The prognostic value of excision repair cross-complementing Group 1 expression in nasopharyngeal cancer patients

Abstract

Background:
Overexpression of excision repair cross-complementing Group 1 (ERCC-1) is related to cisplatin resistance and defective repair of radiation damage. The purpose of this study was to evaluate the clinical significance of excision (ERCC-1) expression in nasopharyngeal cancer (NPC).

Materials and methods:
We conducted a retrospective review of patients diagnosed with NPC between 2000 and 2013. The archived tissues were analyzed using immunohistochemistry to determine ERCC-1 expression. The ERCC-1 expression level along with other clinical factors and overall survival (OS) were analyzed. Hazard ratio (HR) with a 95% confidence interval was calculated to assess the risk.

Results:
The analysis of ERCC-1 expression was available in 262 NPC patients who had medical records at our hospital. Among those patients, 221 (84%) were treated with curative radiotherapy (RT)/concurrent chemoradiotherapy, 22 (7%) were treated with palliative RT alone, and 19 (9%) were given best supportive care. There was no correlation between ERCC-1 expression and stage of cancer or OS. No difference in 5-year OS was found between patients with low ERCC-1 expression and high ERCC-1 expression (38% vs. 36%; P = 0.981). The adjusted HR (aHR) of cancer death increased with cancer stage (aHR = 2.93 for advanced Stages III-IV; P = 0.001) and age (aHR = 2.11 for age >55; P ≤ 0.001). ERCC-1 expression exhibited no prognostic significance in our study (aHR = 1).

Conclusion:
In this study, ERCC-1 expression has no statistical significance to be considered a prognostic factor for OS among NPC patients. On the other hand, cancer stage, age, and types of treatment can be prognostic factors in NPC patients.

Full text

© 2020 Journal of Research in Medical Sciences | Published by Wolters Kluwer - Medknow | 2020 |
1
The prognostic value of excision repair
cross‑complementing Group 1 expression in
nasopharyngeal cancer patients
Imjai Chitapanarux1,2,3, Suree Lekawanvijit4, Patumrat Sripan2,3,5, Pongsak Mahanupab4, Somvilai Chakrabandhu1,2,
Wimrak Onchan1,2, Pichit Sittitrai6, Donyarat Boonlert6, Hanpon Klibngern6, Wisarut Samuckkeethum6
1Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, 2Northern Thai
Research Group of Radiation Oncology (NTRG-RO), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, 3Chiang Mai Cancer
Registry, Maharaj Nakorn Chiang Mai Hospital, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, 4Department of Pathology,
Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand, 5Research Institute for Health Sciences, Chiang Mai University, Chiang Mai,
Thailand, 6Department of Otolaryngology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
rate of 2.7 for males and 1.2 for females.[2] Due to
anatomical location and extension of disease, as well
as a high degree of radiosensitivity, the standard
treatment for NPC is definitive radiotherapy (RT)
with or without chemotherapy, depending on the
stage of the disease. Although the latest evidence
has shown a significant improvement in survival
with the addition of concurrent platinum‑based
chemotherapy, a cornerstone chemotherapy regimen,
to RT in locoregionally advanced NPC,[3] the treatment
outcomes for this group of patients are rather
INTRODUCTION
The incidence rate of nasopharyngeal cancer (NPC)
is high in Southeastern Asia, in both sexes,
with the disease being the sixth most common
among males in this region.[1] In Thailand, the
age‑standardized incidence rates of NPC are
approximately 2.8 and 0.9 per 100,000 in males and
females, respectively.[2] Chiang Mai, a province
in the Northern part of Thailand, hasan incidence
Background: Overexpression of excision repair cross‑complementing Group1(ERCC‑1) is related to cisplatin resistance and defective
repair of radiation damage. e purpose of this study was to evaluate the clinical significance of excision(ERCC‑1) expression in
nasopharyngeal cancer (NPC). Materials and Methods: We conducted a retrospective review of patients diagnosed with NPC
between 2000 and 2013. e archived tissues were analyzed using immunohistochemistry to determine ERCC‑1 expression. e
ERCC‑1 expression level along with other clinical factors and overall survival (OS) were analyzed. Hazard ratio(HR) with a 95%
confidence interval was calculated to assess the risk. Results: e analysis of ERCC‑1 expression was available in 262 NPC patients
who had medical records at our hospital. Among those patients, 221(84%) were treated with curative radiotherapy(RT)/concurrent
chemoradiotherapy, 22(7%) were treated with palliative RT alone, and 19(9%) were given best supportive care. ere was no correlation
between ERCC‑1 expression and stage of cancer or OS. No difference in 5‑year OS was found between patients with low ERCC‑1
expression and high ERCC‑1 expression(38% vs. 36%; P =0.981). e adjusted HR(aHR) of cancer death increased with cancer
stage(aHR=2.93 for advanced Stages III–IV; P=0.001) and age(aHR=2.11 for age>55; P≤0.001). ERCC‑1 expression exhibited
no prognostic significance in our study(aHR=1). Conclusion: In this study, ERCC‑1 expression has no statistical significance to
be considered a prognostic factor for OS among NPC patients. On the other hand, cancer stage, age, and types of treatment can be
prognostic factors in NPC patients.
Key words: Excision repair cross‑complementing Group1, nasopharyngeal cancer, prognostic factor
Address for correspondence: Prof. Imjai Chitapanarux, Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai
University, 110 Intawarorose Road, Chiang Mai 50200, Thailand. E-mail: imjai.chitapanarux@cmu.ac.th
Submitted: 09-Nov-2018; Revised: 10-Dec-2019; Accepted: 30-Dec-2019; Published: 13-Apr-2020
Access this article online
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DOI:
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How to cite this article: Chitapanarux I, Lekawanvijit S, Sripan P, Mahanupab P, Chakrabandhu S, Onchan W, et al. The prognostic value of excision
repair cross-complementing Group 1 expression in nasopharyngeal cancer patients. J Res Med Sci 2020;25:34.
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Chitapanarux, et al.: ERCC‑1 expression in nasopharyngeal cancer patients
Journal of Research in Medical Sciences
| 2020 | 2
unsatisfactory with the 5‑year overall survival (OS) rates
of 53%–80% in Stage III and 28%–61% for Stage IV.[4‑9]
Many studies have suggested a potential use of excision
repair cross‑complementation Group 1 enzyme (ERCC‑1)
as a molecular predictor of the treatment outcome of
platinum‑based chemoradiotherapy in NPC.[10‑14] ERCC‑1 is
an important enzyme in the nucleotide excision repair (NER)
pathway which is involved in the DNA repair mechanism
in tumor cells damaged by treatment with platinum agents.
A study of ERCC‑1 in head‑and‑neck cancer patients
treated with RT alone has shown that the high expression
of ERCC‑1 was associated with poor response to RT, thereby
having a role in the repair of RT‑induced DNA damage.[15]
The objective of this study was to evaluate the clinical
significance including treatment outcomes of ERCC‑1
expression in NPC patients.
MATERIALS AND METHODS
We considered 382 archived NPC specimens from patients
diagnosed between January 2000 and December 2013 at the
Faculty of Medicine, Chiang Mai University. The inclusion
criteria were having biopsy‑proven NPC, having adequate
information on staging and treatment, and having archive
tissues available for ERCC‑1 immunohistochemical (IHC)
staining. The data were extracted from the medical records.
Among the treatment outcome determining factors and
associating factors, age, sex, stage, and type of treatment
were included in this study. The cancer stage was
determined using the American Joint Commiee on Cancer
staging system.[16‑18]
According to clinical practice guidelines for nasopharyngeal
cancer, Stage I disease is generally treated by RT alone,
while higher nonmetastatic stages are received concurrent
chemoradiotherapy (CCRT). In our center, patients
who had tumors conned to the nasopharynx without
lymph node involvement were given curative RT alone
by two‑dimensional RT, three‑dimensional conformal
radiotherapy, or intensity‑modulated radiotherapy. Patients
who have tumor extension beyond nasopharynx and/or
lymph node involvement with good performance status and
adequate renal, bone marrow, and liver function received
CCRT plus either neoadjuvant or adjuvant platinum‑based
chemotherapy.
Neoadjuvant or adjuvant chemotherapy consisted of three
cycles of cisplatin (100 mg/m2) or carboplatin AUC5 on day 1
plus 5‑FU 1000 mg/m2 on days 1–4. Concurrent chemotherapy
regimen was either cisplatin 100 mg/m2 every 3 weeks or
weekly 40 mg/m2 or weekly carboplatin 100 mg/m2. Patients
with advanced disease and poor performance status received
either palliative RT or best supportive care.
Formalin‑xed, paran‑embedded tissue sections were
stained, using VENTANA BenchMark XT platform, with
the antibody against ERCC‑1 (rabbit anti‑human ERCC‑1
monoclonal antibody, Clone SP68, Spring Bioscience,
Pleasanton, CA, USA, 1:100), and then, were visualized
by the ultraView Universal DAB Detection Kit. ERCC‑1
expression was assessed on digital scanned microscopic
images (Aperio, Aperio Technologies Inc., Vista, CA,
USA) using image analysis (ImageScope software) by a
pathologist who was masked to the clinicopathological
data. Only well‑preserved tumor areas were selected from
the whole section for the analysis. Using nuclear count
V9 algorithm, the results in percentage were reported as
0 – negative; 1+ – weakly positive; 2+ – moderately positive;
and 3+ – strongly positive nuclei staining [Figure 1]. As
the result of 1+ nuclei could not be specically observed
at the margin of tissue or at the areas of crushing artifacts,
only percentages of 2+ and 3+ nuclei were used to calculate
ERCC‑1 expression. Patients were then categorized into two
groups: “high expression” or “low expression”, using the
median as a cut point.
Statistical analysis
Data were presented as mean with standard deviation (SD)
or median with interquartile range (IQR) as appropriate
for continuous variables and as counts and percentages
for categorical variables. The proportions of ERCC‑1
high expression in categorical variables were compared
using Fisher’s exact test or Chi‑square test as appropriate.
Student’s t‑test was used to compare the mean age
between high and low expression of ERCC‑1. The time
to events was measured from the time of diagnosis to the
date of events, i.e., death for OS analysis. The survival
rate was calculated using the Kaplan–Meier method, and
the log‑rank test was performed for the signicance test.
The association between baseline characteristics (sex,
age, stage of cancer, type of treatment, and ERCC‑1
expression) and events was assessed using univariable
and multivariable Cox proportional hazards models. Age
and ERCC‑1 expression were dichotomized according
to the median values. Any variable having a signicant
univariate test at P value cuto point of below 0.25 was
selected as a candidate for the multivariate analysis.
All reported P values are two sided and P < 0.05 was
considered statistically signicant. All analyses were
performed using STATA software version 10.1 (StataCorp,
College Station, TX, USA). This study was approved by
the Research Ethics Commiee of Faculty of Medicine,
Chiang Mai University.
RESULTS
Of 382 NPC patients retrieved from the database, only 262
were eligible for the present study. The consort diagram of
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Chitapanarux, et al.: ERCC‑1 expression in nasopharyngeal cancer patients
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3
the study is presented in Figure 2. Among 120 patients who
were excluded from the study, eight were with squamous
cell carcinoma of primary sites other than nasopharynx,
41 were due to the lack of medical records on their staging
or type of treatment, and 71 were due to unavailability of
archive tissues for ERCC‑1 IHC staining.
The mean (SD) age of the study population was 55 years.[13]
Most were male (70%) and in advanced stages (87% in
Stage III–IV). For the type of treatment, 221 patients (84%)
received curative RT/CCRT, while 41 patients (16%)
received either palliative RT or best supportive care. Table 1
summarizes the baseline characteristics of a patient by the
level of ERCC‑1 expression. One hundred and thirty‑ve
patients (52%) had high expression of ERCC‑1 and
127 patients (49%) had low expression of ERCC‑1. There
was no dierence in any baseline characteristics between
both the groups.
The median follow‑up time was 2.8 years (IQR: 1.2–5.8).
For 5‑year survival analysis, 163 patients (62%) had died,
with median OS of 33 months (IQR: 15–69). Age, stage of
cancer, and type of treatment were signicantly predictive
of OS using univariable and multivariable Cox regression
analyses [Table 2]. However, ERCC‑1 expression showed
no prognostic signicance.
Five‑year OS rates were beer in age group below 55 years
than in older group (47% [95% condence interval (CI):
38–55] vs. 28% [95% CI: 20–36]; P < 0.001), in early Stages
(I–II) than in advanced Stages (III–IV) (67% [95% CI: 48–80]
vs. 33% [95% CI: 27–39]; P < 0.001), and in curative RT/CCRT
than palliative RT/best supportive care groups (41% [95% CI:
34–48] vs. 9% [95% CI: 2–25]/21% [95% CI: 7–41]; P < 0.001,
respectively) [Figure 3]. There was no dierence in 5‑year OS
rate between low and high ERCC‑1 expression (38% [95%
CI: 30–47] vs. 36% [95% CI: 29–44]; P = 0.98).
Figure 1: Image analysis for excision repair cross‑complementing Group 1 expression. Tumor areas were selected from excision repair cross‑complementing Group 1
immunohistochemical‑stained section (a) for image analysis, guided by a H and E‑stained section (b). Image analysis results were displayed as shown in panel (c).
Only cells with 2 + and 3 + nuclear staining were used for the statistical analysis
c
b
a
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DISCUSSION
The outcome of chemoradiotherapy in locoregional
advanced NPC patients is still dismal. The 5‑year OS rate
in this retrospective study is very poor when compared
to other studies, as more than half of the patients (56%)
included in our study were at Stage IV at diagnosis. Imaging
study for tumor evaluation, staging, and RT treatment
planning in most of our patients was by CT scanning,
while magnetic resonance imaging is beer for evaluating
intracranial and skull base involvement.[19] This may result
in an underestimate of tumor stage and eect treatment
decision‑making, RT eld, and outcomes. However, when
we analyzed the OS in each stage, the outcome of the
patients in this cohort was in line with other studies.[4‑9] The
5‑year OS of Stage I, II, III, and IV of our patients was 80%,
62%, 42%, and 28%, respectively.
The success of this combination treatment depends on
the eectiveness of lethal cell killing and double‑strand
break by RT and on the synergism eect of cytotoxicity
by platinum‑based chemotherapy. NER is one of four
major pathways to repair damaged DNA.[16] It also plays
an important role in identifying and repairing the DNA
adducts, particularly those induced by cisplatin.[17] ERCC‑1
has a crucial role for the incision step and completion
Table 1: Baseline characteristics and clinicopathological factors by excision repair cross‑complementing Group 1
expression
Variables All patients (n=262), n (%) ERCC‑1
Low expression (n=127), n (%) High expression (n=135), n (%) P*
Sex
Female 79 (30) 40 (51) 39 (49) 0.646
Male 183 (70) 87 (48) 96 (52)
Median age (year), mean (SD) 55 (13) 55 (14) 55 (13) 0.994†
Age groups (years)
<55 128 (49) 57 (44) 71 (56) 0.212
≥55 134 (51) 70 (52) 64 (48)
Stage (n=258)
I10 (4) 4 (40) 6 (60) 0.591‡
II 24 (9) 14 (58) 10 (42)
III 80 (31) 35 (44) 45 (56)
IV 144 (56) 71 (49) 73 (51)
Treatment
Curative RT/CCRT 221 (84) 104 (47) 117 (53) 0.555
Palliative radiotherapy 22 (9) 12 (55) 10 (45)
Best supportive care 19 (7) 11 (58) 8 (42)
*Chi‑square test; †Student’s t‑test; ‡Fisher’s exact test. RT=Radiotherapy; CCRT=Concurrent chemoradiotherapy; CI=Condence interval; SD=Standard deviation;
ERCC‑1=Excision repair cross‑complementing Group 1
Figure 2: Consort diagram of the study
Table 2: Overall survival: Univariable and multivariable
Cox proportional hazard regression analysis
Covariates Univariable analysis Multivariable analysis
HR 95% CI P* aHR 95% CI P*
Sex
Female 1.00 1.00
Male 1.32 0.93-1.86 0.117 1.33 0.93-1.91 0.117
Age groups (years)
<55 1.00 1.00
≥55 1.83 1.34-2.51 <0.001 2.11 1.50-2.97 <0.001
Stage
Early (I-II) 1.00 1.00
Advanced (III-IV) 2.86 1.55-5.28 0.001 2.93 1.58-5.46 0.001
Treatment
Curative RT/CCRT 1.00 1.00
Palliative
radiotherapy
2.82 1.75-4.54 <0.001 2.11 1.27-3.49 0.004
Best supportive
care
2.86 1.68-4.90 <0.001 4.49 2.45-8.24 <0.001
ERCC-1 expression
Low 1.00 1.00
High 1.00 0.74-1.36 0.981 1.08 0.79-1.47 0.647
*P value from partial likelihood ratio tests. RT=Radiotherapy; CCRT=Concurrent
chemoradiotherapy; CI=Condence interval, HR=Hazard ratio; aHR=Adjusted
hazard ratio
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Chitapanarux, et al.: ERCC‑1 expression in nasopharyngeal cancer patients
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5
of the NER pathway.[19] Many studies reported ERCC‑1
to be involved in the different repair mechanisms
such as interstrand cross‑link repair and homologous
recombination repair.[20‑22] Overexpression of ERCC‑1 has
been found in many cancer types, and it has been proposed
that ERCC‑1 overexpression may serve as a prognostic
and/or predictive tumor marker.[23‑28] Overexpression of
ERCC‑1 also predicted low sensitivity to the platinum‑based
regimen for many cancers.[23‑25] Results from these published
data are still inconsistent.[20‑22]
The prognostic values of ERCC‑1 expression have been
studied in nasopharyngeal cancer studies,[10,13,29] but the
values of it remained controversial. Chan et al.[10] identied
that a high ERCC‑1 expression predicted a two‑fold
increase in risk only for locoregional failure but not OS
in a retrospective study of NPC. They also concluded
that chemotherapy response is not aected by ERCC‑1
expression. In line with Chan et al.,[10] our study has not
found any dierences in OS between the high and low
expression of ERCC‑1. Even when we focused on the group
of patients who received CCRT, the expression of ERCC‑1
failed to demonstrate signicant OS dierences between
high and low expression. In contrast with Xu et al.,[29] they
reported higher 3‑year OS, failure‑free survival, locoregional
failure‑free survival, and distant failure‑free survival in the
patients with ERCC‑1 positive and suggested that ERCC‑1
might be a predictor of response to platinum‑based
chemoradiotherapy. The study by Shen et al.[13] also found
that the overall response rate and 5‑year distant recurrence
risk of the patients with high expression of ERCC‑1 are
poorer than those of the control patients with low ERCC‑1
expression. However, their study did not report on OS. In
our study, we found that higher stage, age older than 55, and
not receiving chemoradiotherapy were prognostic factors
of poor OS but not ERCC‑1 expression. We tend to agree
with Hayes et al.[30] for their explanations on the lack of the
usefulness of ERCC‑1 expression as a prognostic factor of
survival, i.e., the synergism of concurrent chemotherapy
and radiation is able to overcome the relative resistance to
platinum conferred by ERCC‑1 expression. In our study,
most of the patients (80%) received CCRT with platinum
based.
As shown in Table 1, we did not find any association
between cancer stage and the level of ERCC‑1 expression
despite using an automated IHC staining platform and
objective evaluation. All cases were positively stained for
ERCC‑1; however, an overall range of expression level
was quite narrow (61%, IQR: 40–76). One limitation in
the tissue study of nasopharyngeal cancer is that biopsied
tissues were usually small, and the crushing artifact was
not uncommonly present. This results in a reduction in
tissue area for evaluation of ERCC‑1 expression. However,
in the present study, all well‑preserved tumor areas were
selected for objective digital image analysis to minimize the
bias. Considering the heterogeneity of the interpretation
method of ERCC‑1 expression, it is dicult to compare
our results to others.
CONCLUSION
ERCC‑1 expression is not a prognostic factor of OS in
patients with nasopharyngeal cancer. Further studies with
Figure 3: Kaplan–Meier curves of overall survival according to prognostic factors. There is a signicant dierence in 5‑year overall survival between early and advanced
stages (b), age group (c) and treatment (d), but not excision repair cross complementing Group 1expression level (a)
d
c
b
a
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Chitapanarux, et al.: ERCC‑1 expression in nasopharyngeal cancer patients
Journal of Research in Medical Sciences
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larger sample sizes are required to investigate whether or
not ERCC‑1 may use as a prognostic factor for this cancer.
Acknowledgments
We would like to thank Faculty of Medicine, Chiang Mai
University for having a role in data collection. This study
was approved by the Research Ethics Commiee of Faculty
of Medicine, Chiang Mai University. Ethical approval
number is 381/2014.
Financial support and sponsorship
This study was nancially supported by the Faculty of
Medicine, Chiang Mai University, for having a role in data
collection.
Conicts of interest
There are no conicts of interest.
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