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

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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.
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© 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:
10.4103/jrms.JRMS_787_18
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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Original article
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Chitapanarux, et al.: ERCC‑1 expression in nasopharyngeal cancer patients
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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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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.
REFERENCES
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D, et al.
Global cancer statistics. CA Cancer J Clin 2011;61:69‑90.
2. Imsamran W, Chaiwerawaana A, Wiangnon S, Pongnikorn D,
Suwanrungruang K, Sangrajrang S, et al. Cancer in Thailand. Vol. 8.
Bangkok, Thailand: National Cancer Institute; 2015.
3. Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, et al.
Chemotherapy and radiotherapy in nasopharyngeal carcinoma:
An update of the MAC‑NPC meta‑analysis. Lancet Oncol
2015;16:645‑55.
4. Au JS, Law CK, Foo W, Lau WH. In‑depth evaluation of the
AJCC/UICC 1997 staging system of nasopharyngeal carcinoma:
Prognostic homogeneity and proposed renements. Int J Radiat
Oncol Biol Phys 2003;56:413‑26.
5. Chua DT, Sham JS, Wei WI, Ho WK, Au GK. The predictive value
of the 1997 American joint commiee on cancer stage classication
in determining failure paerns in nasopharyngeal carcinoma.
Cancer 2001;92:2845‑55.
6. Heng DM, Wee J, Fong KW, Lian LG, Sethi VK, Chua ET,
et al. Prognostic factors in 677 patients in Singapore with
nondisseminated nasopharyngeal carcinoma. Cancer
1999;86:1912‑20.
7. Lai SZ, Li WF, Chen L, Luo W, Chen YY, Liu LZ, et al. How
does intensity‑modulated radiotherapy versus conventional
two‑dimensional radiotherapy inuence the treatment results in
nasopharyngeal carcinoma patients? Int J Radiat Oncol Biol Phys
2011;80:661‑8.
8. Lee AW, Sze WM, Au JS, Leung SF, Leung TW, Chua DT, et al.
Treatment results for nasopharyngeal carcinoma in the modern
era: The Hong Kong experience. Int J Radiat Oncol Biol Phys
2005;61:1107‑16.
9. Leung TW, Tung SY, Sze WK, Wong FC, Yuen KK, Lui CM,
et al. Treatment results of 1070 patients with nasopharyngeal
carcinoma: An analysis of survival and failure paerns. Head
Neck 2005;27:555‑65.
10. Chan SH, Cheung FM, Ng WT, Choi CW, Cheung KN, Yiu KH, et al.
Can the analysis of ERCC1 expression contribute to individualized
therapy in nasopharyngeal carcinoma? Int J Radiat Oncol Biol Phys
2011;79:1414‑20.
11. Hui EP, Ma BB, Chan KC, Chan CM, Wong CS, To KF, et al.
Clinical utility of plasma epstein‑barr virus DNA and ERCC1
single nucleotide polymorphism in nasopharyngeal carcinoma.
Cancer 2015;121:2720‑9.
12. Liang R, Lin Y, Liu ZH, Liao XL, Yuan CL, Liao SN, et al. Correlation
between ERCC1 expression and concurrent chemotherapy and
radiotherapy in patients with locally advanced nasopharyngeal
cancer. Genet Mol Res 2015;14:5804‑11.
13. 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 Cancer Res Ther 2016;12:72‑5.
14. Yang ZH, Dai Q, Kong XL, Yang WL, Zhang L. Association of
ERCC1 polymorphisms and susceptibility to nasopharyngeal
carcinoma. Mol Carcinog 2009;48:196‑201.
15. Carles J, Monzo M, Amat M, Jansa S, Artells R, Navarro A,
et al. Single‑nucleotide polymorphisms in base excision repair,
nucleotide excision repair, and double strand break genes as
markers for response to radiotherapy in patients with stage I to II
head‑and‑neck cancer. Int J Radiat Oncol Biol Phys 2006;66:1022‑30.
16. Kelland L. The resurgence of platinum‑based cancer chemotherapy.
Nat Rev Cancer 2007;7:573‑84.
17. Kirschner K, Melton DW. Multiple roles of the ERCC1‑XPF
endonuclease in DNA repair and resistance to anticancer drugs.
Anticancer Res 2010;30:3223‑32.
18. McNeil EM, Melton DW. DNA repair endonuclease ERCC1‑XPF as
a novel therapeutic target to overcome chemoresistance in cancer
therapy. Nucleic Acids Res 2012;40:9990‑10004.
19. Glastonbury CM, Salzman KL. Pitfalls in the staging of cancer
of nasopharyngeal carcinoma. Neuroimaging Clin N Am
2013;23:9‑25.
20. de Silva IU, McHugh PJ, Clingen PH, Hartley JA. Dening the
roles of nucleotide excision repair and recombination in the repair
of DNA interstrand cross‑links in mammalian cells. Mol Cell Biol
2000;20:7980‑90.
21. Niedernhofer LJ, Odijk H, Budzowska M, van Drunen E, Maas A,
Theil AF, et al. The structure‑specic endonuclease ercc1‑xpf
is required to resolve DNA interstrand cross‑link‑induced
double‑strand breaks. Mol Cell Biol 2004;24:5776‑87.
22. Sargent RG, Meservy JL, Perkins BD, Kilburn AE, Intody Z,
Adair GM, et al. Role of the nucleotide excision repair gene ERCC1
in formation of recombination‑dependent rearrangements in
mammalian cells. Nucleic Acids Res 2000;28:3771‑8.
23. Ciaparrone M, Caspiani O, Bicciolo G, Signorelli D, Simonelli I,
de Campora L, et al. Predictive role of ERCC1 expression in
head and neck squamous cell carcinoma patients treated with
surgery and adjuvant cisplatin‑based chemoradiation. Oncology
2015;89:227‑34.
24. Deng Q, Yang H, Lin Y, Qiu Y, Gu X, He P, et al. Prognostic value
of ERCC1 mRNA expression in non‑small cell lung cancer, breast
cancer, and gastric cancer in patients from Southern China. Int J
Clin Exp Pathol 2014;7:8312‑21.
25. Jacobsen F, Taskin B, Melling N, Sauer C, Wimer C, Hube‑Magg C,
et al. Increased ERCC1 expression is linked to chromosomal
aberrations and adverse tumor biology in prostate cancer. BMC
Cancer 2017;17:504.
26. Klae T, Sei C, Rink M, Rouprêt M, Xylinas E, Karakiewicz P,
et al. ERCC1 as a prognostic and predictive biomarker for urothelial
carcinoma of the bladder following radical cystectomy. J Urol
2015;194:1456‑62.
27. Li S, Wu J, Chen Y, Tang W, Peng Q, Deng Y, et al. ERCC1 expression
levels predict the outcome of platinum‑based chemotherapies in
advanced bladder cancer: A meta‑analysis. Anticancer Drugs
2014;25:106‑14.
28. Maithel SK, Coban I, Kneuertz PJ, Kooby DA, El‑Rayes BF,
Kauh JS, et al. Differential expression of ERCC1 in pancreas
adenocarcinoma: High tumor expression is associated with earlier
[Downloaded free from http://www.jmsjournal.net on Tuesday, April 14, 2020, IP: 88.238.130.122]
Chitapanarux, et al.: ERCC‑1 expression in nasopharyngeal cancer patients
Journal of Research in Medical Sciences | 2020 |
7
recurrence and shortened survival after resection. Ann Surg Oncol
2011;18:2699‑705.
29. Xu S, Yu Y, Rong J, Hu D, Zhang L, Fu S, et al. Expression of BRCA1
and ERCC1 as predictive clinical outcome after radiochemotherapy
in patients with locoregionally moderate‑advanced nasopharyngeal
carcinoma. Oncotarget 2017;8:31355‑67.
30. Hayes M, Lan C, Yan J, Xie Y, Gray T, Amirkhan RH, et al.
ERCC1 expression and outcomes in head and neck cancer
treated with concurrent cisplatin and radiation. Anticancer Res
2011;31:4135‑9.
[Downloaded free from http://www.jmsjournal.net on Tuesday, April 14, 2020, IP: 88.238.130.122]
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Article
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Background Animal model experiments have suggested a role of the DNA repair protein ERCC1 (Excision Repair Cross-Complementation Group 1) in prostate cancer progression. Methods To better understand the impact of ERCC1 protein expression in human prostate cancer, a preexisting tissue microarray (TMA) containing more than 12,000 prostate cancer specimens was analyzed by immunohistochemistry and data were compared with tumor phenotype, PSA recurrence and several of the most common genomic alterations (TMPRSS2:ERG fusions: deletions of PTEN, 6q, 5q, 3p). ResultsERCC1 staining was seen in 64.7% of 10,436 interpretable tissues and was considered weak in 37.1%, moderate in 22.6% and strong in 5% of tumors. High-level ERCC1 staining was linked to advanced pT stage, high Gleason grade, positive lymph nodes, high pre-operative serum PSA, and positive surgical margin status (p < 0.0001 each). High ERCC1 expression was strongly associated with an elevated risk of PSA recurrence (p < 0.0001). This was independent of established prognostic features. A subgroup analysis of cancers defined by comparable quantitative Gleason grades revealed that the prognostic impact was mostly driven by low-grade tumors with a Gleason 3 + 3 or 3 + 4 (Gleason 4: ≤5%). High ERCC1 expression was strongly associated with the presence of genomic alterations and expression levels increased with the number of deletions present in the tumor. These latter data suggest a functional relationship of ERCC1 expression with genomic instability. Conclusion The results of our study demonstrate that expression of ERCC1 - a potential surrogate for genomic instability - is an independent prognostic marker in prostate cancer with particular importance in low-grade tumors.
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In this study, we examined ERCC1 and BRCA1 expression and clinical outcome of 201 phase-III-IV nasopharyngeal carcinoma patients who were treated with cisplatin-based induced chemotherapy and concurrent radiochemotherapy. The chemotherapy response rate of BRCA1- and BRCA1+ patients was 73.6% and 55.8%, respectively. In addition, the chemotherapy response rate of ERCC1- and ERCC1+ patients was 76.9% and 56.6%, respectively. In patients' tissues, ERCC1 expression associated with BRCA1 expression. The chemotherapy response rate of BRCA1- and ERCC1- patients was (82.1%) and higher than that of other groups (range 52.4-73.1%). The radiochemotherapy response rate of BRCA1- and ERCC1- patients was higher than that BRCA1+ and ERCC1+ patients. BRCA1- and ERCC1- patients showed higher 3-year overall survival, failure-free survival, locoregional failure-free survival and distant failure-free survival compared to BRCA1+ or ERCC1+ patients. Moreover, the 3-year overall survival, failure-free survival and distant failure-free survival of the BRCA1- and ERCC1- group were higher than that of other groups. TNM stage, ERCC1 expression and the correlation between BRCA1 and ERCC1 expression seemed significant overall survival factors. In conclusion, in nasopharyngeal carcinoma patients, ERCC1 and BRCA1 may be a predictor of response to platinum-based chemotherapy and concurrent radiochemotherapy.
Article
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Article
Excision repair cross-complementing group 1 (ERCC1) is the key enzyme of the nucleotide excision repair pathway, which maintains genomic stability. ERCC1 has been proposed as a prognostic and predictive biomarker for patients with urothelial carcinoma of the bladder (UCB), but there are limited data for patients following radical cystectomy (RC). ERCC1 was evaluated by immunohistochemistry in RC specimens of 432 patients. Associations with disease-free survival, cancer-specific survival and the effect of adjuvant cisplatin-based chemotherapy were assessed. Further, ERCC1 mRNA expression and the in vitro sensitivity to cisplatin were correlated in 25 UCB cell lines. ERCC1 was expressed in 308 tumors (71.3%). There was no association with clinico-pathological variables (each p>0.4). The median postoperative follow-up was 128 months. On multivariable analyses, patients with ERCC1-positive tumors had significantly better disease-free (HR 0.70, p=0.028) and cancer-specific survival (HR 0.70, p=0.032) than those with ERCC1-negative tumors. The discrimination of the multivariable models increased by 0.7-0.9% following inclusion of ERCC1. There was no modification of the effect of adjuvant cisplatin-based combination chemotherapy by ERCC1 status (p=0.38 and p=0.88) and no correlation between ERCC1 and sensitivity to cisplatin in vitro (R²=0.02, p=0.46). ERCC1 may be a prognostic biomarker in UCB. Patients with ERCC1-positive tumors may have better survival than those with ERCC1-negative tumors, but the efficacy of adjuvant cisplatin-based chemotherapy appears to be not related to ERCC1 status. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Article
In this study, the expression of DNA excision repair cross-complementing gene 1 (ERCC1) in local advanced nasopharyngeal carcinoma has been correlated with the efficacy of concurrent chemoradiotherapy. A total of 76 patients diagnosed with undifferentiated nasopharyngeal carcinoma diagnosed by nasopharyngeal biopsy and undergoing single-agent cisplatin chemotherapy (80 mg/m(2)) with concurrent radiotherapy (on the first, twenty-second, and forty-third day, 5 times per week, mean dose 74 Gy, range 70-78 Gy) at the Affiliated Cancer Hospital of Guangxi Medical University between January and December 2010 were included. After chemoradiotherapy, outcomes and long-term survival were evaluated. Immunohistochemistry was used to detect expression of ERCC1 protein in nasopharyngeal carcinoma. The relationship between the expression of ERCC1 and efficacy of concurrent chemoradiotherapy and long-term survival were analyzed. ERCC1 was expressed in 42.1% of cases. The expression of ERCC1 was correlated with T stage and clinical staging (P < 0.05), but not with gender, age, or N stage. The response rate in the ERCC1-positive and ERCC1-negative groups was 75.0% and 97.7%, respectively (P < 0.05). In the 72 cases with follow-up available, 1-, 2-, and 3-year survival rates were 91.0, 83.3, and 79.0%; they were 92.4, 87.8, 80.5%, respectively, in the ERCC1-positive group, and 87.9, 77.4, 77.4%, respectively, in the ERCC1-negative group. The expression of ERCC1 may be a sensitive prognostic indicator of concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma.
Article
ERCC1 (excision repair cross-complementation group 1) expression predicts survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with chemoradiation. In order to evaluate the predictive role in the adjuvant setting, we investigated ERCC1 expression in radically resected HNSCC patients who underwent surgery and cisplatin chemoradiation. ERCC1 expression levels were determined by immunohistochemistry in primary tumor tissues from 48 patients with stage III-IV cancers. The median follow-up was 38.5 months (range: 5-121). High ERCC1 expression was observed in 36 (75%) patients. Univariate analysis showed that patients with high levels of ERCC1 had significantly worse disease-free survival and overall survival (OS) than patients with low levels (HR = 7.15; 95% CI, 1.68-30.35; p = 0.008 and HR = 9.90; 95% CI, 1.33-73.96; p = 0.025, respectively). In the multivariate analysis, high ERCC1 expression (HR = 7.36; 95% CI, 1.72-31.4; p = 0.007) together with high-risk category (HR = 2.69; 95% CI, 1.01-7.18; p = 0.048) were the best predictors for relapse. High ERCC1 expression was the only unfavorable independent determinant for OS (HR = 9.53; 95% CI, 1.27-71.35; p = 0.028). This investigation suggests that ERCC1 expression might be useful to predict prognosis in radically resected HNSCC patients treated with surgery and chemoradiation. © 2015 S. Karger AG, Basel.
Article
BACKGROUND Single nucleotide polymorphism (SNP) of the excision repair cross-complementing group 1 (ERCC1) gene has been linked with sensitivity to platinum and radiation. The authors hypothesized that the ERCC1 genotype for the SNPs cytosine-to-thymine substitution at codon 118 (C118T) and cytosine-to-adenine substitution at codon 8092 (C8092A) is prognostic in patients with nasopharyngeal carcinoma (NPC) who receive either radiotherapy (RT) or cisplatin plus RT.METHODS The authors tested their hypothesis using biomarker screening samples from the Hong Kong NPC Study Group 0502 trial, which was a prospective, multicenter clinical trial that used post-RT plasma Epstein-Bar virus (EBV) DNA (pEBV) levels to screen patients with high-risk NPC for adjuvant chemotherapy.RESULTSERCC1 SNPs were analyzed in 576 consecutive patients who were screened by pEBV. In the total biomarker population, there was no significant association of ERCC1 C118T or C8092A genotype with relapse-free survival (RFS) or overall survival (OS). There also was no correlation between ERCC1 genotype and ERCC1 protein or messenger RNA expression in a subset of patients who had available paired biopsies. Post-RT pEBV status was the only independent prognosticator for RFS and OS in multivariate analyses. However, there was a significant interaction between ERCC1 C118T genotype and post-RT pEBV status (RFS, P = .0106; OS, P = .0067). The ERCC1 C118T genotype was significantly associated with both RFS (hazard ratio, 1.67; 95% confidence interval, 1.07-2.61; P = .024) and OS (hazard ratio, 2.31; 95% confidence interval, 1.22-4.40; P = .0106) in the post-RT pEBV-negative population, but not in the pEBV-positive population.CONCLUSIONS The current results prospectively validate pEBV as the most significant prognostic biomarker in NPC that can be used to select high-risk patients for adjuvant therapy. The ERCC1 C118T genotype may help to identify a favorable subgroup (approximately 7%) of pEBV-negative patients with NPC who have an excellent prognosis and can be spared the toxicities of further therapy. [See editorial on pages 000-000, this issue.] Cancer 2015. © 2015 American Cancer Society.
Article
Background: A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. Methods: We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. Findings: We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84). Interpretation: Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. Funding: French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.
Article
Background: Excision repair cross complementation group 1 (ERCC1) is a nucleotide excision repair pathway gene which provides protection against platinum-based chemotherapy-induced DNA damage. Methods: ERCC1 mRNA expression was quantified by quantitative real-time reverse-transcription PCR in paraffin-embedded non-small cell lung cancer (NSCLC; n = 357), gastric cancer (n = 106), and breast cancer (n = 363) tissues. Survival curves were generated by Kaplan-Meier analysis; Cox proportional multivariate regression analysis was applied. Results: ERCC1 mRNA expression was significantly higher in breast cancer than gastric cancer or NSCLC (both P < 0.0001), but not significantly different in NSCLC and gastric cancer (P = 0.119). In NSCLC, the low ERCC1 group had significantly longer disease free survival (DFS) than the high ERCC1 group (29.1 vs. 21.0 months, P < 0.0001); in the surgery alone and postoperative platinum-containing chemotherapy subgroups, DFS was significantly longer for the low ERCC1 groups than high ERCC1 groups (30.2 vs. 25.1 months, P = 0.018; 27.0 vs. 19.4 months, P < 0.0001, respectively). In gastric cancer patients receiving surgery alone, the low ERCC1 group had significantly longer overall survival than the high ERCC1 group (47.54 vs. 27.47 months, P = 0.018). Conclusions: High ERCC1 mRNA expression of the NSCLC tumor tissues was associated with poor disease-free survival (DFS), in both the surgery alone and postoperative platinum-containing chemotherapy subgroups. Meanwhile, low ERCC1 mRNA expression had significantly longer overall survival in gastric cancer patients receiving surgery alone. Therefore, ERCC1 expression was a prognostic factor and predictive marker in NSCLC, and gastric cancer after surgery alone, but was not a prognostic factor in breast cancer.