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