Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus

Abstract

Objective

Tumor markers with increased sensitivity and specificity for endometrial cancer are needed to help monitor response to therapy and to detect recurrent disease. Currently, the tumor maker CA125 is utilized in this role with limited value. The objectives of this study were to examine the levels of several novel tumor markers HE4, SMRP, CA72.4 and CA125 as potential markers in patients diagnosed with endometrioid adenocarcinoma of the uterus.

Methods

Pre-operative serum samples from surgically staged patients with endometrioid adenocarcinoma of the uterus were analyzed for levels of HE4, SMRP, CA72-4 and CA125. Control samples were obtained from healthy postmenopausal women. Logistic regression models and receiver operating characteristic (ROC) curves were constructed for each tumor marker and for all combinations, with cross-validation analyses to obtain average sensitivities at set specificities of 90%, 95%, and 98%.

Results

Serum samples from 156 healthy subjects and 171 patients with endometrial cancer (122 stage I, 17 stage II, 26 stage III, and 6 stage IV) were analyzed. At a 95% specificity, the sensitivities for differentiating between healthy subjects and all stages of cancer were 45.5% for HE4 and 24.6% for CA125. For stage I disease, HE4 yielded a 17.1% improvement in sensitivity compared with CA125.

Conclusion

HE4 is elevated in all stages of endometrial can100cer and is more sensitive in early-stage endometrial cancer compared to CA125. Further investigation of HE4 as a marker for early detection of recurrent endometrial cancer and monitoring response to therapy is warranted.

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.