Diagnostic value of serum human epididymis protein 4, carbohydrate antigen 125 and their combination in endometrial cancer: A meta-analysis

Background: To systematically analyze the value of human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) in the diagnosis of endometrial cancer, so as to provide evidence-based medical evidence for the selection of serum tumor markers in the early screening of endometrial cancer. Methods: We comprehensively searched relevant literature in the Cochrane Library, EMBASE, PubMed, Web of Science, CNKI, VIP, WanFang, and CBM from the date of establishment to November 31, 2021. Quality assessment of diagnostic accuracy studies 2 was applied to evaluate the quality of the included literature. We used Stata 16.0 to calculate the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) and plot summary receiver operating characteristic curve, as well as to assess diagnostic accuracy using the area under the curve (AUC). Results: A total of 25 studies, including 1980 patients and 2345 controls, were included in this meta-analysis. The pooled SEN, SPE, PLR, NLR, DOR, and AUC of HE4 were 0.58 (95% CI 0.52–0.63), 0.95 (95% CI 0.92–0.97), 11.57 (95% CI 6.88–19.48), 0.45 (95% CI 0.39–0.51), 25.92 (95% CI 14.84–45.26), and 0.80 (95% CI 0.76–0.83), respectively. The pooled SEN, SPE, PLR, NLR, DOR, and AUC of CA125 were 0.41 (95% CI 0.34–0.49), 0.91 (95% CI 0.85–0.95), 4.55 (95% CI 2.73–7.58), 0.65 (95% CI 0.57–0.74), 7.03 (95% CI 3.92–12.62), and 0.68 (95% CI 0.64–0.72), respectively. The pooled SEN, SPE, PLR, NLR, DOR, and AUC of HE4 + CA125 were 0.67 (95% CI 0.60–0.73), 0.92 (95% CI 0.87–0.95), 8.59 (95% CI 5.32–13.86), 0.36 (95% CI 0.30–0.44), 23.80 (95% CI 13.86–40.86), and 0.85 (95% CI 0.82–0.88), respectively. Conclusion: This Meta-analysis found that HE4 alone or in combination with CA125 showed better diagnostic efficacy than CA125, regardless of clinical stage and pathological type. HE4 + CA125 had slightly higher diagnostic efficiency than HE4, but did not show significant advantages. While the studies were heterogeneous, the credibility of the findings needs to be further confirmed by more homogeneous, prospective, and large sample size studies.

[1]  E. Crosbie,et al.  HE4 as a Biomarker for Endometrial Cancer , 2021, Cancers.

[2]  Jae-Weon Kim,et al.  Endometrial Cancer. , 2021, The New England journal of medicine.

[3]  N. Winer,et al.  Endometrial cancer: A systematic review of HE4, REM and REM-B. , 2020, Clinica chimica acta; international journal of clinical chemistry.

[4]  J. Ket,et al.  DNA methylation markers for endometrial cancer detection in minimally invasive samples: a systematic review. , 2020, Epigenomics.

[5]  Hong-yan Cheng,et al.  Age and menopausal status are important factors influencing the serum human epididymis secretory protein 4 level: a prospective cross-sectional study in healthy Chinese people , 2020, Chinese medical journal.

[6]  Jinping Li,et al.  Comparison of serum human epididymis protein 4 and CA125 on endometrial cancer detection: A meta-analysis. , 2019, Clinica chimica acta; international journal of clinical chemistry.

[7]  M. Bhardwaj,et al.  Diagnostic Performance of Serum Human Epididymis Protein 4 in Endometrial Carcinoma: A Pilot Study. , 2017, Journal of clinical and diagnostic research : JCDR.

[8]  Ping Liu,et al.  Value of HE4 Combined with Cancer Antigen 125 in the Diagnosis of Endometrial Cancer , 2017, Pakistan journal of medical sciences.

[9]  J. Ledermann,et al.  ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer , 2015, International Journal of Gynecologic Cancer.

[10]  P. Zhang,et al.  Determination of reference intervals of serum levels of human epididymis protein 4 (HE4) in Chinese women , 2015, Journal of Ovarian Research.

[11]  A. Dirican,et al.  The diagnostic role of human epididymis protein 4 and serum amyloid-A in early-stage endometrial cancer patients , 2013, Tumor Biology.

[12]  R. Angioli,et al.  The role of novel biomarker HE4 in endometrial cancer: a case control prospective study , 2013, Tumor Biology.

[13]  E. Sartori,et al.  Human epididymis protein 4 as a serum marker for diagnosis of endometrial carcinoma and prediction of clinical outcome , 2012, Clinical chemistry and laboratory medicine.

[14]  Peng Zhang,et al.  [Clinical value of combined detection of serum human epididymal secretory protein E4 and CA(125) in the diagnosis of endometrial carcinoma]. , 2012, Zhonghua fu chan ke za zhi.

[15]  K. Nustad,et al.  Human epididymis protein 4 reference limits and natural variation in a Nordic reference population , 2011, Tumor Biology.

[16]  Susan Mallett,et al.  QUADAS-2: A Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies , 2011, Annals of Internal Medicine.

[17]  A. Jemal,et al.  Cancer statistics, 2011 , 2011, CA: a cancer journal for clinicians.

[18]  S. Calza,et al.  Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients , 2011, British Journal of Cancer.

[19]  Jinping Li,et al.  HE4 as a biomarker for ovarian and endometrial cancer management , 2009, Expert review of molecular diagnostics.

[20]  Holly Janes,et al.  Pivotal Evaluation of the Accuracy of a Biomarker Used for Classification or Prediction: Standards for Study Design , 2008, Journal of the National Cancer Institute.

[21]  Richard G. Moore,et al.  Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus. , 2008, Gynecologic oncology.

[22]  S. Walter,et al.  Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data , 2002, Statistics in medicine.

[23]  P. Buamah.  Benign conditions associated with raised serum CA‐125 concentration , 2000, Journal of surgical oncology.

[24]  J. Ptak,et al.  University of Southern Denmark Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers , 2018 .

[25]  ACOG Committee Opinion No. 734 Summary: The Role of Transvaginal Ultrasonography in Evaluating the Endometrium of Women With Postmenopausal Bleeding. , 2018, Obstetrics and gynecology.

[26]  X. Yi,et al.  Serum human epididymis protein 4 vs. carbohydrate antigen 125 and their combination for endometrial cancer diagnosis: a meta-analysis. , 2016, European review for medical and pharmacological sciences.

[27]  N. Abdalla,et al.  The role of HE4 and CA125 in differentiation between malignant and non-malignant endometrial pathologies. , 2016, Ginekologia polska.

[28]  E. Ouladsahebmadarek,et al.  Diagnostic Value of Novel Biomarker Human Epididymis Protein 4 (HE4) in Detecting Endometrial Cancer , 2016 .

[29]  Lin Ying-yin.  Diagnostic and prognostic value of serum HE4 detection for endometrial carcinoma patients compared with CA 125 , 2014 .

[30]  Z. Ping.  Differential diagnostic value of combined detection of serum HE4 and CA125 in patients with endometrial carcinoma from benign uterus tumor , 2012 .

[31]  Z. Hui.  Clinical value of combined detection of CA125 and HE4 in diagnosis of endometrial carcinoma , 2011 .

[32]  N. Dubrawsky.  Cancer statistics , 2022 .