Serum HE4 Levels Research Articles

Clinical value of risk of ovarian malignancy algorithm in risk stratification of ovarian cancer

The serum specimens were collected from ovarian cancer (n=100), benign ovarian disease (n=69) and healthy women (n=95). The serum levels of HE4 and CA125 were detected. Risk of ovarian maliqnancy algorithm (ROMA) was calculated. Accuracy of prediction was evaluated by the area under receiver operating characteristic curve (ROC-AUC). And validity of prediction was evaluated by sensitivity and specificity. The results showed that the median level of ROMA algorithm was 83.0%, 8.9% and 8.7% in ovarian cancer, benign ovarian disease and healthy women groups respectively. The difference were statistically significant (all P<0.01). Compared with benign ovarian disease group, the ROC-AUC of ROMA algorithm was 0.900 in ovarian cancer group. The sensitivity and specificity were 81.0% and 92.8% in ovarian cancer group respectively. Thus ROMA algorithm is a useful parameter in risk stratification for ovarian cancer. The diagnostic accuracy of ROMA algorithm is better than that of HE4 and CA125 in ovarian cancer. Key words: Ovarian neoplasms; Epididymal secretory proteins

Serum concentrations of HE4 change little during in vitro fertilization

Human epididymal secretory protein 4 (HE4) is a biomarker for ovarian cancer. The effect of follicle stimulating hormone (FSH) stimulation during in vitro fertilization (IVF) on HE4 was evaluated to determine whether substantial hormonal stimulation of the ovaries affects the serum levels of this marker. Findings were compared with serum concentrations of cancer antigen 125 (CA125), currently the most commonly used marker for ovarian cancer. Prospective cohort study. University hospital infertility clinic. Infertility patients undergoing IVF treatment. We determined the serum concentration of HE4 and CA125 in serial blood samples in 20 women treated with IVF. Samples were taken following gonadotrophin-releasing hormone agonist suppression, two to three times during FSH stimulation, at ovum pick-up and 2weeks following embryo transfer at the time of the pregnancy test. Ovarian follicles were counted and serum estradiol concentrations measured throughout treatment. Serum HE4, CA125 and estradiol concentrations. Serum HE4 levels did not increase significantly during the FSH stimulation. The majority of values remained below the normal reference range (<70pm) throughout the treatment. Serum CA125 concentration also remained low during stimulation. Serum estradiol concentration reflected the severity of ovarian stimulation during IVF, increasing 3.9-fold with stimulation. Serum HE4 concentrations respond little if at all to supraphysiological ovarian stimulation, suggesting that the amount of circulating HE4 in women with normal ovaries is independent of gonadotropin stimulation. Hormonal stimulation of the ovaries is unlikely to affect the differential diagnosis of ovarian tumors with HE4.

Investigating the Clinical Potential for 14-3-3 Zeta Protein to Serve as a Biomarker for Epithelioid

INTRODUCTION: Recently, 14-3-3 zeta protein was identified as a potential serum biomarker of epithelioid ovarian cancer. The goal of this study was to investigate the clinical potential of 14-3-3 zeta protein for monitoring epithelioid ovarian cancer progression compared with CA-125 and HE4. In a prospective follow-up study, carried out at the University of Pecs Medical Center Department of Obstetrics and Gynecology/Oncology (Pecs, Hungary), we investigated 13 patients with epithelioid ovarian cancer with advanced-stage (International Federation of Gynecology and Obstetrics IIb–IIIc) epitheloid ovarian cancer who underwent radical surgery and received six consecutive cycles of first-line chemotherapy (paclitaxel, carboplatin) in 21-day intervals. METHODS: Pre- and postchemotherapy computed tomography scans were performed. Serum levels of CA-125, HE4, and 14-3-3 zeta protein were detected by enzyme-linked immunosorbent assay and quantitative electrochemiluminescence assay. RESULTS: Serum levels of CA-125, HE4, and 14-3-3 zeta protein as well as lesion size according to pre- and postchemotherapy computed tomography scans were analyzed. Serum levels of CA-125 and HE4 were found to significantly decrease after chemotherapy, and this was consistent with the decrease in lesion size detected postchemotherapy. In contrast, 14-3-3 zeta protein levels did not significantly differ in healthy postmenopausal patients compared with patients with epithelioid ovarian cancer. CONCLUSIONS: Determination of CA-125 and HE4 serum levels for the risk of ovarian malignancy algorithm does represent a useful tool for the prediction of chemotherapy efficacy for patients with epithelioid ovarian cancer. However, levels of 14-3-3 zeta protein were not found to be a reliable biomarker of epithelioid ovarian cancer.

Stability of HE4 and CA125 in blood samples from patients diagnosed with ovarian cancer

Objective. To investigate the influence of handling and storage on HE4 and CA125 serum and EDTA plasma levels to clarify any important consequences for a clinical setting. Methods. Blood samples from 13 ovarian cancer (OC) patients were collected and allowed to clot or sediment for up to 72 hours at 4°C or 20°C, then processed into serum and EDTA plasma. Furthermore, the effects of up to eight repetitive cycles of freeze/thaw were investigated. HE4 and CA125 were analyzed using a Chemiluminescent Microparticle Immunoassay on the Architect i2000sr System. Results. No significant effect of processing time for HE4 could be shown. HE4 EDTA plasma levels were insignificantly lower (3%) than serum levels (p = 0.41). Similarly, no significant effect of processing time for CA125 could be demonstrated. CA125 levels at 4°C were significantly reduced compared to levels at 20°C (p = 0.024). No significant difference between CA125 serum and plasma levels were found (p = 0.46). Serum and EDTA plasma samples were stable during the eight cycles of freezing and thawing (CA125: all p > 0.2; HE4: all p > 0.5). Conclusion. No systematic difference could be demonstrated for HE4. CA125 is not dependent on processing time, EDTA plasma or serum. Levels of CA125 are significantly reduced at 4°C compared to levels at 20°C, but this difference was less than 6% and is not considered clinically relevant.

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.

Changes and clinical significance of serum levels of HE4 and YKL 40 in patients with endometrial carcinoma

目的 探讨血清人附睾蛋白4(HE4)、人软骨糖蛋白-39(YKL-40)水平在子宫内膜癌患者中的变化及临床意义.方法 应用酶联免疫吸附法检测60例子宫内膜癌、57例子宫内膜增生患者血清HE4、YKL-40水平,并以60例健康体检者作对照.结果 子宫内膜癌组血清HE4、YKL-40水平分别为(214.75±35.36)pmol/L,(99.16±21.39)μg/L,显著高于子宫内膜增生组的(54.23±11.46)pmol/L,(40.58±9.63)μg/L,差异有统计学意义(t=32.88,18.31,均P 0.05);相关性分析表明,HE4与YKL-40表达呈显著正相关(r=0.715,均P<0.01).结论 HE4、YKL-40可作为子宫内膜癌血清学标志物,在子宫内膜癌中的过度表达可能与其发生和发展有关,为判断子宫内膜癌的早期辅助诊断、疗效评估的重要指标之一。

HE4 combined with CA125: favorable screening tool for ovarian cancer

Ovarian cancer is one of the most prevalent malignancies in women. Screening of the disease is done using variety of biomarkers. Diagnostic performance of current biomarkers of the disease such as human epididymis protein (HE4) and CA125 shows contradiction in previous studies. The goal of this study was to evaluate serum levels of CA125 and HE4 in Iranian patients with ovarian cancer and compare specificity and sensitivity of HE4, CA125 and HE4 + CA125 in patients with different stages and diverse histology. To evaluate CA125 and HE4, 32 patients and 34 healthy women were selected. Origin of ovarian cancer was verified by expert gynecological oncologist. Significance and diagnostic performance were determined by ANOVA and receiver operator characteristic (ROC) and areas under the curve (AUC), respectively. Serum levels of CA125 and HE4 were significantly increased in patients in comparison with control group, especially for tumor cells originated from epithelium (p < 0.001). ROC-AUC for HE4, CA125 and HE4 + CA125 were 0.91, 0.86 and 0.91, respectively. Specificity of HE4 was more than CA125 (85 vs. 80 %). Conversely, sensitivity of CA125 was higher in comparison with HE4 (90 vs. 80 %). It is being noticed that cutoff point of HE4 and CA125 was 150 pmol/L and 38 U/mL, respectively. HE4 is slightly more specific for diagnosis of early stages of the disease, but the difference is not remarkable. CA125 and HE4 + CA125 have some diagnostic performance for prediction of advanced stages. Generally, the data of present study suggest that combining of HE4 and CA125 is a better screening tool for diagnosis of ovarian cancer.

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.

The diagnostic role of human epididymis protein 4 and serum amyloid-A in early-stage endometrial cancer patients

The aim of this study was to evaluate the prognostic and predictive efficacy of the human epididymis secretory protein 4 (HE4) and serum amyloid-A (S-AA) together with the other tumor markers (CA 125, CA 15-3, CEA, and CA 19-9) in endometrial cancer patients. The study group consisted of 64 patients with defined stage and grade of endometrial cancer and 60 women with benign uterine diseases. Thirty-four healthy women were defined as the control group. Fasting blood samples were collected prior to surgery and tumor marker levels were determined in blood samples by E170 autoanalyzer. S-AA concentrations were measured by particle-enhanced immunonephelometry. Preoperative serum HE4 and S-AA levels were significantly higher in endometrial cancer patients than in controls, whereas the other measured parameters were not significantly different. Serum levels of HE4 were related to both the stage and grade of tumor. The best cutoff point for HE4 was determined to be 59.7 pmol/L; with 75 % sensitivity and 65.5 % specificity. For S-AA, the cutoff point was 8.8 U/mL, with 68.7 % sensitivity and 58.6 % specificity. The combination of HE4, CA 125, CEA, and S-AA raised the sensitivity to 84 %. Preoperative measurement of serum HE4 and S-AA may be of help in early detection of endometrial cancer. Preoperative screening with these markers may provide important information about the patient's outcome and prognosis.

HE4 and its evolving role in assessing tumor prognosis in gynecological and systemic malignancies

The recent article by Azzam et al. [1] provided for highly stimulating and interesting reading. HE4 may be helpful in assessing clinical prognosis in a number of other systemic malignancies. HE4 may also be of prognostic value in patients with endometrial cancers. In fact, HE4 levels are closely reflective of the myometrium invasion levels in endometrial carcinomas [2]. When using 70 pmol/l as threshold, it has a sensitivity of about 59 %. Its negative predictive value is 71.5 % [3]. HE4 levels bear a close association with overall survival in these patients. When used in conjunction with CA125, the overall specificity and sensitivity are markedly improved. Mutz-Dehbalaie et al. [4] have reported a hazard ratio of 4.04 for overall survival when the dual markers are used simultaneously. When used independently, its positive predictive value is 100 % [5]. The diameter of the primary endometrial carcinoma is also closely co-related with HE4 levels. HE4 is also of value in assessing clinical prognosis and outcome in individuals with lung adenocarcinomas. A 5-year survival rate of 97.1 % has been noticed in patients negative for HE4 in contrast to a 5-year survival rate of 52.6 % in those positive for HE4 [6]. In addition, malignant recurrence of the adenocarcinomas is closely reflected in serum HE4 levels. Nearly 89 % of small cell lung cancer patients showed elevated HE4 levels [7]. In addition, the CEA status of the tumor bears a close positive relationship with the HE4 levels. Similarly, comparatively higher HE4 levels have been noted in malignant pleural effusions in contrast to lower levels in non-malignant effusions. This test has a specificity of about 91 %. Nearly 90 % of nonsmall cell lung carcinomas exhibit accentuated HE4 levels [8]. Interestingly, up regulation of HE4-V3 variation of HE4 is associated with a better clinical overall outcome. The above examples illustrate the importance of assessing HE4 levels in other systemic malignancies and the need for further studies to fully evaluate the role of HE4 in tumor progression in these malignancies.

Significance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response

BackgroundHuman epididymis protein 4 (HE4) is a novel and specific biomarker for ovarian cancer. The aim of this study is to evaluate a new tumor marker, HE4, in comparison with CA125 in diagnosis of epithelial ovarian cancer (EOC) and benign gynecological diseases.MethodsCA125 and HE4 serum levels were determined in 30 patients with epithelial ovarian cancer (21 serous, 6 endometrioid and 3 mucinous tumors), 20 patients with benign gynecological diseases (8 patients with ovarian cyst, 5 patients with endometriosis, 4 patients with fibroid and 3 patients with pelvic inflammatory disease) and 20 healthy women. CA125 and HE4 cut-offs were 35 U/ml and 150 pmol/l, respectively.ResultsSerum HE4 and CA125 concentrations were significantly higher in the ovarian cancer patients compared with those seen in patients with benign disease or in the healthy controls (p = 0.001 and p < 0.001 respectively). In the receiver operating characteristic analysis (ROC), the area under the curve (AUC) values for HE4 was 0.96 (95% confidence interval, 0.9-1.0) and CA125 was 0.82 (95% confidence interval, 0.7-0.94). Compared to CA125, HE4 had higher sensitivity (90% vs. 83.3%), specificity (95% vs. 85%), PPV (93.1% vs. 80.7%) and NPV (92.7% vs. 87.2%), the combination of HE4 + CA125 the sensitivity and PPV reached 96.7% and 97% respectively.ConclusionMeasuring serum HE4 concentrations along with CA125 concentrations may provide higher accuracy for detecting epithelial ovarian cancer.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1060413168685759

Investigating the clinical potential for 14-3-3 zeta protein to serve as a biomarker for epithelial ovarian cancer

ObjectiveRecently, 14-3-3 zeta protein was identified as a potential serum biomarker of epithelial ovarian cancer (EOC). The goal of this study was to investigate the clinical potential of 14-3-3 zeta protein for monitoring EOC progression compared with CA-125 and HE4.DesignProspective follow-up study.SettingUniversity of Pecs Medical Center Department of Obstetrics and Gynecology/Oncology (Pecs, Hungary).PopulationThirteen EOC patients with advanced stage (FIGO IIb-IIIc) epithelial ovarian cancer that underwent radical surgery and received six consecutive cycles of first line chemotherapy (paclitaxel, carboplatin) in 21-day intervals.MethodsPre- and post-chemotherapy computed tomography (CT) scans were performed. Serum levels of CA-125, HE4, and 14-3-3 zeta protein were detected by enzyme-linked immunosorbent assay (ELISA) and quantitative electrochemiluminescence assay (ECLIA).Main outcome measuresSerum levels of CA-125, HE4, and 14-3-3 zeta protein, as well as lesion size according to pre- and post-chemotherapy CT scans.ResultsSerum levels of CA-125 and HE4 were found to significantly decrease following chemotherapy, and this was consistent with the decrease in lesion size detected post-chemotherapy. In contrast, 14-3-3 zeta protein levels did not significantly differ in healthy postmenopausal patients versus EOC patients.ConclusionsDetermination of CA-125 and HE4 serum levels for the determination of the risk of ovarian malignancy algorithm (ROMA) represents a useful tool for the prediction of chemotherapy efficacy for EOC patients. However, levels of 14-3-3 zeta protein were not found to vary significantly as a consequence of treatment. Therefore we question if 14-3-3 zeta protein is a reliable biomarker, which correlates with the clinical behavior of EOC.

Human Epididymis Protein 4 Reference Intervals in a Multiethnic Asian Women Population

Ovarian cancer is ranked as the fifth most common cause of cancer death in women. In Malaysia, it is the fourth most common cancer in females. CA125 has been the tumor marker of choice in ovarian cancer but its diagnostic specificity in early stages is only 50%. Hence, there is a critical need to identify an alternative tumor marker that is capable of detecting detect ovarian cancer at an early stage. HE4 is a new tumor marker proposed for the early diagnosis of ovarian cancer and disease recurrence. Currently, none of the normal ranges of HE4 quoted in the literature are based on data for a multiethnic Asian population. Therefore, the aim of this study was to determine reference intervals for HE4 in an Asian population presenting in University Malaya Medical Centre, a tertiary reference hospital. 300 healthy women were recruited comprising 150 premenopausal and 150 postmenopausal women, aged from 20-76 years. All women were subjected to a pelvic ultrasonograph and were confirmed to be free from ovarian pathology on recruitment. Serum HE4 levels were determined by chemiluminescent microparticle immunoassay (CMIA, Abbott Architect). The reference intervals were determined following CLSI guidelines (C28-A2) using a non-parametric method. The upper limits of the 95th percentile reference interval (90%CI) for all the women collectively were 64.6 pmol/L, and 58.4 pmol/L for premenopausal) and 69.0 pmol/L for postmenopausal. The concentration of HE4 was noted to increase with age especially in women who were more than 50 years old. We also noted that our proposed reference limit was lower compared to the level given by manufacturer Abbott Architect HE4 kit insert (58.4 vs 70 pmol/L for premenopausal group and 69.0 vs 140 pmol/L in the postmenopausal group). The study also showed a significant difference in HE4 concentrations between ethnic groups (Malays and Indians). The levels of HE4 in Indians appeared higher than in Malays (p<0.05), while no significant differences were noted between the Malays and Chinese ethnic groups. More data are needed to establish a reference interval that will better represent the multiethnic Malaysian population. Probably a larger sampling size of equal representation of the Malay, Chinese, Indians as well as the other native ethnic communities will give us a greater confidence on whether genetics plays a role in reference interval determination.

Comparison of HE4, CA125 and ROMA algorithm in women with a pelvic mass: Correlation with pathological outcome

ObjectiveThe quality of first surgery is one of the most important prognostic factors in ovarian cancer patients. Pre-surgical distinction of benign and malignant pelvic mass plays a critical role in ovarian cancer management and survival. The aim of this study was to evaluate the clinical performance of ROMA algorithm and of CA125 and HE4 in the triage of patients with a pelvic mass undergoing surgery, in order to discriminate benign from malignant disease. MethodsThree hundred and forty-nine pre- and post-menopausal women, aged 18years or older undergoing surgery because of a pelvic mass were enrolled: serum concentrations of CA125 and HE4 were determined and ROMA was calculated for each sample. ResultsMedian serum CA125 and HE4 levels were higher in patients with EOC compared to subjects with benign disease (p<0.0001). The resultant accuracy (using Receiver Operating Characteristics, ROC Area) values for HE4, CA125 and ROMA showed a good performance ranging from 89.8% for CA125 in pre-menopausal patients to 93.3% for ROMA in post-menopausal patients: AUC for ROMA resulted significantly higher in comparison to CA125 alone (93.3% vs 90.3%, p=0.0018) in post menopausal patients. A sub-analysis considering the 40 patients with endometrioid disease showed the highest accuracy of HE4 in these patients. ConclusionsData presented confirm the accuracy of HE4 and of the ROMA algorithm in the distinction of ovarian carcinoma from benign disease, with a trend towards better performance for ROMA than for CA125 alone, statistically significant in postmenopausal patients.

HE4 is an independent prognostic marker in endometrial cancer patients

ObjectiveTo evaluate the prognostic value of pretherapeutic serum HE4 in endometrial cancer in comparison to CA125. MethodsHE4 and CA125 serum levels were analyzed by means of chemiluminescent microparticle immunoassays in 183 patients with endometrial cancer treated at the Department of Obstetrics and Gynecology, Innsbruck Medical University, between 1999 and 2009. The Kaplan–Meier method and Cox's proportional hazards analysis were performed to determine the prognostic significance of HE4, CA125 and the combination of both markers. ResultsIn univariate analysis both markers, HE4 and CA125, were of prognostic value for overall survival (p<0.001 and p=0.028) and disease-free survival (p=0.015 and p=0.045). In multivariate analysis HE4 was seen to have independent prognostic value in overall survival (HR 2.407, p=0.017) in contrast to CA125. The combination of both markers showed a higher hazard ratio (HR 4.04, p=0.023) for overall survival in comparison to HE4 alone. In the subgroup endometrioid histological type (n=132) only HE4 was of prognostic value for overall survival in univariate (p=0.001) and multivariate analysis (p=0.023). ConclusionsPretherapeutic serum HE4 levels alone and in combination with CA125 are an independent prognostic marker in endometrial cancer patients.

Serum HE4 concentration is not dependent on menstrual cycle or hormonal treatment among endometriosis patients and healthy premenopausal women

ObjectiveHuman epididymal secretory protein E4 (HE4) is a new promising tumor marker developed for the diagnostics and follow up of ovarian cancer. It has yet to become widely accepted in clinical practice, and its biological properties have not been inclusively studied. The aim of this study was to investigate whether serum HE4 concentration varies within the normal menstrual cycle and whether common gynecological hormonal treatments have an effect on HE4 values. MethodsOur study population consisted of 180 women, including 126 endometriosis patients and 54 healthy women. We measured their serum HE4 and CA125 concentrations and evaluated the effect of the menstrual cycle and the possible hormonal medication on these marker concentrations. ResultsWe found no significant variation in serum HE4 concentrations in samples taken at different phases of the menstrual cycle. The median HE4 concentrations in proliferative, secretory and menstrual phase were 41.5, 45.1 and 35.3pM in healthy women, and 43.4, 44.3 and 43.0pM in endometriosis patients, respectively. The use of combined estrogen and progestin contraceptives did not affect serum HE4 levels significantly. ConclusionsThe present study shows that the HE4 measurement in healthy premenopausal women as well as in women with endometriosis can be carried out at any phase of the menstrual cycle, and irrespective of hormonal medication, extending the benefits of HE4 use in clinical practice.

Subjective assessment by ultrasound is superior to the risk of malignancy index (RMI) or the risk of ovarian malignancy algorithm (ROMA) in discriminating benign from malignant adnexal masses

PurposeThe combination of two tumour markers, CA125 and HE4, in the risk of ovarian malignancy assay (ROMA) has been shown to be successful in classifying patients into those who have a high or low risk of epithelial ovarian cancer. In the present study, the diagnostic accuracy of ROMA was assessed and compared to the diagnostic accuracy of the two most widely used ultrasound methods, namely the risk of malignancy index (RMI) and subjective assessment by ultrasound. MethodsFrom August, 2005 to March, 2009, 432 women with a pelvic mass who were scheduled to have surgery were enrolled in a single-centre prospective cohort study. A preoperative ultrasound was performed and preoperative CA125 and HE4 serum levels were measured. Once the final surgical pathology reports were obtained, the diagnostic accuracy and performance indices of ROMA, RMI and subjective assessment were calculated. ResultsOf the 432 eligible patients, 374 could be analysed. Subjective assessment had the highest area under the receiver operator characteristic curve (AUC) (0.968, 95%CI:0.945–0.984), followed by the RMI (0.931, 95%CI:0.901–0.955). The subjective assessment and RMI both had significantly higher AUCs than the ROMA (0.893, 95%CI:0.857–0.922; P<0.0001 and P=0.0030, respectively). The pre- and postmenopausal populations generated similar results. ConclusionAlthough new tumour markers models are promising, they do not contribute significantly to the diagnosis of ovarian cancer. Ultrasound, especially subjective assessment by ultrasound, remains superior in discriminating malignant from benign ovarian masses.

HE4 and CA72.4 are Useful Biomarkers in the Follow-up of Epithelial Ovarian Cancer

The aim of this study was to investigate the role of serum biomarkers HE4 and CA72.4 at diagnosis and in the follow-up of patients with epithelial ovarian cancer (EOC).Seventy-eight patients with EOC were included and 40 of them were monitored during the follow-up. Serum levels of HE4 and CA72.4 were determined for all patients at diagnosis. Among these patients, the number of cases with an elevated level of each individual marker HE4 and CA72.4 was 85% and 72% respectively. A statistically significant difference was observed between the positivity of HE4 in comparison with Ca72.4 (p<0.02). In the follow-up period, we observed that tumor marker levels showed fluctuations during chemotherapy. As we combined the individual biomarkers, we observed increased values in 75% of the patients for HE4 with CA 72.4. In conclusion, our study has shown that the association of the biomarkers HE4 and CA72.4 provides a valuable contribution to the follow-up of EOC.

Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders

Serum HE4 levels are less frequently elevated than CA125 in women with benign gynecologic disorders

Correlation of serum HE4 with tumor size and myometrial invasion in endometrial cancer

ObjectiveTo evaluate the utility of serum (HE4) as a marker for high risk disease in patients with endometrial cancer (EC). MethodsPreoperative serum HE4 levels were measured from a cohort of 75 patients surgically treated for EC. Cases were compared to matched controls without a history of cancer. HE4 levels were analyzed as a function of primary tumor diameter, grade, stage and histological subtype. Wilcoxon rank-sum test, ROC curve, Spearman rank correlation coefficient and contingency tables were used for statistical analyses. ResultsStage distribution was as follows: 49 stage I, 2 stage II, 20 stage III, 4 stage IV. Type I EC was present in 54 patients, type II in 21. Median HE4 was significantly elevated in both types I and II EC compared to controls (P<0.001 and P=0.019, respectively). There was significant correlation between type I EC, median HE4, deep myometrial invasion (MI) (>50%, P<0.001) and primary tumor diameter (PTD) (>2cm, P=0.002). Low risk patients (type I, MI≤50% and PTD≤2cm) had significantly lower median HE4 compared to all other type I EC patients (P<0.01). In comparison to prior investigations, HE4 (cutoff of 8mfi) was more sensitive than CA125 in detecting advanced stage disease. ConclusionOur data suggest that HE4 is elevated in a high proportion of EC patients, is correlated with PTD and MI, and is more sensitive than CA125 in EC. These observations suggest potential utility of HE4 in the preoperative prediction of high risk disease and the necessity for definitive surgical staging.