HE4 Expression Research Articles

Prognostic values of HE4 expression in patients with cancer: a meta-analysis.

BackgroundTo evaluate the prognostic impact of HE4 expression in patients with cancer.Materials and methodsWe searched the PubMed, Web of Science, Chinese National Knowledge Infrastructure and WangFang databases for publications concerning HE4 expression in patients with cancer. The correlation of HE4 expression level with overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) was analyzed.ResultsIn this meta-analysis, 29 studies, with a total of 4,235 patients, were included. Our results showed that HE4 expression was significantly associated with poorer OS (hazard ratio [HR] =2.15, 95% confidence interval [CI] =1.77–2.62, P<0.001). Further subgroup analysis found that this correlation was not affected by race (White: HR =1.92, 95% CI =1.53–2.39, P<0.001; Asian: HR =2.62, 95% CI =2.06–3.35, P<0.001) or tumor types (endometrial cancer: HR =2.91, 95% CI =1.86–4.53, P<0.001; ovarian cancer: HR =1.82, 95% CI =1.50–2.22, P<0.001; lung cancer: HR =2.31, 95% CI =1.54–3.47, P<0.001). Our meta-analysis showed that HE4 overexpression was significantly associated with DFS (HR =2.50, 95% CI =1.86–3.37, P<0.001) and PFS (HR =1.27, 95% CI =1.11–1.45, P=0.001).ConclusionThese results suggest that expression of HE4 was associated with a worse prognosis in patients with cancer. HE4 is a potential novel prognostic factor in patients with cancer.

Corrigendum to "Expression of HE4 in Endometrial Cancer and Its Clinical Significance".

[This corrects the article DOI: 10.1155/2015/437468.].

HE4 in tumor immune suppression and its potential as a therapeutic target in ovarian cancer

Objective: To determine the impact of HE4 expression on the tumor-immune microenvironment and to identify HE4 as a viable therapeutic target in ovarian cancer.

The clinical significance of the combined detection of serum Smac, HE4 and CA125 in endometriosis-associated ovarian cancer.

This study aims to investigate the clinical significance of serum Smac, HE4 and CA125 alone or combined for detecting endometriosis-associated ovarian cancer (EAOC). The level of serum Smac, HE4 and CA125 in 40 healthy controls, 40 cases of benign endometriosis ovarian tumor, and 60 cases of EAOC were detected by ELISA and electrochemical immune method. Serum Smac expression level was significantly lower in the EAOC group than in the control group and benign ovarian tumor group (P< 0.05), while HE4 and CA125 expression levels were significantly higher in the EAOC group than the other two groups. The sensitivity of Smac single detection was up to 91.67%, and the specificity of HE4 was up to 98.75%. Furthermore, the sensitivity of Smac + HE4 + CA125 combined was the highest, which reached up to 98.33%; but the specificity was low, which reached up to 75%. The serum expression level differences before and after surgery were statistically significant. As the number of chemotherapies increases, the Smac level increased, and HE4 and CA125 levels gradually decreased. Furthermore, Smac increased to normal at the end of the 2nd period of chemotherapy, while HE4 and CA125 decreased to normal in 2nd and 3rd period of chemotherapy, respectively. Serum Smac, HE4 and CA125 may play an important role in predicting EAOC and in monitoring the prognosis of postoperative EAOC.

Tissue expression of human epididymal secretory protein 4 may be useful in the differential diagnosis of uterine cervical tumors.

Human Epididymal Secretory Protein 4 was firstly described as an epididymis-specific protein but more recently it has been demonstrated to be a putative serum tumor marker for different malignancies, especially ovarian epithelial cancers. The aim of this study is to investigate the association between tissue Human Epididymal Secretory Protein 4 expression and the clinicopathological features of uterine cervical tumors. This retrospective study was designed to evaluate the differences of tissue expressions of Human Epididymal Secretory Protein 4 protein in a spectrum of cervical neoplasms. One hundred and seven patients recently diagnosed as having cervical intraepithelial neoplasm or invasive squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma based on pathology databases. Decreased or negative Human Epididymal Secretory Protein 4 expressions were determined in both normal cervical epithelia and in intraepithelial carcinomas, while increased HE4 expression was observed in invasive tumors. This study demonstrated that altered expression of Human Epididymal Secretory Protein 4 may involve in tumorigenesis in the uterine cervix. Our findings also suggested the presence of a correlation between Human Epididymal Secretory Protein 4 expression and the invasive potential of uterine tumors. Therefore it may be thought that the tissue expression of HE4 can be used to differentiate high grade intraepithelial tumors from carcinomas.

Abstract 5132: Evaluation of multi-marker in tissue-derived cancer cells from patients with epithelial ovarian carcinoma

Abstract Objective: The objective of this study is to refine a simple, rapid and reproducible method for the isolation and characterization of epithelial ovarian cancer (EOC) cells from ovarian tumor tissues and to evaluate the intracellular expression of CK-7, CA-125, HE4 and FOLR-1 in primary ovarian cancer cells. Methods: Fourteen patients diagnosed with papillary serous adenocarcinoma of ovary were selected in ASAN Medical Center. Isolation of tumor EOC cells involves the mechanical disruption of the tumor tissue and placed directly into culture with very little manipulation. Primary ovarian cancer cells were monitored after initial plating and every day for following 15 days. Confocal laser scanning microscopy was used for the imaging of intracellular immunofluorescence of CK-7, CA-125, HE4 and FOLR-1. Results: Two days after plating primary ovarian cancer cells began to adhere to the plate by the presence of small adherent clusters. The primary ovarian cancer cells became a confluent monolayer and displayed the typical epithelial cobblestone morphology. The mean duration of passage was 8.5 days, it was revealed variously in the primary ovarian cancer cells. Immunofluorescent detection of CK-7 expression in EOC cells demonstrates the epithelial origin, however their expression was not constant. CA-125, HE-4 and FOLR-1 were expressed by all tissue-derived EOC cells. The expression pattern of CA-125, HE-4 and FOLR-1 was different in each patient and that was not correlated with the serum level of CA-125. Conclusions: The isolation and characterization of tissue-derived cancer cells from patients with EOC using the expression of CK-7, CA-125, HE4 and FOLR-1 were reasonable method. This result could provide clinically relevant models suitable for investigation of the ex vivo biological characteristics of ovarian cancers. Citation Format: Shin-Wha Lee, Sang-Eun Lee, Ha-Young Lee, Dae-Yeon Kim, Jong-Hyeok Kim, Yong-Man Kim, Young-Tak Kim, Joo-Hyun Nam. Evaluation of multi-marker in tissue-derived cancer cells from patients with epithelial ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5132. doi:10.1158/1538-7445.AM2015-5132

Value of detection of serum human epididymis secretory protein 4 and carbohydrate antigen 125 in diagnosis of early endometrial cancer of different pathological subtypes.

This study explored the value of detection of human epididymis secretory protein 4 (HE4) and carbohydrate antigen 125 (CA125) from serum in diagnosis of early endometrial cancer of different pathological subtypes and discussed the mechanism of HE4 and CA125 in diagnosis. In this study, enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to detect HE4 and CA125 from serum in endometrial cancer and control groups. Besides, the concentration of HE4 and CA125 was compared in these two groups, and the expression of CA125 and HE4 and clinicopathological characteristics in patients with endometrial cancer were also analyzed. Compared with the control group, the expression of HE4 was much higher in serum of patients with endometrial cancer, while there was no obvious change in the expression of CA125. The threshold detection value was acquired by receiver operating characteristic analysis method, that is, 141.5 pmol/L and 54.5 U/L, respectively. When comparing the concentration of HE4 in patients with endometrial cancer at the early stage (stage I) with healthy people, the difference therein had statistical significance, but there was no obvious difference in CA125. HE4 and CA125 in diagnosis of endometrial cancer in the stages I and II were found with no statistically significant difference. The difference of HE4 in the stages II and III had statistical significance while the difference of CA125 had no statistical significance. The specificity of both HE4 and CA125 was 95%, and the sensitivity of HE4 to uterine papillary serous carcinomas was higher than that to endometrioid adenocarcinoma. Thus, the serum HE4 is much better than CA125 in detecting the endometrial cancer at an early stage.

HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation

HE4 expression is associated with hormonal elements and mediated by importin-dependent nuclear translocation

Abstract 3073: Detection and isolation of circulating tumor cells in ovarian cancer: Principles and methods

Abstract Objective: The quantitative and qualitative analysis of circulating tumor cells (CTCs) aids in diagnosis of disease, prognosis, disease recurrence, and therapeutic response in several cancers. However, detection and isolation of CTCs from the blood circulation is a difficult task because of their scarcity and the lack of reliable markers to identify these cells. Especially, in epithelial ovarian cancer, there is a little reported data for CTCs and their CTCs has been defined to the EpCAM+ cells, even though EpCAM+ cells are just a few in ovarian cancer. The aim of this study is to investigate the effective principles and methods to detect and isolate CTCs through novel markers in ovarian cancer. Methods: CTC analysis was performed in the spiking test to find cancer cells in the human serum mixed with WBCs. Four cell lines including OVCAR3, SKOV3, SNU8 and SNU251 were used and primary cancer cells from 4 patients were analyzed. Cancer cells were isolated on the basis of cell size by filtration through CytoGen capture device, followed by identification according to validated immunocytochemistry based on the expression of DAPI, CD45, EpCAM, CK, CA-125 and HE4. Results: We obtained cancer cells more than 90% based on the cell size by filtration. Immunocytochemistry confirmed the epithelial origin through the expression of CK and EpCAM in cancer cell lines. The rate of expression was 35-99 % for CK and 1-99 % for EpCAM. A small number of cancer cell lines expressed CD45 that is the marker of WBC. The expression of CA-125 and HE4 showed their ovarian origin. The rate of expression was 7-98 % for CA-125 and 40-99 % for HE4 in cancer cell lines. Primary cancer cells were detected most effectively as the method of combination with 4 markers, including DAPI, CD45, EpCAM and HE4. Conclusion: Our findings provide the first evidence for effective methods to detect and isolate CTCs in ovarian cancer. Combination of DAPI, CD45, EpCAM and HE4 could be a useful marker to support CTCs research in epithelial ovarian cancer. Citation Format: Shin-Wha Lee, Ha-Young Lee, Jin-Young Mo, Byung Chul Kim, Eun Hye Kim, Yong-Man Kim. Detection and isolation of circulating tumor cells in ovarian cancer: Principles and methods. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3073. doi:10.1158/1538-7445.AM2014-3073

HE4 interacts with sex hormones in epithelial ovarian cancer

Objectives: HE4 is a biomarker that is overexpressed in epithelial ovarian cancer (EOC). The biological functions of HE4 in EOC are not known. Several prior studies have suggested that HE4 overexpression promotes EOC growth and chemoresistance. Hormonal-responsive elements present within the HE4 promoter region can influence expression of HE4 in ovarian cancer. This study was designed to determine if hormones alter HE4 expression and if HE4 interacts with hormone receptors.

HE4 (WFDC2) gene overexpression promotes ovarian tumor growth

Selective overexpression of Human epididymal secretory protein E4 (HE4) points to a role in ovarian cancer tumorigenesis but little is known about the role the HE4 gene or the gene product plays. Here we show that elevated HE4 serum levels correlate with chemoresistance and decreased survival rates in EOC patients. HE4 overexpression promoted xenograft tumor growth and chemoresistance against cisplatin in an animal model resulting in reduced survival rates. HE4 displayed responses to tumor microenvironment constituents and presented increased expression as well as nuclear translocation upon EGF, VEGF and Insulin treatment and nucleolar localization with Insulin treatment. HE4 interacts with EGFR, IGF1R, and transcription factor HIF1α. Constructs of antisense phosphorothio-oligonucleotides targeting HE4 arrested tumor growth in nude mice. Collectively these findings implicate increased HE4 expression as a molecular factor in ovarian cancer tumorigenesis. Selective targeting directed towards the HE4 protein demonstrates therapeutic benefits for the treatment of ovarian cancer.

HE4 Expression in Plasma Correlates with Surgical Outcome and Overall Survival in Patients with First Ovarian Cancer Relapse

Epithelial ovarian cancer (EOC) remains the main cause of mortality due to gynecological malignancies. Optimal tumor debulking and platinum response are the most important prognostic factors for overall survival (OS) in primary EOC. In the setting of recurrence, the role of cytoreduction is not clear. A critical point is to predict preoperatively the subgroup of patients with optimal surgical outcome. The aim of the study was to analyze the predictive role of HE4 for surgical outcome and platinum response in EOC patients experiencing a first relapse. Secondary aims were the prognostic role of HE4 for OS and progression-free survival (PFS). Plasma was obtained before secondary cytoreduction from 73 EOC patients. A total of 66.7 % underwent a total macroscopic tumor clearance; 86.3 % of the patients had disease that responded to platinum therapy. HE4 was detected by enzyme-linked immunosorbent assay. For statistical analysis, the chi-square test, Fisher's exact test, Kendall's tau b, and Mann-Whitney U test were used. OS, PFS rates, and respective 95 % confidence intervals (CI) were estimated according to the Kaplan-Meier method. At a HE4 cutoff value of 250 pMk, a sensitivity of 52 % and a specificity of 93.8 % (p = 0.001, 95 % CI 0.601-0.861) were reached in predicting total macroscopic tumor clearance. Plasma HE4 concentrations together with platinum response were the only independent prognostic factors for OS (p < 0.001, hazard ratio [HR] 18.77, 95 % CI 4.68-75.25; and p = 0.044, HR 3.33, 95 % CI 1.03-10.7, respectively). Together with ascites, HE4 was the only independent predictive factor for surgical outcome (p = 0.029, odds ratio [OR] 7.2, 95 % CI 1.22-42.19 and p = 0.036, OR 10.18, 95 % CI 1.16-88.69, respectively). HE4 is an independent predictive marker for surgical outcome and OS in patients with recurrent EOC. Larger population studies are needed to validate these results.

Effect of down-regulation of HE4 gene expression on biologic behavior of ovarian cancer cells

To investigate the effects of HE4 gene knockdown on the proliferation, adhesion and invasion of the ovarian cancer cells SKOV3. The knockdown of HE4 gene was performed by RNAi technology. The recombinant plasmids (pSUPER-HE4 shDNAs) were constructed and transfected into human ovarian cancer cells SKOV3. HE4 expression was then identified by real-time PCR and Western blot analysis. The invasion and adhesion ability of transduced cells were determined. In addition, cell proliferation and growth were analyzed by colonies formation assay. Knockdown of HE4 was achieved, and further confirmed by real-time PCR and Western blot. The proliferation of HE4-down-regulated cells was not affected, but the invasion ability of the transfected cells was reduced (P < 0.05) and the adhesion ability was also reduced to 27.3%. HE4 expression is down-regulated effectively by the constructed HE4 shDNA, and thus knockdown of HE4 inhibits the adhesion and invasion of SKOV3 cells.

Pattern of Tissue Expression of CA-125 and HE4 in Primary Epithelial Ovarian Tumours and Correlation with Serum CA-125 Levels

The objective of this study is to assess tissue expression of CA-125 and HE4 protein in primary benign and malignant epithelial tumours of the ovary and correlate with serum CA-125 levels. A total of 100 formalin-fixed, paraffin embedded sections of ovarian tumours which included serous adenoma (11), mucinous adenoma (42), serous carcinoma (20), mucinous carcinoma (12) and endometrioid carcinoma (15), histologically diagnosed between 1st January 2004 to 31st December 2012 at the University Malaya Medical Centre, were stained for HE4 (rabbit polyclonal antibody, Abcam, UK) and CA-125 (mouse monoclonal antibody clone: OC125, Cell Marque Corporation, Rocklin, California, USA). Pre-operative serum CA-125 levels were obtained from the laboratory information system. Immunoscore (I score) for HE4 and CA-125 was given based on the intensity of staining and percentage of positive tumour cells and considered significant when it was >50 (intensity of staining multiplied by percentage of positive tumour cells). Serum CA-125 levels were compared with the I score of HE4 and CA-125 in tissues. We noted that the CA-125 levels in serum and tissues were significantly raised in malignant compared to benign ovarian tumours (p value<0.05). Tissue expression of HE4 protein was also significantly raised in malignant tumours compared to benign tumours (p value<0.05). We conclude that HE4 can be a useful tissue immunomarker in addition to CA-125.

Myofibroblasts, regeneration or renal fibrosis--is there a decisive hint?

Activated fibroblasts, denoted as myofibroblasts, express smooth muscle actin (SMA) and are considered key mediators of renal fibrosis. To identify and isolate these elusive cells, LeBleu et al. generated a new transgenic mouse model expressing a red fluorescent protein under the control of the alpha SMA promoter. Gene expression profiling from cultured myofibroblasts identified human epididymis protein 4 [HE4, also denoted whey acidic protein (WAP) four-disulphide core domain 2] as the most upregulated gene. Since the WAP domains are implicated in protease inhibition, the authors demonstrate the ability of recombinant HE4 to bind and inhibit a number of known proteases. To demonstrate an involvement of HE4 in disease pathology, the authors next showed that the neutralization of HE4 alleviates kidney fibrosis in murine disease models, i.e. 5/6 nephrectomy, unilateral ureteral obstruction and nephrotoxic serum-induced nephritis. Finally, they went on to verify the enhanced expression of HE4 in human fibrosis-associated fibroblasts in comparison to normal fibroblasts as well as in serum samples of patients with chronic kidney diseases. Thus, they conclude that HE4 can serve as a biomarker as well as a therapeutic target for the treatment of renal fibrosis.

An analysis of preoperatively HE4 and CA125 in matched samples of patients (pts) with benign disease and borderline ovarian tumors (BOT) with and without invasive implants (InvImp).

e22102 Background: Presence of InvImp, quality of surgical staging and residual tumor mass were shown to be major prognostic factors for BOT. Currently, there are no biomarkers that can predict the various types of BOT. Aim of our study was to assess the value of individual CA125 and HE4 values, and the combination of CA125 and HE4 according to the ROMA algorithm for detecting BOT, and for predicting the presence of InvImp. Methods: BOT pts with InvImp (n=14) were matched by age and histology and compared to consecutive pts with benign disease and BOT without InvImp (1 to 4 to 1, respectively). Blood was collected prior surgery. HE4 and CA125 were determined using ELISA. The performance of HE4 and CA125 were analyzed using the receiver operator characteristic (ROC) and logistic regression. Results: HE4 and CA125 were increased in BOT with InvImp (median=73.85pM and 49.5IU/dl) compared with benign diseases and BOT without InvImp (median values: 48pM and 18.5IU/dl, and 61.45pM and 26.5IU/dl, respectively). HE4 and CA125 expression were significantly increased in BOT with InvImp compared to benign diseases (p=0.029 and 0.004, respectively) but not to BOT without InvImp. Furthermore we grouped BOT without InvImp together with benign diseases and compared them with BOT with InvImp. HE4 and CA125 cut off values of 65pM and 60IU/dl, respectively were independent predictive factors for the presence of InvImp (p=0.018, OR=5.32, 95%CI 1.33-21.20 and p=0.031, OR=4.83, 95%CI=1.16-20.13, respectively). ROMA performed better than HE4 or CA125 alone (p=0.002, RR=9.17, 95%CI=2.31-36.36). The OR of a high ROMA score were 0.082 (95%CI: 0.02-0.34; p=0.001) for benign diseases and 0.27 (95%CI: 0.05-1.42; p=0.123) for BOT without InvImp compared to BOT with InvImp. Conclusions: The ROMA score can not predict sufficiently InvImp in BOT. Further multicenter and larger prospective studies are needed.

Surgical outcome score (SOS), a new algorithm based on HE4 and CA125, to predict surgical outcome in primary epithelial ovarian cancer (EOC) patients (pts).

5549 Background: There are no clinical or biomolecular algorithms to predict surgical outcome in EOC pts. Recently, we showed that the combination of HE4 and CA125 predict surgical outcome in advanced primary EOC (ASCO 2012). We validated the cut-off values in an independent cohort and developed a new algorithm to predict surgical outcome-SOS. Methods: Pts with primary EOC (n = 193) were selected for a retrospective study between 2003 and 2011. Preoperative serum HE4 and CA125 levels were measured. The predictive values of HE4 and CA125 were analyzed using the receiver operator characteristic (ROC) with the corresponding area under the curve (AUC). Separate logistic regression algorithms for pre- and postmenopausal women were utilized to categorize pts into low and high-risk for residual disease, using CA125 and HE4 within SOS algorithm. Furthermore we performed a multivariate analysis for prediction of progression free- (PFS) and overall survival (OS). Results: Maximal cytoreduction was achieved in 67.4% pts. Serum HE4 expression correlated with residual disease (p&lt;0.001, RR: 2.74, 95%CI 1.65-4.54), reaching a 76.2% sensitivity (Se), 56.9% specificity (Sp) and 83.1% negative predictive value (NPV), with 235 pM cut-off value. CA125 correlated with residual disease in premenopausal pts (p=0.031, RR: 3.13, 95%CI 1.28-7.65). For a CA125 cut-off of 500 IU/l, the Se, Sp and NPV were 39.7%, 69.8%, and 70.3%, respectively. ROMA predicted surgical outcome (AUC = 0.70, p &lt;0.001, 95% CI = 0.624-0.776, RR = 2.54), reaching a 76.2% Se, 53.5% Sp for 81% cut-off value. SOS algorithm performed better than HE4 or CA125 alone, and ROMA (AUC= 0.741, p &lt; 0.001, 95% CI 0.670-0.812, RR = 4.98). The Se, Sp and NPV was 90.5%, 46.5% and 90.9%, respectively, for a SOS cut off value of 21.5%. FIGO stage and residual disease were the only prognostic factors for both PFS and OS. SOS was an independent prognostic for PFS (p = 0.009, HR = 1.014, 95% CI = 1.004-1.025), but not for OS. Conclusions: This independent validation study confirm the predictive value of CA124 and HE4 on surgical outcome. The combination of HE4 and CA125 within the SOS score improve the prediction of surgical outcome, and therefore of PFS.

Preoperative HE4 expression in plasma predicts surgical outcome in primary ovarian cancer patients: Results from the OVCAD study

ObjectivesEpithelial ovarian cancer (EOC) is the major cause of death due to gynecological malignancies. The most important prognostic factors are residual tumor mass after surgery and platinum-response. No predictive biomarkers are available to identify patients who will benefit from standard treatment. The aim of our study was to analyze the role of HE4 in predicting surgical and clinical outcome in primary EOC. MethodsIn the European multicentric project “OVCAD”, 275 consecutive patients with primary EOC were enrolled. Patients were eligible if radical cytoreductive surgery was performed and platinum-based chemotherapy was applied. Plasma and ascites samples were collected before or during surgery. The concentrations of HE4 and CA125 was determined using ELISA and Luminex technique, respectively. ResultsMedian age at first diagnosis was 58years (range 18–85years). Most patients presented with advanced stage disease, FIGO III or IV (94.6%), grades II–III (96%) and serous histology (86.2%). In most cases a complete cytoreduction to no residual tumor mass was achieved (68.4%). Higher plasma HE4 levels correlated with poor surgery outcome in terms of macroscopically residual tumor mass (p<0.001) and platinum-resistance (p=0.009). Plasma CA125 and the risk index (HE4 and CA125) were independent predictive factors for surgical outcome (p=0.001, OR=3.37, 95% CI=1.61–7.06 and p<0.001, OR=6,041, 95% CI=2.33–15.65, respectively). FIGO stage III was an independent predictive factor for platinum response (p=0.039, OR=0.436, 95% CI=0.198–0.960). ConclusionsThe presented data are showing that the combination of HE4 and CA125 expression in plasma might predict the surgical outcome in EOC and by this may have a prognostic impact on PFS and OS.

Immunohistochemical Localization of HE4 in Benign, Borderline, and Malignant Lesions of the Ovary

Despite advances in the development of novel methods to improve treatment, ovarian carcinoma is still the leading cause of gynecologic cancer death in the United States and other industrialized nations. Improvements in the clinical outcome of ovarian cancer will be achieved if methods can be developed to enable the detection of these tumors at the earliest possible stage. Thus, it is critically important to identify and validate new biomarkers of ovarian cancer. HE4 expression was defined by immunohistochemical analysis of a wide range of benign, borderline, and malignant ovarian lesions, including serous, endometrioid, mucinous, and clear cell lesions of the ovary and in primary tubal carcinomas and the normal fallopian tube. At the cellular level, HE4 was highly expressed in malignant ovarian tumors and in a wide range of benign and borderline ovarian lesions. In addition, HE4 was highly expressed in primary fallopian tube carcinomas and benign fallopian tubal epithelial cells. These results support the conclusion that HE4 is widely expressed in most benign, borderline, and malignant lesions of the ovary and the fallopian tube. The detection of HE4 expression at high levels in some benign lesions and normal tissues suggests that HE4 could have limited specificity as a marker of ovarian or tubal carcinoma. Furthermore, the relatively weak expression that was observed in many ovarian carcinomas indicates that HE4 could fail to detect some cases of primary or recurrent disease.

Use of HE4 and CA125 to predict surgical outcome and for prognostic value for progression-free survival (PFS) and overall survival (OS) in primary epithelial ovarian cancer (EOC) patients (pts).

5034 Background: Optimal surgical cytoreduction and response to platinum (P) based chemotherapy (ChTh) remain the cornerstones of therapeutic management of primary EOC. Aim of this study was to analyze the predictive role of HE4 and CA125 as biomarkers (BM) for clinical outcome in primary EOC pts at diagnosis and during subsequent follow-up. Methods: In the European OVCAD project 275 pts with primary EOC were enrolled. Pts were eligible if radical cytoreductive surgery and P-based ChTh were applied. Plasma collected at first diagnosis and 6 months after 1st line ChTh in P-sensitive pts was analyzed for HE4 and CA125 levels using ELISA and Luminex technique, respectively. Results: Complete cytoreduction with no residual tumor disease (RTD) was obtained in 69.9% pts. HE4 and CA125 expression in plasma at first diagnosis correlated with RTD, p = 0.002 and p=0.002, respectively. The sensitivity (SE) and specificity (SP) of the combinative use of both BM in predicting RTD was 64.8% and 73.5%, respectively. Pts having over-expression of both BM in plasma had a 6.1 greater risk for RTD (p&lt;0.001, OR: 6.107, 95% CI 2.41-15.46). P-resistance occurred more frequently when both BM were over-expressed (p=0.028, OR= 3.1, 95%CI 1.13-8.46). Elevated BM levels during follow-up predicted recurrence (SE 90% and SP 71% for CA125 ≥55U/ml; SE 72.7% and SP 81.4% for HE4 ≥150pM) and when HE4 or CA125 were positive, a SE of 86.4% and SP of 72.9% were achieved. Elevated CA125 and HE4 at 6 months following adjuvant therapy was associated with significantly poorer PFS (p&lt;0.001, HR 9.6, 95%CI 3.93-23.44 with elevated HE4 or CA125, and HR=50.52, 95%CI 14.44-176.78, with elevated HE4 and CA125) and OS (p&lt;0.001, HR=7.42 95%CI 1.43-38.42 with elevated HE4 or CA125 and HR=28.38 95%CI 6.50-123.97 with elevated HE4 and CA125). Conclusions: The combinative use of HE4 and CA125 appears to have a significant value in predicting optimal surgical outcome and development of P resistance disease in EOC pts. Elevated plasma levels 6 months after 1st line ChTh significantly correlate with OS and PFS in P-sensitive pts.