Tumor Biology

, Volume 37, Issue 2, pp 2183–2191 | Cite as

Development of a multi-marker model combining HE4, CA125, progesterone, and estradiol for distinguishing benign from malignant pelvic masses in postmenopausal women

  • Pengjun Zhang
  • Chuanxin Wang
  • Liming Cheng
  • Peng Zhang
  • Lin Guo
  • Wanli Liu
  • Zhongying Zhang
  • Yanchun Huang
  • Qishui Ou
  • Xinyu Wen
  • Yaping Tian


The purpose of this study was to evaluate HE4, CA125, progesterone (Prog), and estradiol (E2) for differentiating pelvic masses in postmenopausal women and aimed to build a multi-marker model which may improve the diagnostic value. HE4, CA125, Prog, and E2 were detected in 57 benign pelvic masses (BPM) and 92 epithelial ovarian cancer (EOC) patients. A total of 66.66 % of the BPM and EOC serum samples were used for building the differentiation model, and the remaining 33.33 % of the BPM and EOC serum samples were used for validation of the differentiation model. After comparing by Z score statistics, HE4 + CA125 + E2 model was chosen as the best multi-marker model. In the training group, the area under curve of the HE4 + CA125 + E2 model was 0.97 (0.93, 1.00), sensitivities of the model for distinguishing BPM from EOC, from early EOC, and from advanced EOC were 90.16, 86.21, and 95.65 %; specificities were 92.11, 92.11, and 92.11 %. In the validation group, sensitivities of HE4 + CA125 + E2 model for distinguishing BPM from EOC, from early EOC, and from advanced EOC were 96.77, 100.00, and 87.50 %, specificities were 84.21, 100.00, and 84.21 %. The multi-marker model showed significant improvement when compared to CA125 or HE4, and it might be an effective pelvic mass differentiation method.


Epithelial ovarian cancer Pelvic mass Human epididymis protein 4 Carbohydrate antigen 125 Progesterone Estradiol 



This work was supported by the National High Technology Research and Development Program 863 (2011AA02A111), China Postdoctoral Science Special Foundation funded project (2014 T70963), China Postdoctoral Science Foundation funded project (2013 M532110), and National Science and Technology Infrastructure (2009BAI86B05), National Natural Science Foundation of China (81071413).

Conflicts of interest



  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9–29. doi: 10.3322/caac.21208.CrossRefPubMedGoogle Scholar
  2. 2.
    Curtin JP. Management of the adnexal mass. Gynecol Oncol. 1994;55(3 Pt 2):S42–6. doi: 10.1006/gyno.1994.1340.CrossRefPubMedGoogle Scholar
  3. 3.
    Bast Jr RC. Status of tumor markers in ovarian cancer screening. J Clin Oncol. 2003;21(10 Suppl):200s–5. doi: 10.1200/JCO.2003.01.068.
  4. 4.
    Drapkin R, von Horsten HH, Lin Y, Mok SC, Crum CP, Welch WR, 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. doi: 10.1158/0008-5472.CAN-04-3924.CrossRefPubMedGoogle Scholar
  5. 5.
    Hellstrom I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, McIntosh M, et al. The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res. 2003;63(13):3695–700.PubMedGoogle Scholar
  6. 6.
    Ferraro S, Braga F, Lanzoni M, Boracchi P, Biganzoli EM, Panteghini M. Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review. J Clin Pathol. 2013;66(4):273–81. doi: 10.1136/jclinpath-2012-201031.CrossRefPubMedGoogle Scholar
  7. 7.
    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. doi: 10.1007/s13277-009-0015-y.CrossRefPubMedGoogle Scholar
  8. 8.
    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. doi: 10.1007/s13277-012-0381-8.CrossRefPubMedGoogle Scholar
  9. 9.
    Moore RG, McMeekin DS, Brown AK, DiSilvestro P, Miller MC, Allard WJ, 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(1):40–6. doi: 10.1016/j.ygyno.2008.08.031.CrossRefPubMedGoogle Scholar
  10. 10.
    Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy index incorporating CA 125, ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol. 1990;97(10):922–9.CrossRefPubMedGoogle Scholar
  11. 11.
    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(3):228 e1–6. doi: 10.1016/j.ajog.2010.03.043.CrossRefGoogle Scholar
  12. 12.
    Karlsen MA, Sandhu N, Hogdall C, Christensen IJ, Nedergaard L, Lundvall L, et al. Evaluation of HE4, CA125, risk of ovarian malignancy algorithm (ROMA) and risk of malignancy index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2012;127(2):379–83. doi: 10.1016/j.ygyno.2012.07.106.CrossRefPubMedGoogle Scholar
  13. 13.
    Montagnana M, Danese E, Ruzzenente O, Bresciani V, Nuzzo T, Gelati M, et al. The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful? Clin Chem Lab Med. 2011;49(3):521–5. doi: 10.1515/CCLM.2011.075.CrossRefPubMedGoogle Scholar
  14. 14.
    Jacob F, Meier M, Caduff R, Goldstein D, Pochechueva T, Hacker N, et al. No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting. Gynecol Oncol. 2011;121(3):487–91. doi: 10.1016/j.ygyno.2011.02.022.CrossRefPubMedGoogle Scholar
  15. 15.
    Lukanova A, Kaaks R. Endogenous hormones and ovarian cancer: epidemiology and current hypotheses. Cancer Epidemiol Biomarkers Prev. 2005;14(1):98–107.PubMedGoogle Scholar
  16. 16.
    Ho SM. Estrogen, progesterone and epithelial ovarian cancer. Reprod Biol Endocrinol. 2003;1:73. doi: 10.1186/1477-7827-1-73.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Han KH, Kim MK, Kim HS, Chung HH, Song YS. Protective effect of progesterone during pregnancy against ovarian cancer. J Cancer Prev. 2013;18(2):113–22.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Laviolette LA, Hodgkinson KM, Minhas N, Perez-Iratxeta C, Vanderhyden BC. 17beta-estradiol upregulates GREB1 and accelerates ovarian tumor progression in vivo. Int J Cancer. 2014;135(5):1072–84. doi: 10.1002/ijc.28741.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Timmerman D, Valentin L, Bourne TH, Collins WP, Verrelst H, Vergote I. Terms, definitions and measurements to describe the sonographic features of adnexal tumors: a consensus opinion from the International Ovarian Tumor Analysis (IOTA) Group. Ultrasound Obstet Gynecol. 2000;16(5):500–5. doi: 10.1046/j.1469-0705.2000.00287.x.CrossRefPubMedGoogle Scholar
  20. 20.
    Moore RG, Brown AK, Miller MC, Skates S, Allard WJ, Verch T, 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(2):402–8. doi: 10.1016/j.ygyno.2007.10.017.CrossRefPubMedGoogle Scholar
  21. 21.
    Fearon WF, Gauri AJ, Myers J, Raxwal VK, Atwood JE, Froelicher VF. A comparison of treadmill scores to diagnose coronary artery disease. Clin Cardiol. 2002;25(3):117–22.CrossRefPubMedGoogle Scholar
  22. 22.
    Chan KK, Chen CA, Nam JH, Ochiai K, Wilailak S, Choon AT, et al. The use of HE4 in the prediction of ovarian cancer in Asian women with a pelvic mass. Gynecol Oncol. 2013;128(2):239–44. doi: 10.1016/j.ygyno.2012.09.034.CrossRefPubMedGoogle Scholar
  23. 23.
    Van Gorp T, Cadron I, Despierre E, Daemen A, Leunen K, Amant F, et al. HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the risk of ovarian malignancy algorithm. Br J Cancer. 2011;104(5):863–70. doi: 10.1038/sj.bjc.6606092.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Azzam AZ, Hashad DI, Kamel NA. Evaluation of HE4 as an extrabiomarker to CA125 to improve detection of ovarian carcinoma: is it time for a step forward? Arch Gynecol Obstet. 2013;288(1):167–72. doi: 10.1007/s00404-013-2722-2.CrossRefPubMedGoogle Scholar
  25. 25.
    Park Y, Lee JH, Hong DJ, Lee EY, Kim HS. Diagnostic performances of HE4 and CA125 for the detection of ovarian cancer from patients with various gynecologic and non-gynecologic diseases. Clin Biochem. 2011;44(10-11):884–8. doi: 10.1016/j.clinbiochem.2011.04.011.CrossRefPubMedGoogle Scholar
  26. 26.
    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. doi: 10.1016/j.ejogrb.2012.10.036.CrossRefPubMedGoogle Scholar
  27. 27.
    Granato T, Porpora MG, Longo F, Angeloni A, Manganaro L, Anastasi E. HE4 in the differential diagnosis of ovarian masses. Clin Chim Acta. 2015;446:147–55. doi: 10.1016/j.cca.2015.03.047.CrossRefPubMedGoogle Scholar
  28. 28.
    Anastasi E, Granato T, Coppa A, Manganaro L, Giannini G, Comploj S, et al. HE4 in the differential diagnosis of a pelvic mass: a case report. Int J Mol Sci. 2011;12(1):627–32. doi: 10.3390/ijms12010627.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Moszynski R, Szubert S, Szpurek D, Michalak S, Krygowska J, Sajdak S. Usefulness of the HE4 biomarker as a second-line test in the assessment of suspicious ovarian tumors. Arch Gynecol Obstet. 2013;288(6):1377–83. doi: 10.1007/s00404-013-2901-1.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Anton C, Carvalho FM, Oliveira EI, Maciel GA, Baracat EC, Carvalho JP. A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses. Clinics (Sao Paulo). 2012;67(5):437–41.CrossRefGoogle Scholar
  31. 31.
    Li F, Tie R, Chang K, Wang F, Deng S, Lu W, et al. Does risk for ovarian malignancy algorithm excel human epididymis protein 4 and CA125 in predicting epithelial ovarian cancer: a meta-analysis. BMC Cancer. 2012;12:258. doi: 10.1186/1471-2407-12-258.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ruggeri G, Bandiera E, Zanotti L, Belloli S, Ravaggi A, Romani C, et al. HE4 and epithelial ovarian cancer: comparison and clinical evaluation of two immunoassays and a combination algorithm. Clin Chim Acta. 2011;412(15-16):1447–53. doi: 10.1016/j.cca.2011.04.028.CrossRefPubMedGoogle Scholar
  33. 33.
    Sandri MT, Bottari F, Franchi D, Boveri S, Candiani M, Ronzoni S, et al. Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: correlation with pathological outcome. Gynecol Oncol. 2013;128(2):233–8. doi: 10.1016/j.ygyno.2012.11.026.CrossRefPubMedGoogle Scholar
  34. 34.
    Urban N, Thorpe JD, Bergan LA, Forrest RM, Kampani AV, Scholler N, et al. Potential role of HE4 in multimodal screening for epithelial ovarian cancer. J Natl Cancer Inst. 2011;103(21):1630–4. doi: 10.1093/jnci/djr359.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bast Jr RC, Skates S, Lokshin A, Moore RG. Differential diagnosis of a pelvic mass: improved algorithms and novel biomarkers. Int J Gynecol Cancer. 2012;22 Suppl 1:S5–8. doi: 10.1097/IGC.0b013e318251c97d.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Diep CH, Daniel AR, Mauro LJ, Knutson TP, Lange CA. Progesterone action in breast, uterine, and ovarian cancers. J Mol Endocrinol. 2015;54(2):R31–53. doi: 10.1530/JME-14-0252.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Salazar-Martinez E, Lazcano-Ponce EC, Gonzalez Lira-Lira G, Escudero-De los Rios P, Salmeron-Castro J, Hernandez-Avila M. Reproductive factors of ovarian and endometrial cancer risk in a high fertility population in Mexico. Cancer Res. 1999;15:3658–62.Google Scholar
  38. 38.
    Liao J, Ding D, Sun C, Weng D, Meng L, Chen G, et al. Polymorphisms of progesterone receptor and ovarian cancer risk: a systemic review and meta-analysis. J Obstet Gynaecol Res. 2015;41(2):178–87. doi: 10.1111/jog.12519.CrossRefPubMedGoogle Scholar
  39. 39.
    Liu T, Chen L, Sun X, Wang Y, Li S, Yin X, et al. Progesterone receptor PROGINS and +331G/A polymorphisms confer susceptibility to ovarian cancer: a meta-analysis based on 17 studies. Tumour Biol. 2014;35(3):2427–36. doi: 10.1007/s13277-013-1322-x.CrossRefPubMedGoogle Scholar
  40. 40.
    Sieh W, Kobel M, Longacre TA, Bowtell DD, deFazio A, Goodman MT, et al. Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. Lancet Oncol. 2013;14(9):853–62. doi: 10.1016/S1470-2045(13)70253-5.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gourley C. Hormone receptors and ovarian cancer survival. Lancet Oncol. 2013;14(9):794–5. doi: 10.1016/S1470-2045(13)70323-1.CrossRefPubMedGoogle Scholar
  42. 42.
    Yu S, Lee M, Shin S, Park J. Apoptosis induced by progesterone in human ovarian cancer cell line SNU-840. J Cell Biochem. 2001;82(3):445–51. doi: 10.1002/jcb.1171.CrossRefPubMedGoogle Scholar
  43. 43.
    McDonnel AC, Van Kirk EA, Isaak DD, Murdoch WJ. Inhibitory effects of progesterone on plasma membrane fluidity and tumorigenic potential of ovarian epithelial cancer cells. Exp Biol Med (Maywood). 2003;228(3):308–14.Google Scholar
  44. 44.
    Romero IL, Lee W, Mitra AK, Gordon IO, Zhao Y, Leonhardt P, et al. The effects of 17beta-estradiol and a selective estrogen receptor modulator, bazedoxifene, on ovarian carcinogenesis. Gynecol Oncol. 2012;124(1):134–41. doi: 10.1016/j.ygyno.2011.08.026.CrossRefPubMedGoogle Scholar
  45. 45.
    Bai W, Oliveros-Saunders B, Wang Q, Acevedo-Duncan ME, Nicosia SV. Estrogen stimulation of ovarian surface epithelial cell proliferation. In Vitro Cell Dev Biol Anim. 2000;36(10):657–66. doi: 10.1290/1071-2690(2000)036<0657:ESOOSE>2.0.CO;2.CrossRefPubMedGoogle Scholar
  46. 46.
    Symonds DA, Merchenthaler I, Flaws JA. Methoxychlor and estradiol induce oxidative stress DNA damage in the mouse ovarian surface epithelium. Toxicol Sci. 2008;105(1):182–7. doi: 10.1093/toxsci/kfn100.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Laviolette LA, Garson K, Macdonald EA, Senterman MK, Courville K, Crane CA, et al. 17beta-estradiol accelerates tumor onset and decreases survival in a transgenic mouse model of ovarian cancer. Endocrinology. 2010;151(3):929–38. doi: 10.1210/en.2009-0602.CrossRefPubMedGoogle Scholar
  48. 48.
    Choi KC, Kang SK, Tai CJ, Auersperg N, Leung PC. Estradiol up-regulates antiapoptotic Bcl-2 messenger ribonucleic acid and protein in tumorigenic ovarian surface epithelium cells. Endocrinology. 2001;142(6):2351–60. doi: 10.1210/endo.142.6.8144.PubMedGoogle Scholar
  49. 49.
    Mabuchi S, Ohmichi M, Kimura A, Nishio Y, Arimoto-Ishida E, Yada-Hashimoto N, et al. Estrogen inhibits paclitaxel-induced apoptosis via the phosphorylation of apoptosis signal-regulating kinase 1 in human ovarian cancer cell lines. Endocrinology. 2004;145(1):49–58. doi: 10.1210/en.2003-0792.CrossRefPubMedGoogle Scholar
  50. 50.
    Kirilovas D, Schedvins K, Naessen T, Von Schoultz B, Carlstrom K. Conversion of circulating estrone sulfate to 17beta-estradiol by ovarian tumor tissue: a possible mechanism behind elevated circulating concentrations of 17beta-estradiol in postmenopausal women with ovarian tumors. Gynecol Endocrinol. 2007;23(1):25–8.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Pengjun Zhang
    • 1
    • 2
  • Chuanxin Wang
    • 3
  • Liming Cheng
    • 4
  • Peng Zhang
    • 5
  • Lin Guo
    • 6
  • Wanli Liu
    • 7
  • Zhongying Zhang
    • 8
  • Yanchun Huang
    • 9
  • Qishui Ou
    • 10
  • Xinyu Wen
    • 2
  • Yaping Tian
    • 1
    • 2
  1. 1.Core Laboratory of Translational MedicineChinese PLA General HospitalBeijingChina
  2. 2.Department of Clinical Biochemistry, State Key Laboratory of Kidney DiseaseChinese PLA General HospitalBeijingChina
  3. 3.Department of Clinical LaboratoryQilu Hospital of Shandong UniversityJinanChina
  4. 4.Department of Clinical Laboratory, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
  5. 5.Department of Clinical LaboratoryTianjin Medical University Cancer Institute and HospitalTianjinChina
  6. 6.Department of Clinical LaboratoryFudan University Shanghai Cancer CenterShanghaiChina
  7. 7.Department of Clinical LaboratorySun Yat-Sen University Cancer HospitalGuangzhouChina
  8. 8.Department of Clinical LaboratoryZhongshan Hospital Xiamen UniversityXiamenChina
  9. 9.Department of Clinical LaboratoryThe Tumor Hospital Affiliated to XinJiang Medical UniversityUrumqiChina
  10. 10.Department of Clinical BiochemistryFirst Affiliated Hospital of Fujian Medical UniversityFuzhouChina

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