The Prognostic and Predictive Value of Combined HE4 and CA-125 in Ovarian Cancer Patients

Objective A risk-of-ovarian-malignancy algorithm (ROMA) based on human epididymis protein 4 (HE4) and CA-125 has been reported to categorize women with a pelvic mass into high or low risk of ovarian malignancy. Originally, the ROMA score was developed for diagnostic purposes and the clinical application of HE4 for other purposes such as a predictor of survival or platinum resistance has not been extensively investigated. The objective of the present study was to evaluate the prognostic importance of prechemotherapy combined levels of HE4 and CA-125 and prediction of platinum resistance. Furthermore, we wanted to investigate the dynamics of the markers during treatment. Materials and Methods Serum from 137 patients with newly diagnosed serous ovarian cancer was analyzed for CA-125 and HE4 using ELISAs in a training data set. Patients with high levels (upper third percentiles) of both HE4 and CA-125 were classified as high-risk patients. Data were validated in an independent data set of an additional 94 patients. HE4 and CA-125 were also analyzed at all cycles of subsequent chemotherapy. Results The combined score of HE4 and CA-125 was highly predictive of both progression-free and overall survival in univariate as well as multivariate survival analysis. Values in the upper third percentiles (66th) were significantly associated with decreased progression-free and overall survival in both the training and in the validation set (P < 0.05 in all analyses). The positive predictive value in relation to platinum resistance was higher for the combination of markers than for the markers individually. The positive predictive values were 64.3% and 60.7% for combined CA-125/HE4 in the training and validation sets, respectively. Conclusions The combination of HE4 and CA-125 levels at baseline just before initiation of chemotherapy was significantly associated with decreased progression-free and overall survival and to some extent with platinum resistance.

[1]  Steven J Skates,et al.  A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. , 2009, Gynecologic oncology.

[2]  G. Anderson,et al.  Influence of Ovarian Cancer Risk Status on the Diagnostic Performance of the Serum Biomarkers Mesothelin, HE4, and CA125 , 2009, Cancer Epidemiology Biomarkers & Prevention.

[3]  D. Lockhart,et al.  Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  L. Shulman.  HE4 and CA125 as a diagnostic test in ovarian cancer: prospective validation of the Risk of Ovarian Malignancy Algorithm , 2011 .

[5]  K. Steffensen,et al.  The Relationship of Platinum Resistance and ERCC1 Protein Expression in Epithelial Ovarian Cancer , 2009, International Journal of Gynecologic Cancer.

[6]  Thorsten Verch,et al.  The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass. , 2008, Gynecologic oncology.

[7]  Michèl Schummer,et al.  The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. , 2003, Cancer research.

[8]  M. lenhard,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 , 2011, Clinical chemistry and laboratory medicine.

[9]  R. Molina,et al.  HE4 a novel tumour marker for ovarian cancer: comparison with CA 125 and ROMA algorithm in patients with gynaecological diseases , 2011, Tumor Biology.

[10]  C. Specchia,et al.  Serum Human Epididymis Protein 4 and Risk for Ovarian Malignancy Algorithm as New Diagnostic and Prognostic Tools for Epithelial Ovarian Cancer Management , 2011, Cancer Epidemiology, Biomarkers & Prevention.

[11]  D. Whang,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 , 2011, Clinical chemistry and laboratory medicine.

[12]  G. Rustin,et al.  Use of CA-125 to assess response to new agents in ovarian cancer trials. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  H. Frierson,et al.  Comprehensive analysis of HE4 expression in normal and malignant human tissues , 2006, Modern Pathology.

[14]  Christopher P Crum,et al.  Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. , 2005, Cancer research.

[15]  Richard G. Moore,et al.  Evaluation of the Diagnostic Accuracy of the Risk of Ovarian Malignancy Algorithm in Women With a Pelvic Mass , 2011, Obstetrics and gynecology.

[16]  H. Labib,et al.  HE4 and mesothelin: novel biomarkers of ovarian carcinoma in patients with pelvic masses. , 2010, Asian Pacific journal of cancer prevention : APJCP.

[17]  Georgios Nakos,et al.  Monitoring , 1976, Encyclopedia of the UN Sustainable Development Goals.

[18]  D. Goldstein,et al.  No benefit from combining HE4 and CA125 as ovarian tumor markers in a clinical setting. , 2011, Gynecologic oncology.

[19]  E. Sartori,et al.  Serum human epididymis protein 4 ( HE 4 ) and Risk for Ovarian Malignancy Algorithm ( ROMA ) as new diagnostic and prognostic tools for epithelial ovarian cancer management , 2011 .

[20]  L. Hood,et al.  Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray. , 1999, Gene.

[21]  Y. Bourbonnais,et al.  Proteins with whey-acidic-protein motifs and cancer. , 2006, The Lancet. Oncology.

[22]  Giuseppe Lippi,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? , 2011, Clinical chemistry and laboratory medicine.

[23]  Jae-Hoon Kim,et al.  Serum HE4 Level is an Independent Prognostic Factor in Epithelial Ovarian Cancer , 2012, Annals of Surgical Oncology.

[24]  M. Poutanen,et al.  Serum HE4 concentration differentiates malignant ovarian tumours from ovarian endometriotic cysts , 2009, British Journal of Cancer.

[25]  G. Lippi,et al.  The utility of serum human epididymis protein 4 (HE4) in patients with a pelvic mass , 2009, Journal of clinical laboratory analysis.

[26]  T Tanaka,et al.  Identification by cDNA microarray of genes involved in ovarian carcinogenesis. , 2000, Cancer research.