Elsevier

Gynecologic Oncology

Volume 112, Issue 1, January 2009, Pages 40-46
Gynecologic Oncology

A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass

https://doi.org/10.1016/j.ygyno.2008.08.031Get rights and content

Abstract

Introduction

Patients diagnosed with epithelial ovarian cancer (EOC) have improved outcomes when cared for at centers experienced in the management of EOC. The objective of this trial was to validate a predictive model to assess the risk for EOC in women with a pelvic mass.

Methods

Women diagnosed with a pelvic mass and scheduled to have surgery were enrolled on a multicenter prospective study. Preoperative serum levels of HE4 and CA125 were measured. Separate logistic regression algorithms for premenopausal and postmenopausal women were utilized to categorize patients into low and high risk groups for EOC.

Results

Twelve sites enrolled 531 evaluable patients with 352 benign tumors, 129 EOC, 22 LMP tumors, 6 non EOC and 22 non ovarian cancers. The postmenopausal group contained 150 benign cases of which 112 were classified as low risk giving a specificity of 75.0% (95% CI 66.9–81.4), and 111 EOC and 6 LMP tumors of which 108 were classified as high risk giving a sensitivity of 92.3% (95% CI = 85.9–96.4). The premenopausal group had 202 benign cases of which 151 were classified as low risk providing a specificity of 74.8% (95% CI = 68.2–80.6), and 18 EOC and 16 LMP tumors of which 26 were classified as high risk, providing a sensitivity of 76.5% (95% CI = 58.8–89.3).

Conclusion

An algorithm utilizing HE4 and CA125 successfully classified patients into high and low risk groups with 93.8% of EOC correctly classified as high risk. This model can be used to effectively triage patients to centers of excellence.

Introduction

Each year in the United States, approximately 289,000 women are hospitalized with an ovarian cyst or pelvic mass. As the incidence of surgery for suspected ovarian neoplasms is increasing, estimates indicate approximately 10% of all women in the United States will undergo surgery for an ovarian neoplasm [1]. However, only a small percentage of these women will ultimately be diagnosed with an epithelial ovarian cancer (EOC), a malignancy that requires comprehensive surgical staging or aggressive cytoreductive surgery. Unfortunately, fewer than half of ovarian cancer patients have their initial surgery by gynecologic oncologists or surgeons that have specialty training in the surgical management of ovarian cancer and therefore many patients undergo inadequate surgical staging or receive suboptimal cytoreductive surgery at their initial surgery[2], [3]. A recent study indicate women who are operated on by surgeons who specialize in the management of EOC and at centers experienced in the management of patients with this disease have decreased morbidity and mortality and an increase in overall survival [4], [5], [6], [7].

Currently, algorithms and triage protocols for the assessment of the probability of a woman with a pelvic mass harboring a malignancy are limited. The serum tumor marker CA125 has been evaluated in this role [8]. However, CA125 is elevated in less than half of early stage EOC and is not expressed in approximately 20% of EOC resulting in decreased sensitivity [9], [10]. Equally problematic, CA125 is elevated in many benign gynecologic diseases that commonly affect premenopausal women and in many medical conditions that affect postmenopausal women resulting in a reduction of specificity [10]. A risk assessment tool that accurately classifies patients into high and low risk groups for having an ovarian malignancy is critical for the ability to triage patients to centers of excellence.

A study examining a panel of serum biomarkers for the detection of malignancy in women presenting with a pelvic mass demonstrated that the addition of HE4 to CA125 improved the sensitivity and specificity over that of CA125 alone for the risk assessment of a malignancy in patients with a pelvic mass [11]. We conducted a prospective multicenter clinical trial to validate a predictive model utilizing the dual marker combination of HE4 and CA125 to assess the risk for EOC in women presenting with a pelvic mass.

Section snippets

Methods

This was a prospective multicenter trial registered with the National Institute of Health clinical trial registry (ClinicalTrial.gov identifier NCT00315692). Each site participating in the study obtained institutional review board approval from their respective institutions. To be eligible for enrollment patients were required to be 18 years of age or older and have a diagnosis of an ovarian cyst or a pelvic mass with a planned surgical intervention. Women with a prior bilateral oophorectomy

Statistical analysis

The primary endpoint of the clinical study was to classify patients with a pelvic mass into high risk or low risk groups for having EOC using the serum biomarkers CA125 and HE4, and to determine the accuracy of these classifications. Prior to the start of this trial, a pilot study conducted at Women and Infants' Hospital of Rhode Island (WIHRI) examining multiple markers in patients with a pelvic mass determined that the dual marker combination of HE4 and CA125 had the highest predictive value

Results

A total of 566 patients were enrolled from 12 different geographic sites across the United States. Patient demographics and characteristics are illustrated in Table 1. Of the 566 patients enrolled onto the trial, 531 patients were evaluable, with 283 postmenopausal women and 248 premenopausal women. A total of 54 women had menopausal status determined by plasma FSH levels, 47 of which had a prior hysterectomy with preservation of at least one ovary. The mean age of the evaluable study cohort

Discussion

The American Cancer Society estimates there will be 22,430 women diagnosed with ovarian cancer resulting in 15,280 deaths in the year 2007 [12]. Surgical debulking and comprehensive surgical staging are the hallmark of ovarian cancer management. Optimal debulking surgeries have been correlated with increased survival rates and surgical staging has also been shown to play a vital role in the management of women diagnosed with ovarian cancer [13], [14], [15]. While patients diagnosed with

Conflict of interest statement

This study was supported by Fujirebio Diagnostics Inc. The following authors have served as consultants and served on the scientific advisory board for Fujirebio Diagnostics Inc. and have received compensation: RM, RB, SS, AB, CM, SM and WJA. RM served as the PI for this trial.

Acknowledgments

This study was supported by Fujirebio Diagnostics Inc. and by NCI grants CA086381 and CA105009 (S. Skates).

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