvero D, et al. The role of novel biomarker HE4 in the diagnosis, prognosis and follow-up of ovarian cancer: a systematic review. Expert Rev Anticancer Ther 2017; 17(9): 827-39.
[http://dx.doi.org/10.1080/14737140.2017.1360138] [PMID: 28756722]
[35]
Cao H, You D, Lan Z, Ye H, Hou M, Xi M. Prognostic value of serum and tissue HE4 expression in ovarian cancer: a systematic review with meta-analysis of 90 studies. Expert Rev Mol Diagn 2018; 18(4): 371-83.
[http://dx.doi.org/10.1080/14737159.2018.1457436] [PMID: 29569984]
[36]
Dai C, Zheng Y, Li Y, et al. Prognostic values of HE4 expression in patients with cancer: a meta-analysis. Cancer Manag Res 2018; 10: 4491-500.
[http://dx.doi.org/10.2147/CMAR.S178345] [PMID: 30349381]
[37]
Steffensen KD, Waldstrøm M, Brandslund I, Petzold M, Jakobsen A. The prognostic and predictive value of combined HE4 and CA-125 in ovarian cancer patients. Int J Gynecol Cancer 2012; 22(9): 1474-82.
[http://dx.doi.org/10.1097/IGC.0b013e3182681cfd] [PMID: 23095772]
[38]
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 1991; 45(2): 350-7.
[http://dx.doi.org/10.1095/biolreprod45.2.350] [PMID: 1686187]
[39]
Plotti F, Guzzo F, Schirò T, et al. Role of human epididymis protein 4 (HE4) in detecting recurrence in CA125 negative ovarian cancer patients [published online ahead of print, 2019 Apr 16]. Int J Gynecol Cancer 2019.
[http://dx.doi.org/10.1136/ijgc-2019-000211]
[40]
Ferraro S, Robbiano C, Tosca N, Panzeri A, Paganoni AM, Panteghini M. Serum human epididymis protein 4 vs. carbohydrate antigen 125 in ovarian cancer follow-up. Clin Biochem 2018; 60: 84-90.
[http://dx.doi.org/10.1016/j.clinbiochem.2018.08.003] [PMID: 30125544]
[41]
Innao P, Pothisuwan M, Pengsa P. Does Human Epididymis Protein 4 (HE4) Have a Role in Prediction of Recurrent Epithelial Ovarian Cancer. Asian Pac J Cancer Prev 2016; 17(9): 4483-6.
[PMID: 27797265]
[42]
Nassir M, Guan J, Luketina H, et al. The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study. Tumour Biol 2016; 37(3): 3009-16.
[http://dx.doi.org/10.1007/s13277-015-4031-9] [PMID: 26419591]
[43]
Manganaro L, Michienzi S, Vinci V, et al. Serum HE4 levels combined with CE CT imaging improve the management of monitoring women affected by epithelial ovarian cancer. Oncol Rep 2013; 30(5): 2481-7.
[http://dx.doi.org/10.3892/or.2013.2682] [PMID: 23970060]
[44]
Schummer M, Drescher C, Forrest R, et al. Evaluation of ovarian cancer remission markers HE4, MMP7 and Mesothelin by comparison to the established marker CA125. Gynecol Oncol 2012; 125(1): 65-9.
[http://dx.doi.org/10.1016/j.ygyno.2011.11.050] [PMID: 22155417]
[45]
Granato T, Midulla C, Longo F, Colaprisca B, Frati L, Anastasi E. Role of HE4, CA72.4, and CA125 in monitoring ovarian cancer. Tumour Biol 2012; 33(5): 1335-9.
[http://dx.doi.org/10.1007/s13277-012-0381-8] [PMID: 22528938]
[46]
Plotti F, Capriglione S, Terranova C, et al. Does HE4 have a role as biomarker in the recurrence of ovarian cancer? Tumour Biol 2012; 33(6): 2117-23.
[http://dx.doi.org/10.1007/s13277-012-0471-7] [PMID: 22875782]
[47]
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(2): 113-9.
[http://dx.doi.org/10.1007/s13277-009-0015-y] [PMID: 20358424]
[48]
Havrilesky LJ, Whitehead CM, Rubatt JM, et al. Evaluation of biomarker panels for early stage ovarian cancer detection and monitoring for disease recurrence. Gynecol Oncol 2008; 110(3): 374-82.
[http://dx.doi.org/10.1016/j.ygyno.2008.04.041] [PMID: 18584856]
[49]
Coakley FV, Choi PH, Gougoutas CA, et al. Peritoneal metastases: detection with spiral CT in patients with ovarian cancer. Radiology 2002; 223(2): 495-9.
[http://dx.doi.org/10.1148/radiol.2232011081] [PMID: 11997559]
[50]
Capriglione S, Luvero D, Plotti F, et al. Ovarian cancer recurrence and early detection: may HE4 play a key role in this open challenge? A systematic review of literature. Med Oncol 2017; 34(9): 164.
[http://dx.doi.org/10.1007/s12032-017-1026-y] [PMID: 28825178]
[51]
Brennan DJ, Hackethal A, Mann KP, et al. Serum HE4 detects recurrent endometrial cancer in patients undergoing routine clinical surveillance. BMC Cancer 2015; 15: 33.
[http://dx.doi.org/10.1186/s12885-015-1028-0] [PMID: 25655024]
[52]
Colombo N, Sessa C, du Bois A, et al. ESMO-ESGO Ovarian Cancer Consensus Conference Working Group. ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol 2019; 30(5): 672-705.
[http://dx.doi.org/10.1093/annonc/mdz062] [PMID: 31046081]
[53]
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines).. Ovarian Cancer (Version 22019) National Comprehensive Cancer Network 2019.https://www.nccn.org/professionals/physician_gls/pdf/ovarian. pdf [18/11/2019].
[54]
Huang J, Chen J, Huang Q. Diagnostic value of HE4 in ovarian cancer: A meta-analysis. Eur J Obstet Gynecol Reprod Biol 2018; 231: 35-42.
[http://dx.doi.org/10.1016/j.ejogrb.2018.10.008] [PMID: 30317143]
[55]
Lin J, Qin J, Sangvatanakul V. Human epididymis protein 4 for differential diagnosis between benign gynecologic disease and ovarian cancer: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2013; 167(1): 81-5.
[http://dx.doi.org/10.1016/j.ejogrb.2012.10.036] [PMID: 23228410]
[56]
Wu L, Dai ZY, Qian YH, Shi Y, Liu FJ, Yang C. Diagnostic value of serum human epididymis protein 4 (HE4) in ovarian carcinoma: a systematic review and meta-analysis. Int J Gynecol Cancer 2012; 22(7): 1106-12.
[http://dx.doi.org/10.1097/IGC.0b013e318263efa2] [PMID: 22854652]
[57]
Lamy PJ, Touraine C, Mollevi C, et al. Kinetics of HE4 and CA125 markers in metastatic ovarian cancer: The META4 study. J Clin Oncol 2017; 35(15_suppl): e17059-9.
[58]
Laasik M, Kemppainen J, Auranen A, et al. Behavior of FDG-avid supradiaphragmatic lymph nodes in PET/CT throughout primary therapy in advanced serous epithelial ovarian cancer: a prospective study. Cancer Imaging 2019; 19(1): 27.
[http://dx.doi.org/10.1186/s40644-019-0215-7] [PMID: 31142357]
[59]
Vallius T, Hynninen J, Auranen A, et al. Postoperative human epididymis protein 4 predicts primary therapy outcome in advanced epithelial ovarian cancer. Tumour Biol 2017; 39(2) 1010428317691189
[http://dx.doi.org/10.1177/1010428317691189] [PMID: 28218038]
[60]
Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 2017; 14(9): 531-48.
[http://dx.doi.org/10.1038/nrclinonc.2017.14] [PMID: 28252003]
[61]
Heitzer E, Haque IS, Roberts CES, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet 2019; 20(2): 71-88.
[http://dx.doi.org/10.1038/s41576-018-0071-5] [PMID: 30410101]
[62]
Pantel K, Alix-Panabières C. Liquid biopsy and minimal residual disease - latest advances and implications for cure. Nat Rev Clin Oncol 2019; 16(7): 409-24.
[http://dx.doi.org/10.1038/s41571-019-0187-3] [PMID: 30796368]
[63]
Pereira E, Camacho-Vanegas O, Anand S, et al. Personalized circulating tumor dna biomarkers dynamically predict treatment response and survival in gynecologic cancers. PLoS One 2015; 10(12) e0145754
[http://dx.doi.org/10.1371/journal.pone.0145754] [PMID: 26717006]
[64]
Christie EL, Fereday S, Doig K, Pattnaik S, Dawson SJ, Bowtell DDL. Reversion of brca1/2 germline mutations detected in circulating tumor dna from patients with high-grade serous ovarian cancer. J Clin Oncol 2017; 35(12): 1274-80.
[http://dx.doi.org/10.1200/JCO.2016.70.4627] [PMID: 28414925]
[65]
Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6(224) 224ra24
[http://dx.doi.org/10.1126/scitranslmed.3007094] [PMID: 24553385]
[66]
Baumgartner JM, Raymond VM, Lanman RB, et al. Preoperative circulating tumor dna in patients with peritoneal carcinomatosis is an independent predictor of progression-free survival. Ann Surg Oncol 2018; 25(8): 2400-8.
[http://dx.doi.org/10.1245/s10434-018-6561-z] [PMID: 29948422]
[67]
Asante DB, Calapre L, Ziman M, Meniawy TM, Gray ES. Liquid biopsy in ovarian cancer using circulating tumor DNA and cells: Ready for prime time? Cancer Lett 2020; 468: 59-71.
[http://dx.doi.org/10.1016/j.canlet.2019.10.014] [PMID: 31610267]
[68]
Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (remark): explanation and elaboration. PLoS Med 2012; 9(5) e1001216
[http://dx.doi.org/10.1371/journal.pmed.1001216] [PMID: 22675273]
[69]
Moons KG, Altman DG, Reitsma JB, et al. Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): explanation and elaboration. Ann Intern Med 2015; 162(1): W1-73.
[http://dx.doi.org/10.7326/M14-0698] [PMID: 25560730]
[70]
Whiting PF, Rutjes AW, Westwood ME, et al. QUADAS-2 Group. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011; 155(8): 529-36.
[http://dx.doi.org/10.7326/0003-4819-155-8-201110180-00009] [PMID: 22007046]
[71]
Zhang Y, Akl EA, Schünemann HJ. Using systematic reviews in guideline development: the GRADE approach. Res Synth Methods 2018; 14: 1313.
[http://dx.doi.org/10.1002/jrsm.1313] [PMID: 30006970]

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