ERCC1 expression as a prognostic and predictivefactor in patients with non-small cell lung cancer:a meta-analysis

Jingwei Jiang • Xiaohua Liang • Xinli Zhou •

Ruofan Huang • Zhaohui Chu • Qiong Zhan

Received: 3 September 2011 / Accepted: 24 January 2012 / Published online: 3 February 2012

� Springer Science+Business Media B.V. 2012

Abstract It is hypothesized that high expression of the

excision repair cross-complementation group 1 (ERCC1) gene

might be a positive prognostic factor, but predict decreased

sensitivity to platinum-based chemotherapy. Results from the

published data are inconsistent. To derive a more precise

estimation of the relationship between ERCC1 and the prog-

nosis and predictive response to chemotherapy of non-small

cell lung cancer (NSCLC), a meta-analysis was performed. An

electronic search of the PubMed and Embase database was

performed. Hazard ratio (HR) for overall survival (OS) was

pooled in early stage patients received surgery alone to analyze

the prognosis of ERCC1 on NSCLC. HRs for OS in patients

received surgery plus adjuvant chemotherapy and in patients

received palliative chemotherapy and relative risk (RR) for

overall response to chemotherapy were aggregated to analyze

the prediction of ERCC1 on NSCLC. The pooled HR indicated

that high ERCC1 levels were associated with longer survival in

early stage patients received surgery alone (HR, 0.69; 95%

confidence interval (CI), 0.58–0.83; P = 0.000). There was no

difference in survival between high and low ERCC1 levels in

patients received surgery plus adjuvant chemotherapy (HR,

1.41; 95% CI, 0.93–2.12; P = 0.106). However, high ERCC1

levels were associated with shorter survival and lower

response to chemotherapy in advanced NSCLC patients

received palliative chemotherapy (HR, 1.75; 95% CI,

1.39–2.22; P = 0.000; RR, 0.77; 95% CI, 0.64–0.93;

P = 0.007; respectively). The meta-analysis indicated that

high ERCC1 expression might be a favourable prognostic and

a drug resistance predictive factor for NSCLC.

Keywords Carcinoma, non-small cell lung � Excision

repair cross-complementation group 1 � DNA-binding

proteins � Drug resistance � Neoplasm � Meta-analysis

Introduction

Lung cancer remains the leading cause of cancer death

worldwide [1]. Non-small-cell lung cancer (NSCLC)

accounts for 80–85% of lung cancers [2]. The most promising

therapy for cure is complete resection. However, 40–50% of

patients with pathological stage I die within 5 years after

complete resection, and the prognosis is worse in more

advanced cases [3]. For the advanced NSCLC patients, plat-

inum-based chemotherapy remains the standard regimens.

Due to the significant variations in response and prognosis for

NSCLC patients receiving uniform treatment, there is a great

need for predictive as well as prognostic markers based on

tumor biology. One of the most promising markers is excision

repair cross-complementation group 1 (ERCC1).

ERCC1 is a critical gene on the NER pathway, which is

the primary DNA repair mechanism that removes plati-

num–DNA adducts from genomic DNA. Differences of

ERCC1 expression in tumor tissue have been associated

with different survival of NSCLC patients. It is hypothe-

sized that low expression of the ERCC1 gene predicts

increased sensitivity to platinum-based chemotherapy;

however a high-ERCC1 level might be a positive prog-

nostic variable [4]. But the results from the published data

are inconsistent, partially because of the possible small

effect of the ERCC1 on the prognosis or predictive

J. Jiang � X. Liang (&) � X. Zhou � R. Huang � Z. Chu �Q. Zhan

Department of Oncology, Huashan Hospital, Fudan University,

No. 12 Wulumuqi Zhong Road, Shanghai 200040, China

e-mail: xiaohualiang2009@gmail.com

J. Jiang � X. Liang � X. Zhou � R. Huang � Z. Chu � Q. Zhan

Department of Oncology, Shanghai Medical College, Fudan

University, Shanghai 200040, China

123

Mol Biol Rep (2012) 39:6933–6942

DOI 10.1007/s11033-012-1520-4

response of NSCLC and the relatively small sample size in

each of published studies. To derive a more precise esti-

mation of the relationship between ERCC1 expression and

the prognosis and predictive response to platinum-based

chemotherapy of NSCLC, we performed this meta-analysis

and systematic review. In order to analyze the prognosis of

ERCC1 on NSCLC, the hazard ratio (HR) for overall

survival (OS) was pooled in early stage patients received

surgery alone. In order to analyze the predictive response

to chemotherapy of ERCC1, the HRs for OS in patients

received surgery plus adjuvant chemotherapy and in

patients received palliative chemotherapy and the relative

risk (RR) for overall response to chemotherapy in patients

received palliative chemotherapy were aggregated.

Methods

Search strategy and study selection

An electronic search of the PubMed and Embase database

was performed. The last search was updated in June, 2011.

The following keywords were used: ‘‘Carcinoma, Non-

Small Cell Lung’’, ‘‘Lung Neoplasms’’, ‘‘non-small cell

lung cancer’’, ‘‘DNA-Binding Proteins’’, ‘‘ERCC1’’,

‘‘Excision Repair Cross-Complementation Group 1’’ and

‘‘Excision repair cross-complementing 1’’. We limited the

published language in English. The published years wer-

en’t limited. Reference lists of original articles and review

articles were also examined for additional studies. Studies

eligible for inclusion in this meta-analysis should meet the

following criteria: (1) measure ERCC1 expression in the

cancer tissue with immunohistochemistry (IHC) or reverse

transcription-polymerase chain reaction (RT-PCR); (2)

patients had to have pathologically confirmed NSCLC; (3)

provide information on survival or response rates according

to ERCC1 expression; (4) only published studies with full

text were included. When the same author reported results

obtained from the same patient population in more than one

publication, only the most recent or complete one was

included in the analysis. Two reviewers independently

determined study eligibility. Disagreements were resolved

by consensus.

Data abstraction

All the data were independently abstracted by two inves-

tigators with the use of standardized data-abstraction

forms. Disagreements were resolved by discussion with an

independent expert. The following information were

sought from each paper, although some papers did not

contain all the information: first authors, years of publi-

cation, regions or countries, disease stage, percentage of

smokers, percentage of adenocarcinoma, percentage of

female, first line therapies, numbers of the patients, the

methods used to measure ERCC1, the cutoff to categorize

high expression and low expression of ERCC1, numbers of

the patients with high and low expression of ERCC1,

numbers of the patients eligible for response evaluation,

numbers of the patients acquired overall response, HRs for

OS and their 95% confidence intervals (CIs), If HR was not

directly reported, estimation of the log HR and variance

from the Kaplan–Meier curves was based on published

methodology [5].

Statistical analysis

The HRs for OS and the RR for overall response to treat-

ment were aggregated by using Stata SE 10.1 package. A

statistical test with a P value less than 0.05 was considered

significant. HR [ 1 reflects high ERCC1 expression was

associated with shorter survival than low ERCC1 expres-

sion; RR [ 1 reflects high ERCC1 expression was associ-

ated with more overall response than low ERCC1

expression, and vice versa. To investigate the statistical

heterogeneity between trials, the standard V2 Q test was

applied (meaningful differences between studies indicated

by P \ 0.10). If fine homogeneity were found, a fixed-

effect model was used for analysis; if not, a random-effect

model was used. If heterogeneity was found, we also per-

formed a meta-regression analysis of multiple covariates to

exploring the sources of heterogeneity. All P values were

two sided. All CIs had a two-sided probability coverage of

95%. Evidence of publication bias was sought by using the

methods of Egger et al. and Begg et al. [6, 7].

Results

Trial flow

Figure 1 showed the flow of the trials selection. Two

hundreds and fifty-six reports were retrieved originally

after electronic searching, and 32 reports [8–39] were

identified after duplicates removed and scanning the titles

and abstracts. Four reports [36–39] were excluded for in

vitro studies (three studies [36–38]) and the same author

reported results obtained from the same patient population

in another publication [23] (one study [39]).

Characteristics of the 28 studies

Twenty-eight studies [8–35] meeting the inclusion criteria

were identified ultimately. All the 28 studies were reported

in full text. Baseline characteristics of the 28 studies were

listed in Table 1. The numbers of studies reported the data

6934 Mol Biol Rep (2012) 39:6933–6942

123

in early stage patients accepted surgery alone, in patients

accepted surgery plus adjuvant chemotherapy and in

patients accepted palliative chemotherapy were six [8, 23,

24, 26, 31, 34], seven [8, 12, 13, 16, 23, 25, 31] and

eighteen [9–11, 14, 15, 17–22, 27–30, 32, 33, 35],

respectively.

OS in early stage patients accepted surgery alone

HRs for OS were available from six studies [8, 23, 24, 26,

31, 34] including 1,161 patients in early stage patients

accepted curative surgery without chemotherapy in the first

line treatment. The pooled HR showed that high ERCC1

expression was associated with longer survival than low

ERCC1 expression in early stage NSCLC patients who

accepted surgery without adjuvant chemotherapy (HR,

0.69; 95% CI, 0.58–0.83; P = 0.000; for heterogeneity:

P = 0.365; Fig. 2).

Because there was only one study [34] used RT-PCR to

detect ERCC1 expression in patients who accepted surgery

alone, we didn’t perform subgroup analyses by laboratory

techniques. We conducted a sensitivity analysis after the

study using RT-PCR to detect ERCC1 was rejected, and it

yielded the same result (HR, 0.71; 95% CI, 0.59–0.85;

P = 0.000; for heterogeneity: P = 0.676).

Publication bias was not detected according to Begg’s

test (P = 0.764) and Egger’s test (P = 0.703).

OS in patients accepted surgery plus adjuvant

chemotherapy

HRs for OS were available from seven studies [8, 12, 13,

16, 23, 25, 31] including 1,084 patients accepted surgery

plus adjuvant chemotherapy in the first line treatment. The

pooled HR didn’t show a significant difference in OS

between high ERCC1 expression and low ERCC1

expression in patients accepted surgery plus adjuvant

chemothrepy (HR, 1.41; 95% CI, 0.93–2.12; P = 0.106;

for heterogeneity: P = 0.001; Fig. 3). Because there were

only two studies [12, 16] used RT-PCR to detect ERCC1

Fig. 1 The flow of the trials

selection for the meta-analysis

Mol Biol Rep (2012) 39:6933–6942 6935

123

Table 1 Baseline characteristics of the 28 eligible studies in the meta-analysis

Authour/

year[ref]

Region Stage Smoking

(%)

Ad

(%)

Female

(%)

No.

of

pts.

Chemotherapy

regimens

Method Cutoff High/low

expression

Surgery alone

Bepler 2011 [8]a Europe and

South

America

I–III – – – 365 – IHC 10 170/195

Okuda 2008 [23]b Japan I–IV – – – 59 – IHC 2 20/39

Lee 2008 [24] Korea I–III 69 39 25 130 – IHC 10 80/50

Zheng 2007 [26]h American I 93 51 46 93 – IHC 65.9 55/38

Zheng 2007 [26]l American I 93 51 46 91 – IHC 65.9 37/54

Olaussen 2006 [31]b France I–III – 32 18 372 – IHC 1 202/170

Simon 2005 [34] American IA–IIIB 88 51 27 51 – RT-PCR 50 NK

Surgery ? chemotherapy

Bepler 2011 [8]b Europe and

South

America

I–III – – – 382 Platinum-based IHC 10 161/221

Li2010 [12] China IIIA(N2) 67 77 24 46 NP/GP (pre) RT-PCR 0.153 23/23

Kang 2010 [13] Korea IB–IIIB – 34 16 82 Platinum-based (pre) IHC NK 57/25

Li 2009 [16] China IB–IIIA 72 58 30 60 DDP-based (GP/NP) RT-PCR 0.1458 NK

Okuda 2008 [23]a Japan I–IV 74 49 19 90 Platinum-based

(pre/pos)

IHC 2 39/51

Fujii 2008 [25]a Japan IIIA–IIIB 80 53 13 15 DDP ? CPT-11 (pre) IHC 50% 7/8

Fujii 2008 [25]b Japan IIIA–IIIB 80 50 30 20 Chemoradiotherapy

(DDP ? DOC) (pre)

IHC 50% 13/7

Olaussen 2006 [31]a France I–III – 32 18 389 DDP-based IHC 1 165/224

Palliative chemotherapy

Wang 2010 [9] China IIIB–IV – 67 35 124 Platinum-based IHC 10% 43/81

Vilmar 2010 [10] Denmark IIIA–IV – 63 49 264 PTX ? DDP ? GEM/

DDP ? VLB

IHC 1 125/139

Ren 2010 [11] China IIIB–IV 63 46 24 100 Platinum-based doublets RT-PCR 50% 53/49

Reynolds 2009 [14] American IIIB–IV – 62 49 65 GEM ± CBP IHC 65.0 19/46

Ota 2009 [15] Japan IV – 61 24 156 Platinum-based IHC 10% 100/56

Li 2009 [17] China IIIB–IV 68 52 29 66 DDP-based RT-PCR 0.122 33/33

Lee 2009 [18] Korea IIIB–IV 70 68 24 50 Platinum-based IHC 6 28/22

Ikeda 2009 [19] Japan IIIA–IV – 33 13 40 CBP ? PTX IHC 10% 27/13

Holm 2009 [20] Denmark IIB–IV 90 57 50 163 GEM ? CBP IHC 1 25/138

Azuma 2009 [21] Japan Recurrent 51 80 40 45 CBP ? PTX IHC 2 20/25

Azuma 2009 [22] Japan IIB–IIIB 79 47 18 34 Chemoradiation

(DDP ? DOC)

IHC 2 16/18

Simon 2007 [27]h American IIIB–IV 89 62 42 21 DOC ? NVB vs

DOC ? CBP

RT-PCR 8.7 14/7

Simon 2007 [27]l American IIIB–IV 89 62 42 32 GEM ? DOC vs

GEM ? CBP

RT-PCR 8.7 20/12

Cobo 2007 [28] European IIIB–IV – 52 17 211 DOC ? GEM vs

DOC ? DDP

RT-PCR NK 89/122

Booton 2007 [29] American III–IV – 26 32 66 DOC ? CBP/

MMC ? IFO ? DDP/

MMC ? VLB ? DDP

RT-PCR 9.0 33/33

Azuma 2007 [30] Japan Recurrent 51 79 43 67 Platinum-based IHC 25% 29/38

Ceppi 2006 [32] Italy III–IV – 54 28 61 GEM ± DDP RT-PCR 4.0 34/27

6936 Mol Biol Rep (2012) 39:6933–6942

123

expression in patients who accepted surgery plus adjuvant

chemotherapy, we didn’t perform subgroup analyses by

laboratory techniques. We conducted a sensitivity analysis

after the studies using RT-PCR to detect ERCC1 were

rejected, and it yielded the same result (HR, 1.10; 95% CI,

0.74–1.64; P = 0.642; for heterogeneity: P = 0.026).

As there was heterogeneity in the OS in patients

accepted surgery plus adjuvant chemotherapy, we per-

formed a meta-regression analysis of multiple covariates to

exploring the sources of heterogeneity. As data of smoking

couldn’t be acquired from three of the seven studies [8, 13,

31] and data of adenocarcinoma and female couldn’t be

acquired from Bepler et al.’s study [8], smoking wasn’t

included in the covariates and Bepler’s study was rejected

in the meta-regression analysis. We considered race

(Whites or Asians), detecting methods (IHC or RT-PCR),

adenocarcinoma and female as four covariates. However,

none of the four covariates was found to be the sources of

heterogeneity (P values for race, detecting methods, ade-

nocarcinoma and female were 0.663, 0.921, 0.556 and

0.994, respectively).

Publication bias was not detected according to Begg’s

test (P = 1.000) and Egger’s test (P = 0.725).

OS in patients accepted palliative chemotherapy

HRs for OS were available from 16 studies [9–11, 14, 15,

17–22, 27, 29, 30, 32, 35] including 1,410 patients accepted

palliative chemotherapy in the first line treatment. The pooled

HR for OS showed that high ERCC1 expression was

Table 1 continued

Authour/

year[ref]

Region Stage Smoking

(%)

Ad

(%)

Female

(%)

No.

of

pts.

Chemotherapy

regimens

Method Cutoff High/low

expression

Bepler 2006 [33] American IIIA–IIIB 94 31 49 35 GEM ? CBP RT-PCR 6.7 18/17

Lord 2002 [35] American IIIB-–IV – 54 14 56 GEM ? DDP RT-PCR 6.7 28/28

Bepler 2011 [8]a, patients treated with surgery only; Bepler 2011 [8]b, patients treated with surgery plus adjuvant chemotherapy; Okuda 2008

[23]a, patients treated with surgery plus adjuvant chemotherapy; Okuda 2008 [23]b, patients treated with surgery only; Olaussen 2006 [31]a,

patients treated with surgery only; Olaussen 2006 [31]b, patients treated with surgery plus adjuvant chemotherapy; Fujii 2008 [25]a, patients

treated with neoadjuvant chemotherapy; Fujii 2008 [25]b, patients treated with neoadjuvant chemoradiotherapy; Zheng 2007 [26]h, all patients

with ribonucleotide reductase 1 (RRM1) high expression tumor; Zheng 2007 [26]l, all patients with RRM1 low expression tumor; Simon 2007

[27]h, all patients with RRM1 high expression tumor; Simon 2007 [27]l, all patients with RRM1 low expression tumor

Ad adenocarcinoma, DDP cisplatin, CBP carboplatin, PTX paclitaxel, DOC docetaxel, CPT-11 irinotecan, MMC mitomycin, IFO ifosfamide,

VLB vinblastine, GEM gemcitabine, GP gemcitabine ? cisplatin, NP Navelbine ? cisplatin, pre preoperative, pos postoperative, IHC immu-

nohistochemistry, RT-PCR reverse transcription-polymerase chain reaction, NK not known

Fig. 2 The pooled HR for OS

in early stage NSCLC patients

who received curative surgery

without chemotherapy in the

first line treatment showed that

high ERCC1 expression was

associated with longer survival

than low ERCC1 expression

(P = 0.000). The P-value in the

figure is P-value for

heterogeneity, which showed

there was not heterogeneity

(P = 0.365)

Mol Biol Rep (2012) 39:6933–6942 6937

123

associated with shorter survival in advanced patients accep-

ted palliative chemotherapy (HR, 1.75; 95% CI, 1.39–2.22;

P = 0.000; for heterogeneity: P = 0.000; Fig. 4). The sub-

group meta-analyses by laboratory techniques also showed

that high ERCC1 expression was associated with shorter

survival than low ERCC1 expression in patients accepted

palliative chemotherapy in the first line treatment in both the

IHC subgroup (HR, 1.65; 95% CI, 1.42–1.92; P = 0.000; for

Fig. 3 The pooled HR for OS

in NSCLC patients who

received surgery plus adjuvant

chemotherapy in the first line

treatment failed to show a

significant difference in survival

between high ERCC1

expression and low ERCC1

expression patients

(P = 0.106). The P-value in the

figure is P-value for

heterogeneity, which showed

there was heterogeneity

(P = 0.001)

Fig. 4 The pooled HR for OS

in late stage NSCLC patients

who received palliative

chemotherapy showed that high

ERCC1 expression was

associated with shorter survival

than low ERCC1 expression

(P = 0.000). A further

subgroup analyses by laboratory

techniques also yielded the

same results (P = 0.000 and

P = 0.027 for IHC subgroup

and RT-PCR subgroup,

respectively). The P-values in

the figure is P-values for

heterogeneity, which showed

there was not heterogeneity in

IHC subgroup (P = 0.296), but

there were heterogeneities in

RT-PCT subgroup (P = 0.000)

and overall populations

(P = 0.000)

6938 Mol Biol Rep (2012) 39:6933–6942

123

heterogeneity: P = 0.296; Fig. 4) and the RT-PCR subgroup

(HR, 1.66; 95% CI, 1.06–2.61; P = 0.027; for heterogeneity:

P = 0.000; Fig. 4).

As there was heterogeneity, we performed a meta-

regression analysis of multiple covariates to exploring the

sources of heterogeneity. As data of smoking couldn’t be

acquired from 8 of the 16 studies [9, 10, 14, 15, 19, 29, 32,

35], smoking wasn’t included in the covariates. We con-

sidered race (Whites or Asians), detecting methods (IHC or

RT-PCR), adenocarcinoma and female as four covariates.

The results showed that gender was one of the sources of

heterogeneity and histology type might be another source

of heterogeneity (P values were 0.041 and 0.052 for female

and adenocarcinoma, respectively; P values for race and

detecting methods were 0.219 and 0.762, respectively).

Publication bias was not detected according to Begg’s

test (P = 0.343), but Egger’s test indicated there might be

Publication bias (P = 0.000).

Overall response in patients accepted palliative

chemotherapy

There were 13 studies [9–11, 15, 17, 18, 21, 22, 28–30, 33,

35] that reported overall response rate. The aggregated RR

for overall response showed that high ERCC1 expression

was associated with lower response to chemotherapy in

advanced patients accepted palliative chemotherapy (RR,

0.77; 95% CI, 0.64–0.93; P = 0.007; for heterogeneity:

P = 0.087; Fig. 5). The subgroup analyses by laboratory

techniques yielded the same results in IHC group (RR,

0.71; 95% CI, 0.56–0.90; P = 0.005; for heterogeneity:

P = 0.229; Fig. 5), but not RT-PCR group (HR, 0.85; 95%

CI, 0.62–1.16; P = 0.300; for heterogeneity: P = 0.096;

Fig. 5).

As there was heterogeneity in the overall response in

patients accepted palliative chemotherapy, we performed a

meta-regression analysis of multiple covariates to explor-

ing the sources of heterogeneity. As data of smoking

couldn’t be acquired from 7 of the 13 studies [9, 10, 14, 15,

19, 29, 35], smoking wasn’t included in the covariates. We

considered race (Whites or Asians), detecting methods

(IHC or RT-PCR), adenocarcinoma and female as four

covariates. However, none of the four covariates was found

to be the sources of heterogeneity (P values for race,

detecting methods, adenocarcinoma and female were

0.493, 0.649, 0.863 and 0.783, respectively).

Discussion

Although platinum-based chemotherapy remains the

‘‘standard’’ in advanced non-small-cell lung cancer, not all

patients derive clinical benefit from such a treatment. Due

to the significant variations in response and prognosis for

Fig. 5 Meta-analysis of the 13

studies eligible for overall

response rate showed that high

ERCC1 expression was

associated with less overall

response than low ERCC1

expression (P = 0.007). The

subgroup analysis by laboratory

techniques also yielded the

same result in patients by using

IHC to measure ERCC1

(P = 0.005), but not RT-PCR

(P = 0.300). The P-values in

the figure is P-values for

heterogeneity, which showed

there was not heterogeneity in

IHC subgroup (P = 0.229), but

there were heterogeneities in

RT-PCT subgroup (P = 0.096)

and overall populations

(P = 0.087)

Mol Biol Rep (2012) 39:6933–6942 6939

123

NSCLC patients receiving uniform treatment there is a

great need for patient-tailored chemotherapy in the light of

tumor markers present in the individual patient in order to

improve outcome. This would also allow identification of

patients who are likely not to respond thus saving them

from toxicity and hospitalization as well as saving eco-

nomical and human resources. Our perception of NSCLC

should be altered seeing each patient as a unique case based

on more specific variables than markers currently used in

the clinical setting such as TNM-stage, performance status,

weight loss, lactate dehydrogenase levels, etc. Thus, a need

for better predictive markers based on tumor biology has

emerged. One of the most promising markers is ERCC1.

ERCC1 is the limiting factor in nucleotide excision

repair, which removes platinum–DNA adducts. ERCC1

may also be involved in the repair of DNA double-strand

breaks, especially those induced by interstrand cross-links.

A high-ERCC1 level might be a positive prognostic vari-

able because of increased capability of removing carcino-

genic DNA lesions and a predictive factor for platinum

resistance because of increased capability of removing

platinum–DNA adducts and repairing DNA double-strand

breaks [4, 40].

The landmark study on ERCC1 by Olaussen et al. [31]

showed that high ERCC1 expression was correlated with

better prognosis in patients that had not received chemo-

therapy. On the other hand, an inverse correlation was

identified when patients were treated with cisplatin-based

chemotherapy, meaning that the benefit from adjuvant

chemotherapy was more profound in patients with low

ERCC1 expression. It was concluded that NSCLC patients

with completely resected ERCC1 negative tumors seem to

derive a substantial benefit from adjuvant cisplatin-based

chemotherapy compared to those with resected ERCC1

positive tumors.

The DNA repair protein ERCC1, which is both a

prognostic marker for survival and a predictor for response

to platinum compounds, is currently an attractive molecu-

lar marker undergoing clinical testing [8–35]. However, no

study has yet provided robust evidence.

The meta-analysis showed that high ERCC1 expression

in patients with early stage NSCLC treated by surgery

alone prognosticated a longer survival than low ERCC1

expression. High ERCC1 expression in patients with

NSCLC treated by surgery plus adjuvant chemotherapy

failed to acquire a longer survival than low ERCC1

expression. Conversely, High ERCC1 expression in late

stage patients who received palliative chemotherapy had a

shorter OS than low ERCC1 expression. The results sug-

gested that high ERCC1 expression might be a favourable

prognostic factor for patients with early stage NSCLC

treated by surgery alone, but a drug resistance predictive

factor for patients with advanced NSCLC treated with

chemotherapy, especially platinum-based regimens. The

analysis for overall response also showed patients with

high ERCC1 expression had a lower overall response rate,

which intensified the conclusion that high ERCC1

expression might be a drug resistance predictive factor for

chemotherapy, especially for platinum-based regimens.

Nearly all the patients received chemotherapy were used

platinum-based regimens.

The sensitivity analyses or subgroup analyses by IHC

and RT-PCR laboratory techniques yielded the same

results, excepted in overall response rate.

The data currently available on ERCC1 and NSCLC are

somewhat promising, but these findings must be further

confirmed by large prospective studies for following rea-

sons: First, studies included in the meta-analysis were

mainly retrospective analyses; Second, patient populations

were small and heterogeneous in most of the studies, and

gender and histology type might be two sources of heter-

ogeneity; Third, an effective and reproducible method to

quantified ERCC1 expression was lack. The efficiency of

RT-PCR varies on the quality of the histological material

used, while IHC may vary on inter-observer variability and

the target lesion chosen for examination; Fourth, cutoff

values were also different in the studies; Fifth, this meta-

analysis is not based on individual patient data, but based

on the publications.

Nagase et al. performed a randomized phase II trial to

study individualized adjuvant chemotherapy based on

quantitative ERCC1 mRNA expression; unfortunately, the

trial was stopped for 93% patients in research arm were

low ERCC1 expression. The researchers are going to

investigate which relates to survival in mRNA expression

and protein expression of ERCC1 strongly in the future

[41]. Another prospective pilot phase II trial was newly

verified by Hellenic Oncology Research Group in August

2010 in ClinicalTrials.gov (NCT00705549), which will try

to investigate individualized therapy based of tumoral

mRNA levels of ERCC1, RRM1 and BRCA1 in advanced

NSCLC. The results are worth anticipating.

In conclusion, high ERCC1 expression might be a

favourable prognostic factor for patients with NSCLC, but a

drug resistance predictive factor for chemotherapy. Patients

with high ERCC1 expression NSCLC may not benefit from

adjuvant chemotherapy or palliative chemotherapy.

Acknowledgments The analysis of the pooled data was supported

by a grant from the scientific research foundation of Huashan Hospital

Fudan University.

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