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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 103-105

Detection of epidermal growth factor receptor mutation in the peripheral blood of patients with esophageal carcinoma to guide epidermal growth factor receptor-tyrosine kinase inhibitor treatment


Department of Oncology, Henan University Huaihe Hospital, Kaifeng, Henan, PR China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Hong Lu
Department of Oncology, Henan University Huaihe Hospital, Kaifeng 475000, Henan
PR China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_735_17

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 > Abstract 

Objective: This study aimed to explore the epidermal growth factor receptor (EGFR) mutation in the peripheral blood of patients with esophageal carcinoma and analyze the relationship between EGFR–tyrosine kinase inhibitor (EGFR–TKI) therapeutic effect and EGFR mutation in peripheral blood.
Methods: A retrospective analysis was performed on 66 patients with esophageal carcinoma treated with EGFR–TKI (Gefitinib) from February 2014 to March 2017 in our hospital. Real-time polymerase chain reaction was applied to detect the mutation of the EGFR gene in peripheral blood specimens before patients were treated with EGFR–TKI. The relationship between EGFR mutation in the peripheral blood and clinical features of patients were analyzed. The correlation between EGFR mutation in peripheral blood and EGFR–TKI treatment response was also demonstrated.
Results: Among the 66 patients, 18 cases were determined as EGFR mutation in peripheral blood. The mutation rate was 27.3%. Among these patients, it observed 1 case of exon 18 2155G>A mutation, 3 cases of exon 19 2235–2249Del mutation, 5 cases of 2236–2250Del mutation, 1 case of 2254–2277Del mutation, 1 case of L747–A750Del mutation, 3 cases of exon 21 2576T>G mutation, 3 cases of 2497T>G mutation, and 1 case of 2504A>T mutation. EGFR mutation in the peripheral blood of patients with esophageal carcinoma was unrelated to the gender, age, and the location of the tumor (P < 0.05). By contrast, EGFR mutation was related to the pathological types of the patients (P < 0.05). The mutation rate of the EGFR of squamous cell carcinoma patients was significantly higher than that of adenocarcinoma patients (P < 0.05). Among EGFR wild-type patients, 8 cases were stable disease (SD), and 40 cases were progressive disease (PD), after EGFR-TIK treatment. No complete response (CR) and partial response (PR) patients were reported. The overall response rate (ORR) was 0.0%. Among the EGFR mutation group, 5 were SD cases, 5 were PD cases, and 8 were PR cases. No CR case was reported. The ORR was 44.4%. The ORR of the EGFR group was significantly higher than that of the wild-type group (P < 0.05).
Conclusion: The detection of EGFR mutation in peripheral blood can be applied as an effective index for EGFR-TKI (Gefitinib) treatment in patients with esophageal carcinoma.

Keywords: Epidermal growth factor receptor, esophageal cancer, gefitinib


How to cite this article:
Xu Y, Xie Z, Lu H. Detection of epidermal growth factor receptor mutation in the peripheral blood of patients with esophageal carcinoma to guide epidermal growth factor receptor-tyrosine kinase inhibitor treatment. J Can Res Ther 2018;14:103-5

How to cite this URL:
Xu Y, Xie Z, Lu H. Detection of epidermal growth factor receptor mutation in the peripheral blood of patients with esophageal carcinoma to guide epidermal growth factor receptor-tyrosine kinase inhibitor treatment. J Can Res Ther [serial online] 2018 [cited 2019 Nov 15];14:103-5. Available from: http://www.cancerjournal.net/text.asp?2018/14/1/103/226756


 > Introduction Top


Esophageal cancer has been one of the most common malignant tumors in clinics. The incidence of esophageal carcinoma was evidently regional.[1] The incidence in China, East Asia, Japan, and other Asian regions has been high, whereas it was low in Europe and the United States. In particular, the incidence of esophageal carcinoma in the Yanshan mountain area in China was noticeably higher than that of in other areas.[2] The prognosis of esophageal carcinoma was poor because it was easily metastasized in the early stage and relapsed after operation. These biological features lead to a low 5-year survival rate among patients with esophageal carcinoma. In recent years, biological targeted therapy has indicated the direction for individual treatment of the tumor. Targeted drugs for the epidermal growth factor receptor (EGFR) have been successfully applied to the clinical treatments of esophageal carcinoma. The survival time of patients has been prolonged with these targeted drugs to a significant extent. At present, most samples for detecting EGFR mutation in patients with esophageal carcinoma were collected from the tumor tissue of patients.[3],[4] Whether EGFR mutation in the peripheral blood could be applied as a basis for guiding EGFR–tyrosine kinase inhibitor (EGFR–TKI) treatment for patients with esophageal carcinoma has not yet been reported in the literature.

In this study, real-time polymerase chain reaction (PCR) was applied to detect EGFR mutation in the peripheral blood of 66 patients with esophageal carcinoma. It aimed to explore the correlation between the EGFR mutation and the curative effects of Gefitinib.


 > Methods Top


Patients

A retrospective analysis was performed on 66 patients with esophageal carcinoma treated with EGFR–TKI (Gefitinib) from February 2014 to March 2017 in our hospital. Real-time PCR was applied to detect EGFR mutation in the peripheral blood of patients before receiving EGFR–TKI treatment. The inclusion criteria were as follows: (1) patients who were pathologically diagnosed with esophageal squamous cell carcinoma or adenocarcinoma, (2) the peripheral blood specimen was extracted before patients who received any EGFR–TKI treatment, (3) patients whose expected lifespan was longer than 6 months, and (4) patients who signed an informed consent to obtain peripheral blood specimen. The exclusion criteria were as follows: (1) patients without pathological or cytological diagnosis, (2) patients who received EGFR–TKI treatment, and (3) patients who had other systemic malignancies combined with esophageal carcinoma.

Detection of epidermal growth factor receptor gene mutation in peripheral blood

Peripheral venous blood (5 mL) was extracted early in the morning after fasting for 12 h. Then, the specimen was centrifuged at low temperature and high speed and allowed to stand for 2 h at room temperature. The serum was extracted with paramagnetic particle method, utilizing the full blood genome DNA extraction kit (Omega, US). The operating procedure was in accordance with the instructions of the kit. The mutation of the EGFR gene was determined and confirmed with fluorescent quantitative PCR, through the release of fluorescence by specific probes.

Clinical efficacy evaluation

On the basis of the RECIST 1.0 standard,[5] clinical efficacy was divided into complete response (CR), in which all target lesions disappeared; partial response (PR), in which the sum of the length and the diameter of the baseline lesion was reduced by ≥30%; stable disease (SD), in which the sum of the length and the diameter of the baseline lesion was decreased, but PR was not reached, or it was increased, but progressive disease (PD) was not reached; PD, in which the sum of the length and the diameter of the baseline lesion was increased by ≥20% or a new lesion appeared; CR + PR, which was involved to calculate the effective rate; and CR + PR + SD, which was involved to calculate the disease control rate. Adverse reactions were divided into levels 0–4 according to the World Health Organization adverse reaction evaluation criteria for anticancer drugs.

Statistical analysis methods

Data were expressed as n (%). The Chi-square test was applied for analyzing the correlation between EGFR mutation and clinical features of patients. Statistical analysis was performed with SPSS 18.0 software (SPSS, Inc., Chicago, IL, USA). Statistical significance was accepted at P < 0.05.


 > Results Top


Epidermal growth factor receptor mutation in peripheral blood

Among the 66 patients, there were 18 cases determined with EGFR mutation in peripheral blood. The mutation rate was 27.3%. Among these patients, there was 1 case of exon 18 2155G>A mutation, 3 cases of exon 19 2235–2249Del mutation, 5 cases of 2236–2250Del mutation, 1 case of 2254–2277Del mutation, 1 case of L747–A750Del mutation, 3 cases of exon 21 2576T>G mutation, 3 cases of 2497T>G mutation, and 1 case of 2504A>T mutation.

Association between patients' clinical features and epidermal growth factor receptor mutation status

EGFR mutation in the peripheral blood of patients with esophageal carcinoma was unrelated to the gender, age of patients, and the location of the tumor (P< 0.05). By contrast, EGFR mutation was related to the pathological types of the patients. The mutation rate of the EGFR of squamous cell carcinoma patients was significantly higher than that of in adenocarcinoma patients (P< 0.05) [Table 1].
Table 1: Correlation between epidermal growth factor receptor mutation and patient clinical features

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Epidermal growth factor receptor mutation and gefitinib treatment response

Among patients with wide-type EGFR, 8 cases were SD and 40 cases were PD. No CR and PR patient was reported. The overall response rate (ORR) was 0.0%. Among the EGFR mutation group, there were 5SD cases, 5 PD cases, and 8 PR cases. No CR case was reported. The ORR was 44.4%. The ORR of the EGFR group was significantly higher than that of the wild-type group. The difference was statistically significant (P< 0.05) [Table 2].
Table 2: Association between epidermal growth factor receptor-tyrosine kinase inhibitor treatment efficacy and epidermal growth factor receptor mutation

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 > Discussion Top


Esophageal carcinoma exhibited a significant regional distribution worldwide.[6] Both the morbidity and mortality of esophageal carcinoma have evidently varied in different areas. China has been one of the countries with a high incidence of esophageal carcinoma.[7],[8] In particular, the morbidity of esophageal carcinoma in the border areas of Henan and Hebei and in the Yanshan mountain area was higher than that of in other regions.[9],[10] Approximately 90% of esophageal carcinoma was squamous cell carcinoma. The cause of this disease was considered to beclosely related to genetic background and acquired dietary habits. However, the molecular mechanism of the occurrence and development of esophageal carcinoma remained unclear.

Adjuvant therapy has been effective in treating early esophageal carcinoma after the operation. However, patients with advanced distant metastasis cannot suffer surgery. Thus, most of these patients received chemotherapy and radiotherapy. The curative effects of these treatments have been poor. With the development of molecular biology and the research on targeted drugs in recent years, targeted therapy for esophageal carcinoma with an EGFR mutation site has significantly improved the prognosis of patients with advanced esophageal carcinoma. Relevant reports [11],[12] have confirmed that targeted drugs exerted a good curative effect on esophageal carcinoma patients with EGFR mutation. The survival time of patients could be effectively prolonged with targeted drugs. At present, most samples for detecting EGFR mutation in patients with esophageal carcinoma had been collected from the tumor tissues. Whether EGFR mutation in the peripheral blood could be applied as a basis for guiding EGFR–TKI treatment for patients with esophageal carcinoma has not yet been reported in the literature.

In this study, 66 patients with esophageal carcinoma were enrolled and EGFR mutation was detected in their peripheral blood. Among the 66 patients, 18 cases exhibited EGFR mutation in their peripheral blood specimen. The mutation rate was 27.3%. The ORR of the EGFR mutation group was significantly higher than that of in wild-type group. Therefore, the detection of EGFR mutation in peripheral blood could be applied as an effective index for gefitinib treatment in patients with esophageal carcinoma, which may guide the selection of targeted therapies for esophageal carcinoma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Chen W, Zheng R, Zhang S, Zeng H, Fan Y, Qiao Y, et al. Esophageal cancer incidence and mortality in China, 2010. Thorac Cancer 2014;5:343-8.  Back to cited text no. 1
    
2.
Zeng H, Zheng R, Zhang S, Zuo T, Xia C, Zou X, et al. Esophageal cancer statistics in China, 2011: Estimates based on 177 cancer registries. Thorac Cancer 2016;7:232-7.  Back to cited text no. 2
    
3.
Petty RD, Dahle-Smith A, Stevenson DAJ, Osborne A, Massie D, Clark C, et al. Gefitinib and EGFR gene copy number aberrations in esophageal cancer. J Clin Oncol 2017;35:2279-87.  Back to cited text no. 3
    
4.
Sudo T, Mimori K, Nagahara H, Utsunomiya T, Fujita H, Tanaka Y, et al. Identification of EGFR mutations in esophageal cancer. Eur J Surg Oncol 2007;33:44-8.  Back to cited text no. 4
    
5.
Kurokawa Y, Shibata T, Ando N, Seki S, Mukaida H, Fukuda H. Which is the optimal response criteria for evaluating preoperative treatment in esophageal cancer: RECIST or histology? Ann Surg Oncol 2013;20:3009-14.  Back to cited text no. 5
    
6.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin 2017;67:7-30.  Back to cited text no. 6
    
7.
Chen W, He Y, Zheng R, Zhang S, Zeng H, Zou X, et al. Esophageal cancer incidence and mortality in China, 2009. J Thorac Dis 2013;5:19-26.  Back to cited text no. 7
    
8.
He YT, Hou J, Chen ZF, Qiao CY, Song GH, Meng FS, et al. Trends in incidence of esophageal and gastric cardia cancer in high-risk areas in China. Eur J Cancer Prev 2008;17:71-6.  Back to cited text no. 8
    
9.
Zhang M, Li X, Zhang S, Chen Q, Wang F, Zhang Y, et al. Analysis of effect of screening of esophageal cancer in 12 cities and counties of Henan province. Zhonghua Yu Fang Yi Xue Za Zhi 2015;49:879-82.  Back to cited text no. 9
    
10.
Lu YF, Liu ZC, Li ZH, Ma WH, Wang FR, Zhang YB, et al. Esophageal/gastric cancer screening in high-risk populations in Henan province, China. Asian Pac J Cancer Prev 2014;15:1419-22.  Back to cited text no. 10
    
11.
Xu Y, Xie Z, Shi Y, Zhang M, Pan J, Li Y, et al. Gefitinib single drug in treatment of advanced esophageal cancer. J Cancer Res Ther 2016;12:C295-7.  Back to cited text no. 11
    
12.
Sohal DP, Rice TW, Rybicki LA, Rodriguez CP, Videtic GM, Saxton JP, et al. Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: A retrospective analysis of two clinical trials. Dis Esophagus 2015;28:547-51.  Back to cited text no. 12
    



 
 
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  [Table 1], [Table 2]



 

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