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    -  Liu W
    -  Lin K
    -  Liu Y
    -  Hu H
    -  Yang L

 
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ORIGINAL ARTICLE
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A clinical study of serum human epididymis protein 4 (HE4) in the diagnosis of pancreatic cancer


1 Department of Clinical Laboratory, Maternal and Children Health Care Hospital (Huzhong Hospital) of Huadu, Guangzhou, China
2 Department of Clinical Laboratory, Chancheng Centre Hospital, Foshan, Guangdong, China
3 Department of Clinical Laboratory, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China

Date of Submission24-Jul-2019
Date of Decision06-Sep-2019
Date of Acceptance17-Jul-2020
Date of Web Publication16-Jul-2021

Correspondence Address:
Weiling Liu,
Department of Clinical Laboratory, Chancheng Centre Hospital, Foshan, Guangdong
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_752_19

PMID: 34380855

  Abstract 


Background: Pancreatic cancer (PC) has poor early diagnosis rates due to its insidious onset. Since human epididymis protein 4 (HE4) is highly expressed in patients with PC, we assessed whether serum HE4 could be a marker for the detection 3 of PC.
Method: Between May 2017 and October 2018, 127 patients with PC were recruited for the study along with 108 healthy controls who underwent health examinations. Serum HE4 concentrations were determined together with levels of carcinoembryonic antigen (CEA) and carbohydrate antigens (CA) 242 (CA242), CA19-9, CA15-3, and CA72-4 by electrochemiluminescence immunoassay (ECLIA) or chemiluminescence immunoassay (CLIA). Correlations between these biomarkers were assessed.
Results: Serum levels of all six biomarkers were higher in patients with PC than in controls (P < 0.05). No correlation was observed between the serum levels of HE4 and the five other tumor markers, although there were strongly significant positive correlations between CA19-9 and CA15-3, and between CA242 and CA72-4. The lack of correlation indicates that HE4 has independent value in the diagnosis of PC. The combined assessment of serum HE4 levels and the other tumor markers improved the sensitivity of diagnosis. In particular, HE4 combined with CA19-9 performed significantly better than HE4 alone, or CA19-9 combined with the other markers. The HE4/CA19-9 combination resulted in 94.49% sensitivity and 99.07% specificity (95% confidence interval: 96.9–100).
Conclusion: HE4 is a biomarker associated with PC with a high specificity , either used alone, or evaluated with other biomarkers together improving the detection of PC. This study may provide a new clinical diagnostic approach for PC detection.


Keywords: Early detection of pancreatic cancer, pancreatic cancer, receiver operating characteristic, tumor markers
Key Message: HE4 has high diagnostic value in the diagnosis of pancreatic cancer and may become a new tumor marker.



How to cite this URL:
Liu W, Liu W, Lin K, Liu Y, Hu H, Yang L. A clinical study of serum human epididymis protein 4 (HE4) in the diagnosis of pancreatic cancer. Indian J Cancer [Epub ahead of print] [cited 2021 Oct 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=321673





  Introduction Top


Pancreatic cancer (PC) is a disease with poor prognosis, and high morbidity and mortality rates.[1],[2] In the UK, the average life expectancy of a patient is only 4–6 months after PC detection, and the 5-year relative survival rate is only 3%.[3] In China, PC ranked among the top ten malignant tumors in 2003–2013, with incidence rates in males and females ranking as 8th and 11th among all cancers.[4] The onset of PC is insidious because early signs are not obvious, and tumors have frequently already metastasized by the time patients are diagnosed with PC; this often results in patients missing the optimal operative time window for surgical resection.

Currently, there is no reliable screening test, including molecular- or imaging-based examination, to detect PC in asymptomatic populations. Because of the relatively low incidence of this disease, no cost-effective and efficient therapeutic approach has been developed.[5] Although imaging examinations, e.g., magnetic resonance imaging (MRI) and abdominal computed tomography (CT), are conducted extensively, these tests often fail to diagnose small (1–2 cm diameter) pancreatic tumors, leading to delay in detection. Alternative examinations such as endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) are not appropriate to screen asymptomatic populations as being invasive, expensive, or clinically risky.[6]

At present, multiple serum tumor markers, such as carbohydrate antigen (CA) 19-9 (CA19-9), serum carcinoembryonic antigen (CEA), CA242, CA72-4, and various microRNAs (miRNAs), have been investigated for tumor diagnosis.[7],[8],[9] Detection of CA19-9 levels showed a specificity of up to 75.4% with a sensitivity of 77.6% for PC diagnosis.[7] However, since about 10% of patients with PC were found to be negative for Lewis antigen and their CA19-9 levels were not elevated, it is necessary to supplement CA19-9 data with alternative tumor markers, for which CA15-3, CA125, and CEA have been proposed.[10],[11] One study indicated that CA19-9 might not be appropriate for large-scale screening of asymptomatic populations,[12] but changes in CEA levels were found to correlate with the tumor stage and the predicted overall survival.[13] CA72-4 appeared to be a better predictor of inoperability during resection than CA19-9 or CA125.[14] However, whether a single tumor marker or a particular combination of different markers can lead to improved specificity and sensitivity of diagnosis remains to be determined.

Human epididymis protein 4 (HE4) is a secretory protein with a relatively low molecular weight containing two four-disulfide core domains characteristic of whey acidic proteins (WAPs). Although HE4 was discovered in male epididymis tissue as early as 1991, its full physiological function is still not well understood. This protein presents in diverse malignant tissues, e.g., ovarian, lung, stomach, and endometrial cancer. The specificity of serum HE4 levels as a tumor marker was found to be higher than that of CA125 for the detection of ovarian cancer,[15] and the combination of serum HE4 and CA125 levels increased early detection rates of ovarian cancer.[16] Likewise, in combination with CA72-4, CA125 was used successfully for the follow-up of ovarian cancer.[17] In addition, HE4 may be used as a potential marker for lung cancer,[18],[19] but high levels of HE4 may result in poor prognosis in patients with non-small-cell lung cancer, especially if they also have adenocarcinoma.[20]

Several studies investigated HE4 in relation to PC. O'Neal et al. detected HE4 in 103 out of 220 patients with PC using tissue microarray analysis, while the protein was not found in patients with sarcomatoid carcinoma.[21] Galgano et al. investigated expression levels of HE4 in PC by DNA chip analysis. Of six PC specimens, HE4 was moderately expressed in four and highly expressed in one.[22] Proteomic analysis revealed that plasma HE4 levels were significantly elevated in mice with pancreatic ductal adenocarcinoma in comparison to healthy mice, indicating a close relationship between HE4 and PC in this animal model.[23]

In this study, we tested the suitability, sensitivity, and specificity of serum HE4 levels as a tumor marker for PC detection. We showed that the levels of HE4, combined with those of tumor markers CEA, CA242, CA19-9, CA15-3, and CA72-4, can improve the diagnostic efficacy of PC remarkably. Further research is needed to verify the reported findings of the present study.


  Materials and Methods Top


Human subjects

In the current study, we recruited 127 patients with PC who were admitted to our hospital between May 2017 and October 2018. Subjects with other pancreatic diseases or acute biliary infections were excluded. We based the criteria for inclusion on the American Joint Committee on Cancer (AJCC) Cancer Staging Manual.[24] We determined the tumor stage of patients who tolerated operation based on surgical outcomes. For patients who could not undergo surgery, the tumors were staged with the help of EUS, MRI, and CT. The final diagnosis of PC was carried out based on histological assessment of unequivocal histo-cytopathologic, EUS-guided fine-needle aspiration biopsy, as well as blending of the unified diagnostics (e.g., ERCP, MRI, and CT).

As a control group, 108 healthy subjects with normal results were selected from a voluntary health examination conducted in the same hospital. The health examination included routine physical and biochemical tests (alanine aminotransferase, aspartate aminotransferase, blood lipids, blood glucose, etc.), chest X-ray, B-scan ultrasonography, and identification of tumor markers CEA, CA242, CA19-9, CA15-3, and CA72-4. All subjects signed a written informed consent form. There was no significant age difference between the control group and the patient group (p > 0.05).

For each subject, we collected 5 mL of venous blood using a vacuum blood collection tube at room temperature and centrifuged the sample immediately at 3000 rpm for 10 minutes. Lipemic and hemolyzed blood samples were rejected. Serum supernatants were stored at -70°C until use. The age and gender of both groups and the clinical stage of tumors in the patient group are presented in [Table 1].
Table 1: Characteristics of patients with PC and of the control group

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Serum concentrations of HE4, CEA, CA242, CA19-9, CA15-3, and CA72-4

We measured the serum concentrations of HE4, CEA, CA19-9, CA15-3, and CA72-4 using the Roche Cobas E601 analyzer (Roche Diagnostics, Risch-Rotkreuz, Switzerland). This analyzer uses the electrochemiluminescence immunoassay (ECLIA), which adds an electrochemical reaction to the luminescence reaction. For calibration purposes, we used HE4, CEA, CA19-9, CA15-3, and CA72-4 standards (Roche Diagnostics, Risch-Rotkreuz, Switzerland). We determined the concentration of CA242 by direct chemiluminescence, using a MAGLUMI 2000 automatic chemiluminescence immunoassay analyzer (Shenzhen New Industries Biomedical Engineering Co., Ltd., Shenzhen, China). We strictly performed all operations based on surgical guidelines. We performed internal quality controls before the experiments.

Statistical analysis

Statistical analysis was conducted with the Mann-Whitney U test using SPSS statistical software 17.0, MedCalc version 15.2.2, and Prism 5 for Windows Version 5.01. The performance was assessed by the Youden's index. Receiver operating characteristic (ROC) curves were produced, and the area under curve (AUC) values were calculated with a 95% confidence interval (95% CI). The level of statistical significance was set at P < 0.05.


  Results Top


Serum concentrations of HE4, CEA, CA242, CA19-9, CA15-3, and CA72-4

To investigate the diagnostic relevance of HE4 in PC, we determined the serum levels of HE4 in the PC and control groups. We determined the sensitivity and specificity of serum HE4 levels to distinguish the PC from the control groups. These results showed that the serum HE4 concentration of patients (P25 62.30 pmol/L, P50 82.90 pmol/L, P75 113.70 pmol/L) in comparison to that of controls (P25 41.10 pmol/L, P50 47.89 pmol/L, and P75 58.90 pmol/L) were significantly higher (P < 0.05) [Figure 1].
Figure 1: Serum HE4 concentrations in control and pancreatic cancer (PC) groups

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ROC curves for detection of the optimum serum levels for PC diagnostics

We constructed ROC curves [Figure 2] to determine the optimal serum levels of all six biomarkers examined, and we used interrupted points for maximum accuracy. Regression analysis was also performed, with results summarized in [Table 2]. The Youden's index varied from 0.373 (CEA) to 0.912 (CA19-9), while HE4 produced a Youden's index of 0.609. The sensitivity of HE4 was 75.80%, and its specificity was 86.11%.
Figure 2: Receiver operating characteristic (ROC) curves of serum levels of HE4, CA19-9, CA72-4, CEA, CA15-3, and CA242 for the diagnosis of pancreatic cancer

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Table 2: Summary of the assessment of biomarker performance. The value of area under curve (AUC), 95% Confidence Interval (95% CI), Youden's index, cutoff, and the sensitivity and specificity of six serum markers are listed. The cutoff value was determined by the maximum of Youden's index

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The correlation between the individual markers in the PC group was next assessed. As illustrated in [Table 3], no significant correlation in serum concentration was observed between HE4 and the other biomarkers (P > 0.05), indicating that HE4 was an independent tumor marker. However, there was a strongly significant positive correlation between CA19-9 and CA15-3 (P = 0.000), and also between CA72-4 and CA242 levels (P = 0.001), as well as a weakly significant positive correlation between CEA and CA242 (P < 0.05).
Table 3: Correlations among serum levels of the individual tumor markers in the pancreatic cancer group

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Diagnosis of PC with serum HE4 combined with the other tumor markers

In combination with a second tumor marker, HE4 enhanced the accuracy compared to the performance of individual markers alone [Figure 3]. [Table 4] summarizes the sensitivity and specificity of pair-wise combinations of HE4 with each of the other markers, illustrating the potential clinical relevance of including HE4 levels in the detection of PC. In particular, the combination of HE4 with CA19-9 increased the sensitivity of that marker alone [91.34%, [Table 2]] to 94.49%, compared with 74.80% for HE4 alone. The combination resulted in only a slight decrease in the specificity of CA19-9 (99.07%, down from 100%). The combination of HE4 with CA72-4 increased the sensitivity to 77.17% compared to each of these by single-use (74.80% for HE4 and 40.94% for CA72-4), while the specificity of CA72-4 was slightly reduced. Combining HE4 with CEA or CA15-3 increased both the sensitivity and specificity compared to the single application of these markers [cf. [Table 2] and [Table 4]]. Likewise, combining HE4 with CA242 improved the sensitivity to 87.40% (from 74.80% for HE4 or 66.93% for CA72-4 alone), although it caused a marginal decrease in the specificity of CA242 (down from 96.30% to 89.81%).
Figure 3: Receiver operating characteristic (ROC) curves of serum HE4 combined with CA19-9, CA72-4, CEA, CA15-3, and CA242 for the diagnosis of pancreatic cancer

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Table 4: Analysis of the efficacy of serum HE4 in the diagnosis of pancreatic cancer when combined with CA19-9, CA72-4, CEA, CA15-3, and CA242

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  Discussion Top


In view of the rising incidence of PC and its poor prognosis,[2] the discovery of early tumor markers is of great importance. The detection of early PC is a challenge with existing methods.[25] The diagnosis of PC is typically based on radiology or invasive endoscopic techniques,[26] which seems inappropriate in screening early-stage patients not yet presenting with symptoms or with negative biological markers. In recent years, various new tumor markers have been proposed for the diagnosis of PC, such as circulating free DNA (cfDNA) and microRNA (miRNA). One study reported a number of miRNAs (e.g., miR-205, miR-210) and related indicators in pancreatic juice and ductal fluid that were associated with poor prognosis of PC.[27] However, acquiring pancreatic juice and ductal fluid is not only invasive but also relatively ineffective for screening patients at an early stage of the disease. Serum tumor markers, including CA72-4, CA19-9, and CA242, have a significant clinical value for PC diagnosis.[28],[29],[30] It has been shown that HE4 is found at low levels in tissues adjacent to PC lesions and normal tissues, whereas its level is significantly higher in PC tissues.[31] Our study shows that the level of HE4 in the serum of patients with PC is also higher than in the control group. Thus, in patients suspected of PC, it is worthwhile to assess the serum HE4 levels as a potential predictor of early prognosis or as a screening marker.

In the present study, we compared serum HE4 levels from patients with PC and the control group by ECLIA, revealing higher levels in the patient group. When the serum HE4 concentration was higher than 63.01 pmol/L, the maximum value of the Youden's index in the diagnosis of PC was 0.609, with a sensitivity and specificity of 74.80% and 86.11%, respectively. The sensitivity of prediction we obtained using HE4 was significantly higher than previously reported[31]; this may be related to the high sensitivity of the ECLIA method used here. Our findings are in line with those previously reported,[22],[23],[27],[28] which illustrated the potential role of serum HE4 levels as an efficient biomarker for diagnosis of patients with PC.

We compared the serum levels of HE4 with those of CEA, CA242, CA19-9, CA15-3, and CA72-4; these were all higher in patients with PC than in controls (P < 0.05). No correlation was identified between serum levels of HE4 and those of the other markers, indicating that HE4 represents an independent variable in the diagnosis of PC. In contrast, strong correlations were observed between CA19-9 and CA15-3, and between CA242 and CA72-4, suggesting that these markers are not completely independent.

It has previously been reported that the diagnostic value of serum HE4 could be enhanced through combinations with other biomarkers.[31],[32],[33] Indeed, we found that the combination of HE4 with one of the other biomarkers tested increased the sensitivity compared to that of most single markers, although it caused a slight decrease in the specificity of a few other biomarkers. The best combination was HE4 and CA19-9. Since combining serum HE4 with alternative tumor markers resulted in an improvement in sensitivity, we conclude serum HE4 can be applied as a new tumor marker for PC.

The present study has some limitations. The serum samples were mainly from patients with PC with stage III and IV disease, and the sample size was relatively small. In particular, patients at stage I accounted for only 15.75%, limiting the relevance of this study for potential early diagnosis of PC. HE4 and the other tumor markers may show high sensitivity and specificity in advanced PC; thus, the present findings need to be validated with larger study groups and more early-stage patients, to confirm the efficacy of the ECLIA-based HE4 serum test, and to evaluate its suitability as a non-invasive tool for early screening and diagnosis of PC.

In conclusion, HE4 is a promising tumor marker for the diagnosis of PC. The level of HE4 detected in patients with PC was significantly higher than in controls. High sensitivity and specificity were obtained, indicating a potential use of serum HE4 levels as a biomarker for diagnosis of PC. Through combination with other biomarkers, in particular CA19-9, the diagnostic value of the serum HE4 level was greatly enhanced. This combination produced an ROC curve of PC that was significantly higher than that of HE4 alone, of other markers alone (CEA, CA242, CA15-3, and CA72-4), or HE4 in combination with any marker other than CA19-9. This study may provide a new clinical diagnostic approach for PC detection.

Ethical approval

This study was approved by the Ethics Committee of Foshan Chancheng Center Hospital.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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