Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus
Introduction
Approximately 40,100 new cases of uterine cancer are diagnosed in the United States annually, resulting in 7470 deaths[1]. Unlike many malignancies, endometrial cancer patients often exhibit signs and symptoms such as postmenopausal bleeding that lead to the diagnosis of the malignancy in the early stages of the disease. As a result, 70% of endometrial cancers are detected as stage I malignancies and have an excellent prognosis. The need for tumor markers to detect early-stage endometrial cancer is not as critical as is the development of markers to detect premalignant or early-stage malignancy in ovarian cancer, a cancer that generally presents with treatable, but fundamentally incurable disease. However, certain high risk groups, including women with Lynch syndrome, are at extremely high risk for endometrial cancer and may benefit from a serum marker for early detection.
In addition, for the group of endometrial cancer patients at high risk for recurrence or for patients with systemic and advanced stage disease, sensitive tumor markers for monitoring are needed. Similar to the value of the CA125 tumor marker employed in ovarian cancer, a marker for endometrial cancers that is useful in the early detection of recurrent disease or for the evaluation of response to treatment is critical. Patients diagnosed with stage I disease who have intermediate or high risk factors based on deep myometrial invasion, lymphvascular space invasion or high grade tumors have recurrence rates of 20% to 30% [2], [3]. At the present time, the detection of recurrent disease is through monitoring for clinical symptoms and the use of imaging modalities, which normally detect disease in advanced stages. Elevated CA125 levels have been demonstrated to correlate with advanced disease [4], [5], [6], [7], [8], however, the use of CA125 for the detection of early recurrent endometrial cancer is limited. Only 10% to 20% of patients with early-stage disease and approximately 25% of patients with asymptomatic recurrent disease will have an elevated CA125 level [9], [10].
A number of serum tumor markers have been studied for their potential clinical utility in patients with endometrial cancer including CA15.3, CA19.9, CA72.4, CEA, OVX1, and M-CSF [11], [12], [13], [14], [15]. More recently, proteomic analysis has also been employed to identify novel makers for endometrial cancer such as chaperonin 10 [16]. Despite these technical advances, only a few studies have examined multiple markers, such as CA125 and CA19-9, and their expression in the serum of endometrial cancer patients with promising results [17]. The objectives of this study were to examine the expression levels of CA125 and the novel serum tumor markers HE4, soluble mesothelin-related peptide (SMRP), and CA72.4 in patients with endometrioid adenocarcinoma of the uterus and to evaluate the detection sensitivity and specificity of these biomarkers to differentiate between healthy women and women with cancer when used alone and in multiple combinations.
Section snippets
Methods
Blood samples were obtained from patients enrolled in a prospective study conducted at Women and Infants' Hospital/Brown University and retrospectively from the serum bank at The University of Texas M.D. Anderson Cancer Center (UTMDACC). All enrolled patients provided written informed consent prior to the collection of any blood samples. The prospective study protocol at Women and Infants' Hospital was reviewed and approved by the institutional review board (IRB) at Women and Infants' Hospital.
Statistical analysis
Tumor marker levels in normal healthy controls and endometrial cancer patients were compared using the Wilcoxon rank-sum test (Mann–Whitney two sample statistic). The use of logistic regression analysis with constructs of receiver operator characteristic curves and the estimates of sensitivity at set specificities for analysis of multiple markers have been fully described in a previous paper analyzing multiple marker use in ovarian cancer[18]. In summary, logistic regression models were
Results
Serum samples were obtained from 171 patients with surgically staged endometrial cancer (92 from Women and Infants' Hospital and 79 from MDACC) and from 156 healthy subjects. The median age for cancer patients was 62 years (range 25 to 95) and for controls was 62 years (range 51 to 78). Of the 171 patients with surgically staged endometrial cancer, 122 (71%) were diagnosed with stage I disease, 17 (10%) with stage II disease, 26 (15%) with stage III disease, and 6 (4%) with stage IV disease.
The
Discussion
Endometrial cancer patients often present with signs or symptoms that result in the diagnosis of their disease in the early stages and therefore most women have an excellent prognosis. With this in mind the utility of a tumor marker used as a screening tool in the general population is not as critical as a marker for early detection in cancers that are most often diagnosed in the late stages such as ovarian and pancreatic cancer. However, for women that are at increased risk for the development
Conflict of interest statement
Richard G. Moore: Fujirebio Scientific Advisory Board, Research Funding
Amy K. Brown: Fujirebio Scientific Advisory Board
M. Craig Miller: Statistical Consultant
Donna Badgwell: There are no conflicts of interest.
Zhen Lu: There are no conflicts of interest.
W. Jeffrey Allard: Fujirebio VP of Clinical Affairs.
C.O. Granai: There are no conflicts of interest.
Robert C. Bast Jr: Fujirebio Scientific Advisory Board, Royalties, Research Funding
Karen Lu: There are no conflicts of interest.
Acknowledgments
This work was supported in part by the Endometrial Cancer SPORE (P50 CA098258) and the Ovarian Cancer SPORE (P50 CA083639) awarded to U.T. M.D. Anderson Cancer Center.
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