Correlation between EGFR mutation status and response to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer
OncoTargets and Therapy
correlation between EGFR mutation status and response to first-line platinum-based chemotherapy in patients with advanced non-small cell lung cancer
8 1 0 2 - l u J - 3 1 n o 7 5 1 . 9 2 1 . 6 9 1 . 5 y b / m o c . s s rvpee l.yno PowerdbyTCPDF(ww.tcpdf.org)
O r i g i n a l; r e s e a r c h
shu Fang 1
Jun guo 2
Jie liu 2
changzheng li 2
lin liu 2
huan shi 2
liyan liu 2
huihui li 2
chao Xie 2
Wenwen sun 1
Minmin li 1
1school of Medicine and life sciences,
University of Jinan-Shandong Academy
of Medical sciences, 2Department of
Oncology, shandong cancer hospital,
Jinan, s handong Province, People’s
republic of china
Background: The purpose of this research was to investigate the relationship between epidermal
growth factor receptor (EGFR) mutations and the response to first-line chemotherapy in patients
with advanced non-small cell lung cancer (NSCLC).
Methods: A total of 266 patients with stage IIIB or IV NSCLC who received platinum-based
doublet therapies as first-line chemotherapy were investigated retrospectively, and their clinical
data were assessed according to EGFR mutation.
Results: EGFR mutations were identified in 45.5% of patients. There was no significant
difference in response rate between EGFR mutation carriers and EGFR wild-type carriers (P=0.484).
Among the patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type, however,
those with EGFR mutations responded better to treatment than EGFR wild-type patients (46.2%
versus 20.8%, P=0.043). The disease control rate associated with pemetrexed-based treatments
was higher than for vinorelbine-based therapies in EGFR mutation patients (P=0.001). EGFR
mutation was found in patients with longer progression-free survival and median survival time,
and improved 1-year and 2-year overall survival when compared with EGFR wild-type patients
(6.1 versus 5.0 months, P=0.004; 18.9 versus 13.8 months, P=0.001; 81.0% versus 63.4%,
P=0.002; and 33.9% versus 22.8% P=0.044, respectively). Patients with the EGFR exon 19
mutation had longer progression-free survival than those with EGFR exon 21 mutation (P=0.007).
Multivariate analysis showed that the response to first-line chemotherapy and the presence of
EGFR mutations were independent prognostic factors in patients with advanced NSCLC.
Conclusion: Our data showed that the presence of EGFR mutations meant longer survival
times for patients with advanced NSCLC who received platinum-based doublet first-line
chemotherapy, especially in those with the exon 19 deletion mutation. Among KRAS wild-type
patients, those with EGFR mutation responded better to first-line chemotherapy than EGFR
Keywords: non-small cell lung cancer, chemotherapeutic agents, epidermal growth factor
receptor mutation, targeted therapy, prognosis
Lung cancer continues to be the main cause of carcinoma-related death throughout
the world,1 and 75%–80% of these cancers are non-small cell lung cancer (NSCLC).2
Although surgery is the most effective treatment for NSCLC, about 70% of patients
with NSCLC miss the opportunity for surgical resection because of their advanced
disease at presentation.3 Chemotherapy is the preferred treatment for these patients.
There has been research showing that NSCLC patients
with the epidermal growth factor receptor (EGFR) mutation
respond better to EGFR tyrosine kinase inhibitors (TKIs) in
terms of long-term survival.4 Several Phase III clinical trials
also indicated that NSCLC patients with mutated EGFR had
better clinical outcomes from treatment with erlotinib or
gefitinib than from normal chemotherapy.5–7 At present, EGFR is
8 the primary predictor of a curative effect of EGFR TKIs, and
-102 the relevant research8–10 has shown that the mutation status
l-Ju of EGFR is probably the main determinant of response to
n13 first-line chemotherapy and the prognosis in patients with
57o advanced NSCLC.
.129 The standard first-line regimen for advanced NSCLC is
.16 platinum-based doublet chemotherapy.11,12 Common
.51 therapeutic agents are gemcitabine, docetaxel, vinorelbine,
/yb and pemetrexed, but there continues to be a lack of predictive
.com biomarkers to select drugs for first-line chemotherapy. On this
ss background, we reviewed the clinical outcomes in patients
rvpee l.yno with advanced NSCLC who received platinum-based doublet
.dow lsue therapies as first-line chemotherapy, and analyzed the
predic/ww ano tive value of EGFR mutation status with regard to short-term
ttsp rspe effects and long-term survival in order to optimize the
h ro ment of individual patients with advanced NSCLC.
Patients and methods
A total of 665 cases of stage IIIB or IV NSCLC treated at
Shandong Tumor Hospital from July 2008 to December 2011
were screened, and 266 who received platinum-based doublet
chemotherapy as their first-line treatment were analyzed
retrospectively. These patients satisfied the following
selection criteria: having a pathological diagnosis of NSCLC,
clear EGFR mutation status, platinum-based doublet first-line
chemotherapy for at least two cycles, measurable lesions, no
uncontrolled diabetes or other serious disease, and an Eastern
Cooperative Oncology Group performance status of 0–1.13
EGFR mutation analysis
Sequence analysis of EGFR exons 18–21 was done by
pyrosequencing, as described elsewhere.14 Briefly, the
presence of tumor cells was identified on sections stained with
hematoxylin and eosin. Formalin-fixed paraffin-embedded
tissue samples were microdissected to confirm that the
samples contained not less than 80% tumor cells. Xylene
and ethanol were used to remove paraffin from the tumor
tissues, and the samples were placed in proteinase K. Genomic
DNA was extracted using a QIAamp DNA formalin-fixed
paraffin-embedded tissue kit (Qiagen, Hilden, Germany)
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according to the manufacturer’s instructions. Subsequently,
EGFR exons 18–21 were amplified by nested polymerase
chain reaction and subjected to pyrosequencing. The
polymerase chain reaction products were analyzed by
electrophoresis in 3% agarose gel to confirm successful
amplification. The pyrosequencing assay was performed
using the PyroMark Q24 ID system (Qiagen) following the
manufacturer’s protocols. Samples harboring mutations were
resequenced using the same test conditions.
Based on the Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 guidelines,15 the response to treatment was
classified as a complete response, partial response, stable
disease, or progression of disease. Complete response and
partial response were defined as the response rate, and
complete response, partial response, and stable disease were
defined as the disease control rate.
Follow-up was undertaken in all patients. The last follow-up
was in January 2014, and the median duration of follow-up
was 25.1 months. Overall survival was defined as the time
from the date of receiving the first-line chemotherapy to death
or last follow-up. Progression-free survival was defined as the
time from the date of receiving the first-line chemotherapy
to disease progression or death.
The statistical analysis was performed using Statistical
Package for the Social Sciences version 17.0 software (SPSS
Inc., Chicago, IL, USA). Rates were compared using the
χ2 test. Fisher’s exact test was used to analyze categorical
variables. Median progression-free survival was calculated
using the Kaplan–Meier method. The Cox regression model
was used to identify independent prognostic factors for
advanced NSCLC. We used the Kaplan–Meier method to
draw survival curves and tested these by log-rank.
Twosided P-values ,0.05 were considered to be statistically
Patient characteristics are shown in Table 1. The research
cohor t comprised 266 NSCLC patients of median
age 57 (range 28–81) years, with 53.4% being male. One
hundred and eighty patients had stage IV disease (67.7%),
and 242 had adenocarcinoma (91.0%). The most common
no of patients
sites of metastasis were the lung (33.3%, 60/180), pleura
(26.7%, 48/180), bone (24.4%, 44/180), brain (21.1%,
38/180), and liver (15.6%, 28/180). All patients were
treated with platinum-based doublet chemotherapy as
firstline treatment, with gemcitabine, docetaxel, vinorelbine,
and pemetrexed regimens administered in 56 (21.1%), 62
(23.3%), 50 (18.8%), and 98 patients (36.8%), respectively.
After first-line chemotherapy, 82 patients received an EGFR
TKI as second-line or third-line therapy, while 106 cases
received continuous chemotherapy. EGFR mutations were
identified in 121 patients (45.5%). Sixty-four patients
(52.9%) harbored in-frame deletions in exon 19, which
were caused by loss of codons 746–750 (delE746–A750).
Fifty patients (41.3%) had tumors harboring amino acid
replacements in exon 21, ie, leucine to arginine at codon 858
(L858R). Exon 18 (G719S) and exon 20 (T790M) mutations
were found in f ive (4.1%) and two (1.7%) patients,
respectively. There were more women (50.8%, 63/124) than
men (40.8%, 58/142), more nonsmokers (58.6%, 89/152)
than smokers (28.1%, 32/114), more patients with an
Eastern Cooperative Oncology Group performance status
of 1 (45.9%, 100/218) than 0 (43.8%, 21/48), and more with
a weight loss of ,5% (46.1%, 107/232) than a weight loss
$5% (41.2%, 14/34).
association of EGFR mutations
with response to first-line chemotherapy
All 266 patients were treated with platinum-based regimens.
In these patients, a partial response was documented in 30.1%
(80/266), stable disease in 51.1% (136/266), and
progression of disease in 18.8% (50/266). The overall response and
disease control rates were 30.1% and 81.2%, respectively.
In 145 patients with wild-type EGFR, the response rate and
disease control rate were 28.3% and 83.4%, respectively.
No differences in response rate or disease control rate
were found when gemcitabine-based, docetaxel-based,
vinorelbine-based, and pemetrexed-based treatments were
compared (30.0% versus 29.3%, 26.3% , 27.3%, and 76.7%,
85.4%, 84.2%, and 85.5%, respectively). We found that
carriers of the EGFR mutation had a response rate of 32.2%
to chemotherapy, which was similar to the 28.3% for
wildtype EGFR carriers (P=0.484). The disease control rate was
78.5%. No differences in response rate were found between
gemcitabine-based, docetaxel-based, vinorelbine-based, and
pemetrexed-based therapy in 121 patients with EGFR
mutations (34.6% versus 28.6%, 29.0%, and 34.9%). However,
the disease control rate was higher in pemetrexed-treated
patients than in vinorelbine-treated patients (90.7% versus
58.1%, respectively, P=0.001). Further, although not
significantly different, the response rates for the exon 19
mutation and the exon 21 mutation were 37.5% (24/64) and
24.0% (12/50, P=0.124). Differences in characteristics and
response to chemotherapy between patients who received
gemcitabine-based, docetaxel-based, vinorelbine-based,
and pemetrexed-based therapies are shown according to
EGFR status in Table 2.
relationship between EGFR
mutation and survival
The median progression-free survival for the 266 patients
was 5.7 months (95% confidence interval [CI] 5.4–6.0), the
median survival time was 16.8 months, and the 1-year and
2-year overall survival was 72.2% and 28.6%, respectively.
There was a signif icant difference in progression-free
survival between patients with EGFR mutation and those
with EGFR wild-type (6.1 versus 5.0 months, respectively,
P=0.004, Figure 1). EGFR mutation was found in patients
with a longer median survival time (18.9 months, 95% CI
18–19.8) and 1-year and 2-year overall survival (81.0% and
33.9%, respectively) when compared with wild-type EGFR
patients (13.8 months, 95% CI 12.7–15.1, and 63.4% and
22.8%, respectively, P=0.001, Figure 2). Patients with the
EGFR exon 19 mutation had longer progression-free survival
than those with the EGFR exon 21 mutation (P=0.007).
Patients with the EGFR exon 19 mutation had a longer
median survival time and 1-year and 2-year overall survival
no of patients
age (median years)
than those with the EGFR exon 21 mutation (19.2 months,
90.6%, and 37.5% versus 17.8 months, 70.0%, and 30.0%,
respectively), but the difference was not statistically
significant (P=0.908). Moreover, in 180 patients with stage IV
disease, those with EGFR mutation had a longer median
survival time, and better 1-year and 2-year survival rates,
than those with wild-type EGFR (P=0.028). The relationship
between clinical characteristics, EGFR mutation state, and
survival is shown in Table 3.
In EGFR wild-type patients, there were no statistically
significant differences in progression-free survival between
the gemcitabine-based, docetaxel-based, vinorelbine-based,
and pemetrexed-based treatments (5.7 months versus 4.6, 5.6,
and 4.9 months, respectively, P=0.946, Figure 3). Further,
there was no statistically significant difference in
progressionfree survival between the four treatment groups in patients
with EGFR mutation (6.0 months versus 6.3, 6.4, and 5.9
months, P=0.814, Figure 4).
Univariate analysis of various prognostic factors,
and the data showed that the important ones were
clinical stage (P=0.001), response to first-line chemotherapy
(P=0.001), histological type (P=0.008), whether TKIs
were received after first-line chemotherapy (P=0.023),
and EGFR mutation status (P=0.001). Cox multivariate
Table 3 results of the univariate analysis of EGFR mutation with
regression analysis was used to determine underlying
factors influencing survival, eg, age, sex, smoking history,
Eastern Cooperative Oncology Group status, histological
diagnosis, weight loss, whether TKIs are received after
first-line chemotherapy, tumor stage, EGFR mutation,
and the efficacy of first-line chemotherapy. The results
showed that response to front-line chemotherapy and
EGFR mutation status were independent prognostic
factors (Table 4).
relationship between EGFR mutation
and response to first-line chemotherapy
and survival in KRAS wild-type patients
Among the 266 cases, a subgroup of 83 patients was
evaluated for Kirsten rat sarcoma viral oncogene
homolog (KRAS) mutation status. Twenty patients
(24.1%) had KRAS mutation and 63 (75.9%) were KRAS
wild-type. KRAS wild-type patients with EGFR mutation
responded better to first-line chemotherapy (46.2% versus
20.8%, P=0.043) and longer progression-free survival
(7.0 months versus 4.6 months, P=0.042, Figure 5).
relationship between EGFR mutation
and response to second-line treatment
After failure of first-line chemotherapy, 82 patients accepted
EGFR TKIs (as second-line chemotherapy in 62 cases and
as third-line chemotherapy in 20 cases). The remaining
106 patients continued their systemic chemotherapy, while
78 decided not to continue treatment. Compared with those
who did not receive TKI therapy, patients who accepted
EGFR TKIs had a statistically significant increase in
longterm survival (P=0.023). Comparing patients treated with
EGFR TKIs (n=62) and those given conventional
chemotherapy (n=106) as their second-line therapeutic regimen,
we did not find a statistically significant difference in median
survival time (21.6 months versus 18.0 months, respectively,
These data show that active EGFR mutations portend a
longer survival time in patients with advanced NSCLC,
especially those with the exon 19 mutation. KRAS
wildtype patients with the EGFR mutation responded better to
first-line chemotherapy, and EGFR mutation and curative
first-line chemotherapy were independent prognostic factors
for advanced NSCLC.
Platinum-based doublet chemotherapy is presently the
most common first-line treatment for advanced NSCLC.11,12
Therefore, it is important to explore the relationship between
EGFR mutation, effect of chemotherapy, and clinical
outcome. The relationship between EGFR mutation
status and response to chemotherapy is not well understood.
Kalikaki et al16 reported that chemotherapy was more
effective in patients with EGFR mutation than in EGFR wild-type
patients (P=0.023). The Iressa Pan-Asia Study17 indicated that
the response rate was higher in the patients with EGFR
mutations compared with wild-type EGFR cases who received
paclitaxel/carboplatin as the first-line chemotherapy (47.3%
versus 23.5%). A study reported by Lee et al9 found no
obvious relationship between presence of EGFR mutation and the
effectiveness of first-line chemotherapy. However, a recent
Japanese study indicated that patients with the EGFR
mutation were less sensitive to docetaxel than those with wild-type
EGFR.10 Our study showed that the response rate and disease
control rate of the first-line chemotherapy platinum
containing regimens were both higher in patients with the EGFR
mutation than in patients with EGFR wild-type in advanced
NSCLC. No statistically significant differences were found
between these two groups, which is probably due to the small
sample size. However, we did find that patients with the
sex (male vs female)
smoking history (yes vs no)
ecOg (1 vs 0)
histologic type (adenocarcinoma vs
squamous cell carcinoma)
Weight loss ($5% vs ,5%) 1.088 0.678–1.746 0.728 1.142 0.698–1.869 0.596
EGFR mutation (yes vs no) 0.661 0.487–0.898 0.008 0.649 0.481–0.875 0.005
Response to the front-line chemotherapy 0.552 0.412–0.741 ,0.001 0.523 0.390–0.700 ,0.001
(cr + Pr vs sD + PD)
Whether receiving TKIs after first-line 0.852 0.638–1.138 0.278 0.893 0.673–1.185 0.434
chemotherapy (yes vs no)
clinical stage (iiiB vs iV) 0.826 0.622–1.097 0.186 0.854 0.633–1.153 0.304
Abbreviations: vs, versus; EGFR, epidermal growth factor receptor; ecOg, eastern cooperative Oncology group; cr, complete response; Pr, partial response; sD, stable
disease; PD, progression of disease; TKIs, tyrosine kinase inhibitors; HR, hazard ratio; CI, confidence interval.
EGFR mutation responded better to first-line chemotherapy
(46.2% versus 20.8%, P=0.043) and a longer progression-free
survival (7.0 months versus 4.6 months, P=0.042) than those
without EGFR mutation in KRAS wild-type patients. Earlier
research18 showed that patients with the KRAS mutation had
shorter survival than their KRAS wild-type counterparts,
suggesting that KRAS mutation and EGFR mutation might have
opposing effects. Both the EGFR and KRAS genes predict
the prognosis of NSCLC.19,20
Exon 19 deletion mutation and a mutation in exon 21
(L858R) are the two main types of EGFR mutation. Riely et al21
found that patients with the EGFR exon 19 mutation had a
longer median survival time than those with the EGFR exon 21
mutation after receiving gefitinib or erlotinib (34 versus 8
months, respectively; P=0.01, log-rank). Park et al22
investigated 217 patients with NSCLC and found that those with
EGFR mutations who received paclitaxel had a better disease
control rate and longer progression-free survival, which was
more pronounced in patients with the exon 19 deletion
mutation. Cappuzzo et al8 found no clear relationship between
EGFR mutation status and the effectiveness of first-line
chemotherapy, but patients with the exon 19 mutation showed a higher
objective response rate after receiving chemotherapy (46.6%
versus 0%, P=0.02). Our research also indicates that patients
with the exon 19 deletion mutation had a longer survival time
after first-line platinum-based chemotherapy than those with
the exon 21 mutation (P=0.007). Further, the effectiveness of
first-line chemotherapy was greater in patients with the exon
19 mutation than in those with the exon 21 mutation (37.5%
versus 24.0%, P=0.124), but the difference was not
Pemetrexed is a new-generation multitargeted
antifolate agent that maintains tumor cell division in S phase by
destroying the folate-dependent metabolic pathway within
the cells, thereby limiting tumor growth.23 Pemetrexed is now
the preferred second-line treatment for NSCLC in the USA.24
In recent years, clinical researchers had demonstrated the
positive effects of this agent in advanced NSCLC, and
pemetrexed has gradually become a first-line agent for treatment
of the disease.23 Meanwhile, there is some prospective and
retrospective evidence25,26 from Phase III research showing
longer overall survival in patients with nonsquamous NSCLC
treated with pemetrexed than in their counterparts treated
with gemcitabine or docetaxel. These observations indicate
that pemetrexed had higher activity in nonsquamous cell
cancer. In the present study, we found that the disease
control rate was higher for pemetrexed-based chemotherapy
than for vinorelbine-based chemotherapy in patients with
EGFR mutation. However, we cannot conclude that EGFR
mutation improves the sensitivity to pemetrexed, because our
results might have arisen from the fact that the majority of
our patients with the EGFR mutation had adenocarcinoma of
the lung (96.7%, 117/121) and pemetrexed has been shown
to be more effective than other chemotherapeutic agents in
this type of cancer.25,26 Our retrospective analysis has some
limitations, and there remains a need for prospective research
in large samples to resolve whether EGFR mutation could
improve the sensitivity to pemetrexed in advanced NSCLC
Our analysis of survival in 266 patients with NSCLC
indicates that those with EGFR mutations had longer
progression-free survival than those with wild-type EGFR.
This finding is similar to that of Hotta et al,27 who analyzed
survival data in 194 patients and found that patients with
EGFR mutation had longer progression-free survival.
However, other researchers have reported that EGFR mutation
status has no impact on the effect of chemotherapy or
longterm survival.9 The current research analyzed the
relationship between EGFR mutation status and progression-free
survival, and indicated that EGFR mutation had a greater
survival benef it when compared with wild-type status
(P=0.004). Multifactorial analysis revealed that EGFR
mutation and efficacy of first-line chemotherapy were
independent prognostic factors in patients with advanced NSCLC,
which is consistent with the results of other research.28
Currently, the international recommendations for
secondline treatment are docetaxel, pemetrexed, and EGFR TKIs.
One hundred and forty-six patients were included in the
Phase III INTEREST (Gefitinib versus docetaxel in previously
treated non-small-cell lung cancer) trial,29 the main aim of
which was to compare overall survival between gefitinib and
docetaxel by testing for noninferiority. Overall survival was
7.6 months in the gefitinib group and 8.0 months in the
docetaxel group, and the 1-year survival rate was 32% and 34%,
respectively (hazards ratio 1.020, 96% CI 0.905–1.150), which
met the preset requirement that the hazards ratio be ,1.154.
Gefitinib was significantly higher than that of docetaxel in the
quality of life improvement, drug safety, and tolerability. The
results of this study, albeit not reaching statistical significance,
indicate that survival time in patients with advanced NSCLC
is longer with second-line use of EGFR TKIs when compared
with conventional chemotherapy.
Our research indicates that active EGFR mutations mean
higher survival time for patients with advanced NSCLC who
:s rs receive platinum-based doublet first-line chemotherapy,
h ro cially those with the exon 19 deletion mutation. Among KRAS
wild-type patients, those with EGFR mutation responded
better to first-line chemotherapy. In this study, EGFR
mutation and a curative effect of first-line chemotherapy were
independent prognostic factors in advanced NSCLC.
The authors report no conflicts of interest in this work.
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of management programs and new therapeutic agents and protocols on
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