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Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis

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Tumor Biology

Abstract

CA125, human epididymis secretary protein 4 (HE4) and the Risk of Ovarian Malignancy Algorithm (ROMA) could be used for diagnosing ovarian cancer (OCa). However, it has not been conclusively determined which of these markers yields the best diagnostic accuracy. Therefore, we conducted a meta-analysis to evaluate the diagnostic value of these markers. We systematically searched the PubMed and ScienceDirect databases and identified 32 studies that evaluated the role of CA125, HE4 and ROMA in diagnosing OCa. The bivariate random-effects approach was used to calculate the pooled estimates by considering the heterogeneity of major related parameters such as the menopausal status, International Federation of Gynecology and Obstetrics stages, detection method and blinded design. Three tests yielded similar discriminatory performances in the OCa diagnosis (AUC [95 % CI]—0.89 [0.86–0.92] for HE4; 0.87 [0.84–0.90] for CA125; 0.91 [0.88–0.93] for ROMA). HE4 yielded a higher specificity than CA125 and ROMA (HE4 93.60 [90.00–95.90] > CA125 82.10 [76.60–86.50] and ROMA 82.40 [77.40–86.50]), especially in the premenopausal subgroup (HE4 93.80 [88.40–96.80] > CA125 76.30 [63.30–85.70] and ROMA 85.10 [80.40–88.80]). In contrast, CA125 and ROMA performed significantly better in the postmenopausal subgroup than in the premenopausal subgroup (AUC [95 % CI]—CA125-premenopausal 0.85 [0.82–0.88] < post 0.92 [0.89–0.94]; ROMA-premenopausal 0.86 [0.83–0.89] < post 0.93 [0.90–0.95]). HE4 might be useful for diagnosing OCa due to its high specificity, especially in the premenopausal population. CA125 and ROMA are more suitable for diagnosing OCa in the postmenopausal population. More high-quality RCTs are needed.

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References

  1. Somigliana E, Vigano P, Tirelli AS, Felicetta I, Torresani E, Vignali M, et al. Use of the concomitant serum dosage of CA 125, CA 19-9 and interleukin-6 to detect the presence of endometriosis. Results from a series of reproductive age women undergoing laparoscopic surgery for benign gynaecological conditions. Hum Reprod. 2004;19(8):1871–6.

    Article  CAS  PubMed  Google Scholar 

  2. Moore RG, Miller MC, Eklund EE, Lu KH, Bast RC, Jr., Lambert-Messerlian G. Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age. Am J Obstet Gynecol. 2011.

  3. Escudero JM, Auge JM, Filella X, Torne A, Pahisa J, Molina R. Comparison of serum human epididymis protein 4 with cancer antigen 125 as a tumor marker in patients with malignant and nonmalignant diseases. Clin Chem. 2011;57(11):1534–44.

    Article  CAS  PubMed  Google Scholar 

  4. Holcomb K, Vucetic Z, Miller MC, Knapp RC. Human epididymis protein 4 offers superior specificity in the differentiation of benign and malignant adnexal masses in premenopausal women. Am J Obstet Gynecol. 2011;205(4):358.e1–6.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. Ono K, Tanaka T, Tsunoda T, Kitahara O, Kihara C, Okamoto A, et al. Identification by cDNA microarray of genes involved in ovarian carcinogenesis. Cancer res. 2000;60(18):5007–11.

    CAS  PubMed  Google Scholar 

  7. 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(8):1315–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. 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.

    PubMed  Google Scholar 

  9. 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Whiting P, Rutjes AW, Reitsma JB, Bossuyt PM, Kleijnen J. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in systematic reviews. BMC Med Res Methodol. 2003;3:25.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Riley RD, Abrams KR, Sutton AJ, Lambert PC, Thompson JR. Bivariate random-effects meta-analysis and the estimation of between-study correlation. BMC Med Res Methodol. 2007;7:3.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Reitsma JB, Glas AS, Rutjes AW, Scholten RJ, Bossuyt PM, Zwinderman AH. Bivariate analysis of sensitivity and specificity produces informative summary measures in diagnostic reviews. J Clin Epidemiol. 2005;58(10):982–90.

    Article  PubMed  Google Scholar 

  15. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med. 1999;18(20):2693–708.

    Article  CAS  PubMed  Google Scholar 

  17. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.

    Article  CAS  PubMed  Google Scholar 

  18. Lenhard M, Stieber P, Hertlein L, Kirschenhofer A, Furst S, Mayr D, et al. The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses. Clin Chem Lab Med : CCLM / FESCC. 2011;49(21):2081–8.

    CAS  Google Scholar 

  19. Lawicki S, Bedkowska GE, Gacuta-Szumarska E, Szmitkowski M. The plasma concentration of VEGF, HE4 and CA125 as a new biomarkers panel in different stages and sub-types of epithelial ovarian tumors. J Ovarian Res. 2013;6(1):45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Anastasi E, Granato T, Falzarano R, Storelli P, Ticino A, Frati L, et al. The use of HE4, CA125 and CA72-4 biomarkers for differential diagnosis between ovarian endometrioma and epithelial ovarian cancer. J Ovarian Res. 2013;6(1):44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Kondalsamy-Chennakesavan S, Hackethal A, Bowtell D, Obermair A. Differentiating stage 1 epithelial ovarian cancer from benign ovarian tumours using a combination of tumour markers HE4, CA125, and CEA and patient’s age. Gynecol Oncol. 2013;129(3):467–71.

    Article  CAS  PubMed  Google Scholar 

  22. Kaijser J, Van Gorp T, Van Hoorde K, Van Holsbeke C, Sayasneh A, Vergote I, et al. A comparison between an ultrasound based prediction model (LR2) and the Risk of Ovarian Malignancy Algorithm (ROMA) to assess the risk of malignancy in women with an adnexal mass. Gynecol Oncol. 2013;129(2):377–83.

    Article  PubMed  Google Scholar 

  23. Hamed EO, Ahmed H, Sedeek OB, Mohammed AM, Abd-Alla AA, Abdel Ghaffar HM. Significance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response. Diagn Pathol. 2013;8:11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. 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. 2012;128(2):233–8.

    Article  PubMed  Google Scholar 

  25. Novotny Z, Presl J, Kucera R, Topolcan O, Vrzalova J, Fuchsova R, et al. HE4 and ROMA index in Czech postmenopausal women. Anticancer Res. 2012;32(9):4137–40.

    PubMed  Google Scholar 

  26. 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.

    Article  PubMed  Google Scholar 

  27. 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. Clin (Sao Paulo). 2012;67(5):437–41.

    Article  Google Scholar 

  28. Freydanck MK, Laubender RP, Rack B, Schuhmacher L, Jeschke U, Scholz C. Two-marker combinations for preoperative discrimination of benign and malignant ovarian masses. Anticancer Res. 2012;32(5):2003–8.

    CAS  PubMed  Google Scholar 

  29. Zheng H, Gao Y. Serum HE4 as a useful biomarker in discriminating ovarian cancer from benign pelvic disease. Int J Gynecol Cancer. 2012;22(6):1000–5.

    Article  PubMed  Google Scholar 

  30. Kadija S, Stefanovic A, Jeremic K, Radojevic MM, Nikolic L, Markovic I, et al. The utility of human epididymal protein 4, cancer antigen 125, and risk for malignancy algorithm in ovarian cancer and endometriosis. Int J Gynecol Cancer. 2012;22(2):238–44.

    Article  PubMed  Google Scholar 

  31. Bandiera E, Romani C, Specchia C, Zanotti L, Galli C, Ruggeri G, et al. Serum human epididymis protein 4 and risk for ovarian malignancy algorithm as new diagnostic and prognostic tools for epithelial ovarian cancer management. Cancer Epidemiol Biomarkers Prev. 2011;20(12):2496–506.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Molina R, Escudero JM, Auge JM, Filella X, Foj L, Torne A, et al. HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases. Tumour Biol : J Int Soc for Oncodevelopmental Biol Med. 2011;32(6):1087–95.

    Article  CAS  Google Scholar 

  33. Moore RG, Miller MC, Disilvestro P, Landrum LM, Gajewski W, Ball JJ, et al. Evaluation of the diagnostic accuracy of the Risk of Ovarian Malignancy Algorithm in women with a pelvic mass. Obstet Gynecol. 2011;118(2 Pt 1):280–8.

    Article  PubMed Central  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Park Y, Kim Y, Lee EY, Lee JH, Kim HS. Reference ranges for HE4 and CA125 in a large Asian population by automated assays and diagnostic performances for ovarian cancer. Int J Cancer. 2011;130(5):1136–44.

    Article  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. Kim YM, Whang DH, Park J, Kim SH, Lee SW, Park HA, et al. Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA125 for detecting ovarian cancer: a prospective case-control study in a Korean population. Clin Chem Lab Med. 2011;49(3):527–34.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  39. 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 : CCLM / FESCC. 2011;49(3):521–5.

    Article  CAS  Google Scholar 

  40. Abdel-Azeez HA, Labib HA, Sharaf SM, Refai AN. HE4 and mesothelin: novel biomarkers of ovarian carcinoma in patients with pelvic masses. Asian Pac J Cancer Prev. 2010;11(1):111–6.

    PubMed  Google Scholar 

  41. 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 : J Int Soc for Oncodevelopmental Biol Med. 2010;31(2):113–9.

    Article  CAS  Google Scholar 

  42. Nolen B, Velikokhatnaya L, Marrangoni A, De Geest K, Lomakin A, Bast Jr RC, et al. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol. 2010;117(3):440–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Shah CA, Lowe KA, Paley P, Wallace E, Anderson GL, McIntosh MW, et al. Influence of ovarian cancer risk status on the diagnostic performance of the serum biomarkers mesothelin, HE4, and CA125. Cancer Epidemiol Biomarkers Prev. 2009;18(5):1365–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. Pitta Dda R, Sarian LO, Barreta A, Campos EA, Andrade LL, Fachini AM, et al. Symptoms, CA125 and HE4 for the preoperative prediction of ovarian malignancy in Brazilian women with ovarian masses. BMC Cancer. 2013;13:423.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Zhejiang University, Hangzhou, China

    Jiwen Wang

  2. Department of Thoracic Surgery, Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China

    Jiwen Wang

  3. Clinical Laboratory, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, 100021, Beijing, China

    Jia Gao, Zongyong Wu, Minjie Wang & Jun Qi

  4. Department of Gynecologic Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, 100021, Beijing, China

    Hongwen Yao

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  1. Jiwen Wang
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Correspondence to Minjie Wang or Jun Qi.

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Jiwen Wang and Jia Gao have contributed equally to this work.

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Wang, J., Gao, J., Yao, H. et al. Diagnostic accuracy of serum HE4, CA125 and ROMA in patients with ovarian cancer: a meta-analysis. Tumor Biol. 35, 6127–6138 (2014). https://doi.org/10.1007/s13277-014-1811-6

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  • DOI: https://doi.org/10.1007/s13277-014-1811-6

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