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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 5  |  Page : 72-75

Expression of excision repair cross-complementation group 1 in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy


1 Department of Otolaryngology, The 6th Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang, China
2 Department of Oncology, The 6th Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang, China

Date of Web Publication7-Oct-2016

Correspondence Address:
Lingling Chen
Department of Oncology, The 6th Affiliated Hospital of Wenzhou Medical University, Lishui 323000, Zhejiang
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.191636

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 > Abstract 


Objective: The purpose of this study was to evaluate the expression of excision repair cross-complementation group 1 (ERCC1) in locoregionally advanced nasopharyngeal carcinoma (NPC) treated with cisplatin-based induction chemotherapy.
Methods: Eighty-five patients with locoregionally advanced NPC treated with cisplatin-based induction chemotherapy were included in this study. The expression level of ERCC1 protein in cancer tissues was detected by immunohistochemistry, and the expression level was divided into the high- and low-expression groups according to their expression level. The objective response rate (ORR) and the long-term disease control rate of two groups were compared between the two groups.
Results: The expression level of ERCC1 in NPC tissues was detected by immunohistochemistry. Forty-one cases had the high ERCC1 expression, and 44 cases had the low ERCC1 expression. The cases for complete response, partial response, stable disease, and progression disease were 1, 19, 21 in the ERCC1 high expression group and 3, 29, 12 for the ERCC1 low-expression group which indicated that the ORR in ERCC1 low group were significant higher than that of ERCC1 high expression group (P < 0.05). The 5-year overall survival, 5-year disease-free survival (DFS), and 5-year local recurrence-DFS were not statistical different between two group (P < 0.05); but the 5-year distant-DFS for ERCC1 low group were significant higher than ERCC1 high group (P < 0.05).
Conclusion: Cisplatin-induced short-term ORR was decreased in nasopharyngeal carcinoma patients with high ERCC1 expression, which increased the risk of metastasis.

Keywords: Cisplatin, induction chemotherapy, nasopharyngeal carcinoma, radiotherapy


How to cite this article:
Shen C, Chen L, Fu J, Lin H. Expression of excision repair cross-complementation group 1 in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy. J Can Res Ther 2016;12:72-5

How to cite this URL:
Shen C, Chen L, Fu J, Lin H. Expression of excision repair cross-complementation group 1 in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy. J Can Res Ther [serial online] 2016 [cited 2018 Aug 16];12:72-5. Available from: http://www.cancerjournal.net/text.asp?2016/12/5/72/191636




 > Introduction Top


Recent clinical studies and meta-analyses have shown that radiotherapy combined with chemotherapy can increase the prognosis of patients with nasopharyngeal carcinoma (NPC) and control the risks associated with local recurrence (LR) and distant metastasis.[1],[2] However, the results show that radiotherapy combined with chemotherapy can only improve survival by 4–6%, and only a small number of patients can benefit from the combined radiotherapy and chemotherapy treatment. Therefore, exploring the marker for the combined radiotherapy and chemotherapy treatment for NPC and avoiding over-medicalization has become a research hotspot in the combined treatment of radiotherapy and chemotherapy for NPC.

The excision repair cross-complementation group 1 (ERCC1), a DNA repair protein, can correct damages to DNA molecules caused by chemotherapy or radiotherapy. The previous studies have shown that the highly expressed ERCC1 is related to the poor prognosis of various tumors.[1] In this study, the relativity between the expression level of ERCC1 in the cancer tissues (CTs) of NPC patients and the cisplatin-induced chemosensitivity is explored.


 > Methods Top


Clinical data

A total of 85 patients admitted to our hospital with locally advanced NPC in recent years and received cisplatin-induced chemotherapy + three-dimensional (3D) conformal radiotherapy were enrolled as the subjects investigated. The expression level of ERCC1 in the CTs of the patients before the combined radiotherapy and chemotherapy treatment was detected by immunohistochemistry. The patients were grouped by expression level.

Inclusion criteria

(1) With a lump or mass in the nasopharynx as revealed by imaging, (2) histopathologically diagnosed as NPC before the combined radiotherapy and chemotherapy treatment, (3) expected survival longer than 6 months, (4) combined radiotherapy and chemotherapy treatment not received previously, and (5) complete follow-up data.

Exclusion criteria

(1) Not histopathologically diagnosed, (2) no follow-up data or incomplete data, or (3) radiotherapy combined with chemotherapy received previously.

Reagents and instruments

(1) ERCC1 monoclonal antibody (human antimouse, primary antibody) provided by Santa Cruz, (2) rabbit anti-mouse horseradish peroxidase (secondary antibody) antibody provided by Sigma, (3) phosphate-buffered saline (PBS) buffer solution provided by BOSTER, and (4) trisodium citrate and trypsin provided by Beilian Chemical, microwave oven, thermostat incubator, refrigerator, and micropipette.

Test method

The tissue slice after conventional dewaxing and hydration was placed into 0.01 mol/L, pH 6.0 citrate buffer solution for HTHP antigen retrieval (set in a pressure cooker for 1.5 min). After natural cooling, the tissue slice was taken out and rinsed with tap water and then with PBS (5 min × 3 times). By adding 3% hydrogen peroxide, the slice was incubated for 10 min at room temperature and rinsed with PBS (5 min × 3 times). The slice was dripped with the primary antibody ERCC1 (diluted by 1:50), and it was placed overnight in a refrigerator at 4°C and then rinsed with PBS (5 min × 3 times). The slice was then dripped with the secondary antibody, incubated for 15 min at room temperature, and then rinsed with PBS (5 min × 3 times). Finally, the slice was developed with DAB, stained with hematoxylin, and mounted with neutral gum.

Evaluation criteria

Using the double-blind under a microscope, a uniformly stained ×400 power field was randomly chosen for the upper, lower, left, right, and central parts of the slice.[2] Through cell staining in the five fields, ERCC1-positive cells were detected with brown granular nuclei, and the percentage of positive cells was calculated (total cell count was not <1000). The results were determined as follows: the results were negative (−) when the percentage of positive cells was <10%; the results were weakly positive (+) when it was within the range of 10–25%; the results were moderately positive (++) when it was within the range of 26–75%; and the results were highly positive (+++) when it was >75%. (−) and (+) were defined as two low expression levels, and (++~+++) was defined as a high expression. Clinical efficacy was assessed by the response evaluation criteria in solid tumors (RECIST) 1.0 as follows: (1) Complete response (CR): All target lesions disappear, (2) partial response (PR), The sum of the long baseline lesion diameter narrows ≥30%, (3) stable disease (SD): The sum of the long baseline lesion diameter narrows or widens but does not reach the extent of PR or progression disease (PD), (4) PD the sum of the long baseline lesion diameter widens ≥20% or new lesions emerge, and (5) response rate (RR) calculated by CR + PR and disease control rate calculated by CR + PR + SD.[3]

Statistical analysis

All measurement data were expressed as mean ± standard deviation. The between-group comparison adopted the t-test, with all count data expressed by rate. The between-group comparison adopted the Chi-square test or Fisher exact test. Survival analysis was conducted using a proportional hazard model for the log-rank test with a difference in statistical significance. Stata 11.0 software (http://www.stata.com; Stata Corporation, College Station, TX, USA) was used for statistical analysis.


 > Results Top


  1. General information of patients of the two groups: Among all cases, 41 had highly expressed ERCC1 at the average age of 48.9 ± 11.4 (including 31 males and 10 females), and 44 had poorly expressed ERCC1 (including 33 males and 11 females). The between-group comparison is presented in [Table 1] without statistically significant differences in the baseline clinical data (P > 0.05)
  2. The expression of ERCC1 in the CTs from the NPC patients was detected by immunohistochemistry. Among the patients, 41 cases (48.2%) had high expression and 44 cases (51.8%) had low expression
  3. ERCC1 expression and induced chemotherapy efficacy: The group with the highly expressed ERCC1 included 1 case with CR, 19 cases with PR, and 21 cases with SD The objective RR (ORR) was 48.8%. The poorly expressed ERCC1 included 3 cases with CR, 29 cases with PR, and 12 cases with SD. The ORR was 72.7%, which was significantly higher than that of the highly expressed group and had a statistically significant difference (P < 0.05) [Table 2]
  4. ERCC1 expression and prognosis: The 5-year survival, 5-year disease-free survival (DFS), and 5-year local progression-free survival of the group with highly expressed ERCC1 were 63.4%, 51.2%, and 90.2%, respectively. The 5-year survival, 5-year DFS and 5-year local progression-free survival of the group with poorly expressed ERCC1 were 70.5%, 63.6%, and 90.9%, respectively, without a statistically significant difference in the between-group comparison (P > 0.05) [Table 3]. The 5-year distant progression-free survival of the group with highly expressed ERCC was 48.8%, and that of the group with poorly expressed ERCC was 72.7%. The former was significantly higher than the latter with a statistically significant difference (P < 0.05) as shown in [Figure 1].
Figure 1: Distant disease-free survival curve according to excision repair cross-complementation group 1 expression

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 > Discussions Top


Many types of malignancies may occur in the nasopharynx. Among them, cancers account for over 99%, most of which are poorly differentiated or not differentiated at all. According to estimates, 80% of the world's NPC occur in Guangdong and Guangxi. In Europe and the United States, NPC with incidence below 1/100,000 accounts for a relatively rare tumor. Epidemiological studies have shown that the incidence of NPC begins to increase at the age of 30 and peaks at the age of 50–60 and that the prevalence of such a disease among males is significantly higher than that among females.[4] Radiotherapy is the main regimen for NPC, but most NPC patients are sensitive to radiotherapy, and the ORR may exceed 50%. Recent clinical studies have shown that radiotherapy combined with induced chemotherapy for NPC patients can improve the prognosis and mitigate risks for LR and distant metastasis.[5] However, the results show that only 5% of the patients benefitted from the cisplatin-induced chemotherapy that most of the patients hardly benefitted at all. How to differentiate the population that can benefit from the cisplatin-induced chemotherapy + 3D conformal radiotherapy from others and how to avoid or reduce risks for over-medicalization have already become research hotspots in NPC in recent years. According to a study, ERCC1 is highly expressed in NPC patients with poor prognosis, thus suggesting that the ERCC1 is likely a marker related to the prognosis of NPC. For other malignancies, such as lung cancer and gastric cancer, among others, the highly expressed ERCC1 is usually related to tolerance to cisplatin.
Table 1: The general characteristics of the two groups

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Table 2: The recent clinical efficacy comparison of the two groups

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Table 3: The 5-year disease control rate comparison

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ERCC1 is a highly conservative single-stranded DNA endonuclease located on the chromosome-l9q13.2; it has the full length of 15 × 103 bp, contains l0 exons, and encodes 297 amino acid proteins.[6] The product of the highly expressed ERCC1 and the DNA xeroderma pigmentosum F form a tight heterodimer, which is a specific endonuclease linked to the 5' terminal. Harbin determined the rules of identifying damage and excising the 5' terminal, which plays an important role in limiting or regulating the speed of DNA synthesis. The studies have shown that ERCC1 can detect and repair any DNA sequence damaged by chemotherapy and radiotherapy, thus inhibiting the killing effects of chemotherapy or radiotherapy on tumor cells.

This study found that the ORR of the group with the highly expressed ERCC1 is appreciably lower than that of the control group. Moreover, the 5-year distant recurrence risk for the highly expressed group also significantly increases. Therefore, patients with highly expressed ERCC1 can hardly benefit from the cisplatin-induced chemotherapy + 3D conformal radiotherapy. However, this study is a retrospective study with a relatively small sampling size, and thus it is prone to confounding factors. Therefore, a prospective head-to-head crossover trial is planned in the future according to the specific expression level of ERCC1. This trial aims to further assess the feasibility of using ERCC1 as the cisplatin-induced NPC chemosensitivity marker.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Chen C, Wang F, Wang Z, Li C, Luo H, Liang Y, et al. Polymorphisms in ERCC1 C8092A predict progression-free survival in metastatic/recurrent nasopharyngeal carcinoma treated with cisplatin-based chemotherapy. Cancer Chemother Pharmacol 2013;72:315-22.  Back to cited text no. 1
[PUBMED]    
2.
Huang PY, Li Y, Mai HQ, Luo RZ, Cai YC, Zhang L. Expression of ERCC1 predicts clinical outcome in locoregionally advanced nasopharyngeal carcinoma treated with cisplatin-based induction chemotherapy. Oral Oncol 2012;48:964-8.  Back to cited text no. 2
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3.
William WN Jr., Pataer A, Kalhor N, Correa AM, Rice DC, Wistuba II, et al. Computed tomography RECIST assessment of histopathologic response and prediction of survival in patients with resectable non-small-cell lung cancer after neoadjuvant chemotherapy. J Thorac Oncol 2013;8:222-8.  Back to cited text no. 3
    
4.
Ng WT, Yuen KT, Au KH, Chan OS, Lee AW. Staging of nasopharyngeal carcinoma – The past, the present and the future. Oral Oncol 2014;50:549-54.  Back to cited text no. 4
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5.
Li W, Sun Q, Lu M. Correlation between expression of ERCC1 and the treatment of cisplatin-based chemotherapy in local advanced nasopharyngeal carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2015;29:144-6.  Back to cited text no. 5
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6.
Jagdis A, Phan T, Klimowicz AC, Laskin JJ, Lau HY, Petrillo SK, et al. Assessment of ERCC1 and XPF protein expression using quantitative immunohistochemistry in nasopharyngeal carcinoma patients undergoing curative intent treatment. Int J Radiat Oncol Biol Phys 2013;85:1340-5.  Back to cited text no. 6
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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