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Tumor Biology

, Volume 37, Issue 4, pp 4973–4978 | Cite as

The role of HE4 in endometrial cancer recurrence: how to choose the optimal follow-up program

  • Roberto Angioli
  • Stella Capriglione
  • Giuseppe Scaletta
  • Alessia Aloisi
  • Andrea Miranda
  • Carlo De Cicco Nardone
  • Corrado Terranova
  • Francesco Plotti
Original Article

Abstract

The aim of this study was to evaluate for the first time in the literature the role of HE4, at primary diagnosis, compared to CA125 as an indicator of endometrial cancer (EC) recurrence. Our study is a retrospective analysis of 252 EC patients treated, between January 2009 and July 2013, at the Division of Gynaecologic Oncology of Campus Bio-Medico University of Rome. Thirty-seven patients experienced recurrence. Median follow-up was 38 months. HE4 and CA125 levels were analyzed at primary diagnosis, during follow-up and either after histological or radiological confirmation of recurrent disease or at last registered visit, when patients returned to our Department with no evidence of recurrent disease. A statistically significant difference was observed between HE4 values at primary diagnosis and at recurrence, respectively, comparing recurrent and non-recurrent patients (p < 0.05), while CA125 values resulted not statistically significant (p = 0.08) at each time point. Considering the poor specificity of HE4 at threshold of 70 pmol/L at primary diagnosis, in our cohort of patients, we found out that HE4 cut-off of 201.3 pmol/L is able to correctly classify patients at high or low risk of EC recurrence, with a sensitivity of 80 % and a specificity of 91 % (PPV = 90.3 % and NPV = 90.8 %). In particular, HE4 performance improves in cases of endometrioid histotype. HE4 levels at primary diagnosis correlate with an increased risk of EC recurrence, particularly in cases of endometrioid histotype, and they may help to recognize patients who may need a more intensive follow-up.

Keywords

Endometrial cancer HE4 Prognostic factor Recurrence 

Notes

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon: International Agency for Research on Cancer; 2013.Google Scholar
  2. 2.
    Ueda SM, Kapp DS, Cheung MK, et al. Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths. Am J Obstet Gynecol. 2008;198:218.e211–6.CrossRefGoogle Scholar
  3. 3.
    Fung-Kee-Fung M, Dodge J, Elit L, Lukka H, Chambers A, Oliver T, et al. Follow-up after primary therapy for endometrial cancer: a systematic review. Gynecol Oncol. 2006;101(3):520–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Smith CJ, Heeren M, Nicklin JL, Perrin LC, Land R, Crandon AJ, et al. Efficacy of routine follow-up in patients with recurrent uterine cancer. Gynecol Oncol. 2007;107(1):124–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Salani R, Backes FJ, Fung MF, et al. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol. 2011;204:466–78.CrossRefPubMedGoogle Scholar
  6. 6.
    Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C, Sessa C; ESMO Guidelines Working Group. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013 Oct;24 Suppl 6:vi33–8.Google Scholar
  7. 7.
    Aggarwal P, Kehoe S. Serum tumour markers in gynaecological cancers. Maturitas. 2010;67:46–53.CrossRefPubMedGoogle Scholar
  8. 8.
    Bignotti E, Ragnoli M, Zanotti L, Calza S, Falchetti M, Lonardi S, et al. Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer. 2011;104(9):1418–25.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Moore RG, Brown AK, Miller MC, Badgwell D, Lu Z, Allard WJ, et al. Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus. Gynecol Oncol. 2008;110(2):196–201.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zanotti L, Bignotti E, Calza S, Bandiera E, Ruggeri G, Galli C, et al. Human epididymis protein 4 as a serum marker for diagnosis of endometrial carcinoma and prediction of clinical outcome. Clin Chem Lab Med. 2012;50(12):2189–98.CrossRefPubMedGoogle Scholar
  11. 11.
    Capriglione S, Plotti F, Miranda A, Ricciardi R, Scaletta G, Aloisi A, et al. Utility of tumor marker HE4 as prognostic factor in endometrial cancer: a single-center controlled study. Tumour Biol. 2015;36(6):4151–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Angioli R, Miranda A, Aloisi A, Montera R, Capriglione S, De Cicco NC, et al. A critical review on HE4 performance in endometrial cancer: where are we now? Tumour Biol. 2014;35(2):881–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Angioli R, Capriglione S, Aloisi A, Luvero D, Cafà EV, Dugo N, et al. REM (risk of endometrial malignancy): a proposal for a new scoring system to evaluate risk of endometrial malignancy. Clin Cancer Res. 2013;19(20):5733–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Angioli R, Plotti F, Capriglione S, Montera R, Damiani P, Ricciardi R, et al. The role of novel biomarker HE4 in endometrial cancer: a case control prospective study. Tumour Biol. 2013;34(1):571–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Kalogera E, Scholler N, Powless C, Weaver A, Drapkin R, Li J, et al. Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer. Gynecol Oncol. 2012;124(2):270–5.CrossRefPubMedGoogle Scholar
  16. 16.
    Brennan DJ, Hackethal A, Metcalf AM, Coward J, Ferguson K, Oehler MK, et al. Serum HE4 as a prognostic marker in endometrial cancer—a population based study. Gynecol Oncol. 2014;132(1):159–65.CrossRefPubMedGoogle Scholar
  17. 17.
    Moore RG, Miller CM, Brown AK, Robison K, Steinhoff M, Lambert-Messerlian G. Utility of tumor marker HE4 to predict depth of myometrial invasion in endometrioid adenocarcinoma of the uterus. Int J Gynecol Cancer. 2011;21(7):1185–90.PubMedGoogle Scholar
  18. 18.
    Mutz-Dehbalaie I, Egle D, Fessler S, Hubalek M, Fiegl H, Marth C, et al. HE4 is an independent prognostic marker in endometrial cancer patients. Gynecol Oncol. 2012;126(2):186–91.CrossRefPubMedGoogle Scholar
  19. 19.
    Brennan DJ, Hackethal A, Mann KP, Mutz-Dehbalaie I, Fiegl H, Marth C, et al. Serum HE4 detects recurrent endometrial cancer in patients undergoing routine clinical surveillance. BMC Cancer. 2015;15:33.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet. 2005;366(9484):491–505.CrossRefPubMedGoogle Scholar
  21. 21.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.CrossRefGoogle Scholar
  22. 22.
    Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Warlam-Rodenhuis CC, et al. Survival after relapse in patients with endometrial cancer: results from a randomized trial. Gynecol Oncol. 2003;89(2):201–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Lajer H, Jensen MB, Kilsmark J, Albaek J, Svane D, Mirza MR, et al. The value of gynecologic cancer follow-up: evidence-based ignorance? Int J Gynecol Cancer. 2010;20:1307–20.PubMedGoogle Scholar
  24. 24.
    Zanagnolo V, Ming L, Gadducci A, Maggino T, Sartori E, Zola P, et al. Surveillance procedures for patients with cervical carcinoma: a review of the literature. Int J Gynecol Cancer. 2009;19:194–201.CrossRefPubMedGoogle Scholar
  25. 25.
    Sartori E, Pasinetti B, Chiudinelli F, Gadducci A, Landoni F, Maggino T, et al. Surveillance procedures for patients treated for endometrial cancer: a review of the literature. Int J Gynecol Cancer. 2010;20:985–92.CrossRefPubMedGoogle Scholar
  26. 26.
    Lo SS, Khoo US, Cheng DK, Ng TY, Wong LC, Ngan HY. Role of serial tumor markers in the surveillance for recurrence in endometrial cancer. Cancer Detect Prev. 1999;23(5):397–400.CrossRefPubMedGoogle Scholar
  27. 27.
    Patsner B, Orr Jr JW, Mann Jr WJ. Use of serum CA 125 measurement in posttreatment surveillance of early-stage endometrial carcinoma. Am J Obstet Gynecol. 1990;162(2):427–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Rose PG, Sommers RM, Reale FR, Hunter RE, Fournier L, Nelson BE. Serial serum CA 125 measurements for evaluation of recurrence in patients with endometrial carcinoma. Obstet Gynecol. 1994;84(1):12–6.PubMedGoogle Scholar
  29. 29.
    Lv YW, Yang L, Zhang M, Jiang LH, Niu JH, Hou J, et al. Increased human epididymis protein 4 in benign gynecological diseases complicated with chronic renal insufficiency patients. Genet Mol Res. 2015;14(1):2156–61.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Roberto Angioli
    • 1
  • Stella Capriglione
    • 1
  • Giuseppe Scaletta
    • 1
  • Alessia Aloisi
    • 1
  • Andrea Miranda
    • 1
  • Carlo De Cicco Nardone
    • 1
  • Corrado Terranova
    • 1
  • Francesco Plotti
    • 1
  1. 1.Department of ObstetricsUniversity of Rome “Campus Bio-Medico”RomeItaly

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