Objective
The human epididymis protein 4 (HE4) is a novel biomarker for ovarian cancer. This study measured the HE4 and CA125 levels in women with benign gynecological disorders.
Study Design
Sera were obtained from women prior to surgery for a pelvic mass and HE4 and CA125 levels were determined. The proportions of patients with elevated biomarker levels were compared.
Results
There were 1042 women with benign disease. HE4 levels were less often elevated than CA125 (8% vs 29%, P < .001). A marked difference was observed in patients with endometriosis in which HE4 was elevated in 3% of patients and CA125 in 67% ( P < .0001). Serous ovarian tumors were associated with elevated levels of HE4 in 8% of patients and CA125 in 20% ( P = .0002); uterine fibroids in 8% vs 26% ( P = .0083); dermoids in 1% vs 21% ( P = .0004); and inflammatory disease in 10% vs 37% ( P = .014).
Conclusion
HE4 is elevated less frequently than CA125 in benign disease, particularly in premenopausal patients.
For nearly 3 decades, CA125 has been used as a biomarker for monitoring the course of ovarian cancer. CA125 is a high-molecular-weight mucin (>1 million daltons) that is enzymatically cleaved and shed from the surface of ovarian cancer cells. Approximately 80% of ovarian cancers express CA125.
Only a few normal tissues express low levels of CA125 including the endometrium, fallopian tube epithelium, lung parenchyma, and cornea. Significant levels of CA125 are found in deposits of endometriosis during the first trimester of normal pregnancy and in some benign ovarian tumors. Any condition that irritates the peritoneum, pericardium, or pleura can also elevate CA125. Consequently, CA125 levels can be elevated in pelvic inflammatory disease, cirrhosis with ascites, and congestive heart failure with pleural effusions. False-positive elevations of CA125 have been a particular problem in premenopausal women in whom endometriosis is more active, pregnancy occurs, and CA125 can be modestly elevated by normal menstruation.
Because ovarian cancer occurs more frequently in postmenopausal women and the uterus and fallopian tubes are removed during cytoreductive surgery, CA125 has been a highly specific biomarker for monitoring women with epithelial ovarian cancer during treatment and subsequent follow-up for recurrent disease. Preoperative serum levels of CA125 and the rate of decline of CA125 in women undergoing chemotherapy treatment for epithelial ovarian cancer have been shown to be prognostic indicators for this disease. In differentiating benign from malignant pelvic masses, consideration of the CA125 level has improved prediction using ultrasound and age in a risk of malignancy index, but the limited specificity of CA125 has left room for improvement.
Recently, the human epididymis protein 4 (HE4) has been shown to be a promising marker for epithelial ovarian cancer with increased specificity over CA125 and improved sensitivity for distinguishing malignant from benign pelvic masses. HE4 is a whey acid protein with a 4-disulfide core originally isolated from epithelial cells of the human epididymis. HE4 is expressed in numerous tissues throughout the body, including the female reproductive tract. Importantly, at least from the perspective of ovarian cancer detection, HE4 circulates in the bloodstream and is overexpressed in patients with serous and endometrioid epithelial ovarian carcinomas but is not expressed in normal ovarian surface epithelium. Several recent studies from our group have demonstrated that HE4 in combination with CA125 yields a higher specificity and sensitivity for distinguishing malignant from benign pelvic masses compared with either marker alone.
To date, there are no large studies that have examined serum HE4 levels in healthy premenopausal and postmenopausal women with benign gynecological disorders. In a complementary article reported in this issue of the American Journal of Obstetrics and Gynecology , we have defined normal levels of HE4 in sera from healthy women and found that HE4 levels increase with age and decrease during pregnancy. In the present study, we have documented that HE4 is less frequently elevated than CA125 in many, but not all, benign conditions and diseases.
Materials and Methods
The Institutional Review Board (IRB) for Human Studies at Woman and Infants Hospital (WIH) approved an analysis that utilized serum biomarker levels of HE4 and CA125 from 3 IRB prospective trials (WIH Pilot trial, FDI-03 trial, registered with the National Institutes of Health clinical trial registry ClinicalTrial.gov identifier NCT00315692 and the FDI-15 trial registered with the National Institutes of Health clinical trial registry ClinicalTrial.gov identifier NCT00987649 ) as well as serums obtained from IRB-approved serum repositories at the Massachusetts General Hospital (MGH) and the M. D. Anderson Cancer Center (MDACC) to evaluate biomarker levels of HE4 and CA125.
All serum samples were obtained from women prior to surgery for an ovarian cyst or pelvic mass. Serum HE4 levels were determined using the HE4 EIA assay kit (Fujirebio Diagnostics Inc, Malvern, PA), and serum CA125II levels were measured on the Abbott i2000 ARCHITECT assay platform (Abbott Diagnostics Inc, Abbott Park, IL). Serum assays were run at 3 different laboratories (MGH, MDACC, and Fujirebio Diagnostics). All HE4 values were derived using cubic spline interpolation. Pathology reports were reviewed at the time of each study and used for histopathologial classification of the benign neoplasms.
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