Tumor Biol.

(2014) 35:24372444
DOI 10.1007/s13277-013-1323-9

RESEARCH ARTICLE

EGFR mutation status and its impact on survival of Chinese

non-small cell lung cancer patients with brain metastases
Dongdong Luo & Xin Ye & Zheng Hu & Kaiwen Peng &
Ye Song & Xiaolu Yin & Guanshan Zhu & Qunsheng Ji &
Yuping Peng

Received: 11 September 2013 / Accepted: 14 October 2013 / Published online: 7 November 2013
# International Society of Oncology and BioMarkers (ISOBM) 2013

Abstract Brain metastasis (BM) is a leading cause of death in

patients with non-small cell lung cancer (NSCLC). EGFR
mutations in primary NSCLC lesions have been associated
with sensitivity to EGFR tyrosine kinase inhibitor (TKI).
Therefore, it has become important to understand EGFR
mutation status in BM lesions of NSCLC, and its clinical
implications. BM samples of 136 NSCLC patients from South
China, in which 15 had paired primary lung tumors, were
retrospectively analyzed for EGFR mutation by amplification
mutation refractory system (ARMS). Effect of BM EGFR
mutations on progression-free survival (PFS) and overall
survival (OS) was evaluated by KaplanMeier curves and
log-rank test. EGFR mutations were detected in 52.9 % (72
of 136) of the BM lesions, with preference in female and
never-smokers. A concordance rate of 93.3 % (14 of 15)
was found between the primary NSCLC and corresponding
BM. Positive prediction value of testing primary NSCLCs for
BM EGFR mutation is 100.0 %, and negative prediction
value is 87.5 %. Median PFS of BM surgery was 12 and
10 months (P =0.594) in the wild-type and mutant group,
respectively. Median OS of BM surgery was 24.5 and
15 months (P =0.248) in the wild-type and mutant group,
respectively. In conclusion, EGFR mutation status is highly
concordant between the primary NSCLC and corresponding

D. Luo and X. Ye contributed equally to this work.

D. Luo : Z. Hu : K. Peng : Y. Song : Y. Peng (*)
Department of Neurosurgery, Nanfang Hospital,
Southern Medical University, Guangzhou 510515, China
e-mail: pengyupingch@yeah.net
D. Luo
Department of Neurosurgery, Cancer Center of Guangzhou Medical
University, Guangzhou 510095, China
X. Ye : X. Yin : G. Zhu : Q. Ji
Innovation Center China of AstraZeneca R&D, Shanghai, China

BM. The primary NSCLC could be used as surrogate samples

to predict EGFR mutation status in BM lesions or vice versa.
Moreover, EGFR mutations showed no significant effect on
PFS or OS of NSCLCs with BM.
Key words Brain metastasis . EGFR mutations . Non-small
cell lung cancer

Introduction
Lung cancer is the leading cause of cancer-related mortality
worldwide [1]. Non-small cell lung cancer (NSCLC) accounts
for approximately 85 % of all lung cancers, with the most
prevalent subtype, adenocarcinoma, markedly increasing in
incidence over recent years [2]. Brain is one of the main
metastatic sites in patients with lung cancer, and brain
metastases (BMs) remain a major cause of morbidity and
mortality. Nearly 50 % of NSCLC patients with distal
metastasis will be affected by BM during the course of disease
[3, 4].
EGFR mutation has been demonstrated to be an important
contributor to the development of NSCLC in Asia population
[5, 6]. The small molecular EGFR tyrosine kinase inhibitors
(EGFR-TKIs), gefinitib and erlotinib, are currently used for
the treatment of patients with advanced NSCLC harboring
somatic EGFR mutations with 6080 % response rate [7, 8].
Recently, clinical activity of gefitinib in BMs was also
observed in some NSCLC patients, indicating the existence
of activating EGFR mutations in the brain metastatic lesions
[9, 10]. Therefore, it becomes clinically important to
understand EGFR mutation status in the BMs of NSCLC.
In patients with advanced NSCLC, it might not be practical
to retrieve the BM lesions in most cases. The primary lung
tumor could be the only tissue sample available for EGFR
mutation detection. In some other cases, biopsy or resection of

2438

BMs may be the first step to enable histological diagnosis,

while neither biopsy nor resection of primary tumor could take
place. In either scenario, it would be important to understand
whether the EGFR mutation status is consistent between
primary lung tumor and BM lesions for a better prediction
of TKI therapy. In this study, 136 BM samples from Chinese
NSCLC patients, including 15 corresponding primary lung
tumors, were evaluated for the EGFR mutation frequency and
concordance. In addition, progression-free survival (PFS) and
overall survival (OS) of these patients following surgical
resection of BM lesions were also studied retrospectively.

Material and methods

Patients and tumor samples
We retrospectively evaluated NSCLC patients with metastatic
dissemination to the brain, who had been enrolled in eight
centers in south China from November 2007 to November
2012. Formalin-fixed, paraffin-embedded tissues of primary
tumors and corresponding BMs obtained from histologically
confirmed NSCLC patients were included. A total of 136
patients were included, whose BM samples of resection or
biopsy were obtained. Among these patients, 15 had matched
primary lung tumor samples obtained by resection or biopsy.
All tissue samples went through pathological evaluation once
again in the center of Southern Medical University Affiliated
Nanfang Hospital to confirm the diagnosis of NSCLC and the
percentage of tumor cells. As the analytical sensitivity of
amplification mutation refractory system (ARMS) assay is
around 1 %, only the tumor specimens with more than 1 %
of tumor contents were qualified for the following EGFR
mutation evaluation in primary tumors and matched
metastases.
Clinical characteristics, including age, sex, smoking
history, treatment, time to progression and survival time, were
obtained from medical records from the eight centers. Clinical
staging was performed according to the 7th AJCC Cancer
Staging System [11].
The study was reviewed and approved by the Institutional
Review Board of Southern Medical University Affiliated
Nanfang Hospital. All patients gave their informed consent
to participate in this study.

Tumor Biol. (2014) 35:24372444

The concentration of each DNA sample was normalized to

0.4 ng/l whenever possible. The concentration of 29 DNA
samples was lower than 0.4 ng/l, for which the original
concentration was applied.
EGFR mutation analysis
The EGFR Mutation Detection Kit (Amoy Diagnostics,
Xiamen, China), which is based on the ARMS technology,
was used to detect the 29 most common types of EGFR
mutations in lung cancer. All experiments were performed
following the user manual. Briefly, 4.7 l DNA was added
to 35.3 l PCR master mix of each assay which contains PCR
primers, fluorescent probes, PCR buffer, and Taq DNA
polymerase. PCR thermal cycling was as follows: 5 min
incubation at 95 C, followed by 15 cycles of 95 C for
25 s, 64 C for 20 s, 72 C for 20 s, and then 31 cycles of
93 C for 25 s, 60 C for 35 s, 72 C for 20 s. The primer
sequences for EGFR gene were as follows: forward primer
5- CTCTTACACCCAGTGGAGAA-3, reverse primer 5CATCCACTTGATAGGCA CTT-3, the length is 572 bp.
Fluorescent signal was collected from FAM and HEX
channels. The results were analyzed according to the
instructions in the user manual.
Statistic analysis
The McNemar's test and Pearson Chi-square test were used to
determine whether EGFR mutation differed significantly
between primary tumors and corresponding BMs. Pearson
Chi-square test was used to determine whether EGFR
mutation was significantly relevant to the corresponding
clinical characteristics. P values less than 0.05 were
considered statistically significant (difference). An association
between mutation status of EGFR and survival outcomes was
analyzed. PFS was assessed from the date of BM surgery to
the date of the first recurrence, second primary lung
malignancy, any other metastases, or death from any cause.
OS was calculated from the date of BM surgery to the date of
the last follow-up or death from any cause. KaplanMeier
curves were generated for PFS and OS. The survival
difference between groups was assessed by the log-rank test.
A P value less than 0.05 was considered statistically
significantly different. SPSS 13.0 (SPSS, Chicago, IL) for
Windows was used for the statistical analyses.

DNA extraction and quality check

QIAamp DNA formalin-fixed paraffin-embedded Tissue Kit
(Qiagen, Hilden, Germany) was used for DNA extraction
from tumor tissue samples following the instruction of the
manufacturer. Extracted DNA samples were quantified with
the real-time quantitative PCR method using commercial
Taqman assay for RNase P gene (Life Technologies, USA).

Results
Clinical characteristics of the patients
Clinical characteristics of the 136 patients are shown in
Table 1. Median age of the patients at initial diagnosis was

Tumor Biol. (2014) 35:24372444

2439

Table 1 Correlation of clinical characteristics with EGFR mutation in NSCLC patients with BM
No. of Patients
value (%) (n =136)
Age at Diagnosis
Median
55 years
<55 years
Sex
Male
Female
Smoking history
Never-smoker
Former and current smoker
Unknown
KPS
50
60
70
80
90
Stage at diagnosis (Stage T)
T1
T2
T3
T4
Stage at diagnosis (Stage N)
N0
N1
N2
N3
Primary sites in lung
Right Lung
Left Lung
Metastatic sites in brain
Right cerebral hemisphere
Left cerebral hemisphere
Right cerebellar hemisphere
Left cerebellar hemisphere
Brain metastases number of lesions
Single
Multiple
Brain metastases size of largest lesions
<2 cm
2 cm, 3c m
3 cm, 4 cm
>4 cm
Pathological grading
Undifferentiation
Poorly differentiated
Moderately differentiated
Highly differentiated

WT (n =64)

EGFR
MT (n =72)

P value
0.293

55 (range, 2679)
70 (51.5 %)
66 (48.5 %)

36 (51.4 %)
28 (42.4 %)

34 (48.6 %)
38 (57.6 %)
0.000

83 (61.0 %)
53 (39.0 %)

53 (63.9 %)
11 (20.8 %)

30 (36.1 %)
42 (79.2 %)

73 (53.7 %)
51 (37.5 %)
12 (8.8 %)

27 (37.0 %)
35 (68.6 %)
2 (16.7 %)

46 (63.0 %)
16 (31.4 %)
10 (83.3 %)

5 (3.7 %)
20 (14.7 %)
24 (17.6 %)
62 (45.6 %)
25 (18.4 %)

5 (100.0 %)
8 (40.0 %)
11 (45.8 %)
28 (45.2 %)
12 (48.0 %)

0 (.0 %)
12 (60.0
13 (54.2
34 (54.8
13 (52.0

75 (55.1 %)
52 (38.2 %)
5 (3.7 %)
4 (2.9 %)

33 (44.0 %)
27 (51.9 %)
2 (40.0 %)
2 (50.0 %

42 (56.0 %)
25 (48.1 %)
3 (60.0 %)
2 (50.0 %)

51 (37.5 %)
33 (24.3 %)
39 (28.7 %)
13 (9.6 %)

30 (58.8 %)
14 (42.4 %)
15 (38.5 %)
5 (38.5 %)

21 (41.2 %)
19 (57.6 %)
24 (61.5 %)
8 (61.5 %)

80 (58.8 %)
56 (41.2 %)

38 (47.5 %)
26 (46.4 %)

42 (52.5 %)
30 (53.6 %)

62 (45.6 %)
41 (30.1 %)
21 (15.4 %)
12 (8.8 %)

24 (38.7 %)
19 (46.3 %)
13 (61.9 %)
8 (66.7 %)

38 (61.3 %)
22 (53.7 %)
8 (38.1 %)
4 (33.3 %)

90 (66.2 %)
46 (33.8 %)

42 (46.7 %)
22 (47.8 %)

48 (53.3 %)
24 (52.2 %)

0.000

0.189
%)
%)
%)
%)
0.828

0.198

0.902

0.141

0.898

0.490
9 (6.6 %)
38 (27.9 %)

3 (33.3 %)
15 (39.5 %)

6 (66.7 %)
23 (60.5 %)

45 (33.1 %)
44 (32.4 %)

24 (53.3 %)
22 (50.0 %)

21 (46.7 %)
22 (50.0 %)

2 (1.5 %)
69 (50.7 %)
60 (44.1 %)
5 (3.7 %)

2 (100.0 %)
32 (46.4 %)
30 (50.0 %)
0 (.0 %)

0 (.0 %)
37 (53.6 %)
30 (50.0 %)
5 (100.0 %)

2440

Tumor Biol. (2014) 35:24372444

Table 1 (continued)

Pathological classification
Adenocarcinoma
Squamous cell carcinoma
Adenosquamous carcinoma
Others (large cell carcinoma)
Pulmonary symptoms at diagnosis
Cough
Blood sputum
No specific symptoms
Brain symptoms at diagnosis
Intracranial hypertension
Paraesthesia
Palalysis
Ataxia
Seizure
Aphasia
Loss of attention
Treatment
WBRT
SRT
Adjuvant chemotherapy
EGFR TK inhibitors
Progression-free survivor
Mean SD
Survival
Death
Live
Censoring
Mean SD

No. of Patients
value (%) (n =136)

WT (n =64)

EGFR
MT (n =72)

112 (82.4 %)
5 (3.7 %)
8 (5.9 %)
11 (8.1 %)

48 (42.9 %)
3 (60.0 %)
6 (75.0 %)
7 (63.6 %)

64 (57.1 %)
2 (40.0 %)
2 (25.0 %)
4 (36.4 %)

22 (16.2 %)
6 (4.4 %)

10 (45.5 %)
2 (33.3 %)

12 (54.5 %)
4 (66.7 %)

108 (79.4 %)

52 (48.1 %)

56 (51.9 %)

103 (75.7 %)
13 (9.6 %)
31 (22.8 %)
29 (21.3 %)
16 (11.8 %)
8 (5.9 %)
50 (36.8 %)

47 (45.6 %)
3 (23.1 %)
16 (51.6 %)
16 (55.2 %)
7 (43.8 %)
2 (25.0 %)
23 (46.0 %)

56 (54.4 %)
10 (76.9 %)
15 (48.4 %)
13 (44.8 %)
9 (56.2 %)
6 (75.0 %)
27 (54.0 %)

42 (30.9 %)
13 (9.6 %)
57 (41.9 %)
7 (5.1 %)

25 (59.5 %)
8 (61.5 %)
30 (52.6 %)
0 (.0 %)

17 (40.5 %)
5 (38.5 %)
27 (47.4 %)
7 (100.0 %)

83 (61.0 %)

38 (45.8 %)

45 (54.2 %)

24 (17.6 %)
29 (21.3 %)
19.57214.7856

12 (50.0 %)
14 (48.3 %)

12 (50.0 %)
15 (51.7 %)

P value
0.183

0.768

13.76311.0014

EGFR epidermal growth factor receptor, MT mutant, WT wild-type, KPS Karnofsky Performance Status, WBRT whole brain radiation therapy, SRT
stereotactic radiotherapy, TK inhibitors tyrosine kinase inhibitors

55 years (range, 2679 years). No statistical significance (P =

0.293) was shown for EGFR mutation status in different age
groups (cut point at 55 years). Overall, 86 (61.0 %) patients
were men and 53 (39.0 %) were women. Women had a higher
risk for EGFR mutations (P =0.000). Fifty-one (37.5 %)
patients had a history of smoking, and EGFR mutation rate
was higher in non-smokers (P = 0.000). The Karnofsky
Performance Status (KPS) Score of the patients was 50
90 at presentation. All the patients had stage IV disease when
BMs were diagnosed. In this cohort, 58.8 % of the primary
tumors occurred in the right lung, and 75.7 % of the BMs were
located in cerebral hemisphere, while 24.3 % were in
cerebellar hemisphere. Overall, 66.2 % of BM lesions were
single and 65.5 % had the largest lesion (i.e., >3 cm in size).
A n d 11 2 ( 8 2 . 4 % ) s a m p l e s w e r e d i a g n o s e d a s

adenocarcinoma; no significant difference in EGFR mutation

status was observed among the different pathological types of
NSCLC (P =0.183). A total of 129 (94.8 %) samples were
pathologically staged as being poorly or moderately
differentiated. The clinical symptoms in the patients with
BM included intracranial hypertension (75.7 %), paraesthesia
(9.6 %), paralysis (22.8 %), ataxia (21.3 %), seizure (11.8 %),
aphasia (5.9 %) and loss of attention (36.8 %). It is worth
noting that 108 (79.4 %) patients were initially admitted
without any pulmonary symptoms at presentation. The brain
metastatic lesions in all patients were surgically removed, and
42 (30.9 %) patients had undergone whole brain radiation
therapy (WBRT) after the operation, and 13 (9.6 %) had
undergone stereotactic radiotherapy (SRT). Moreover, 57
(41.9 %) patients received postoperative adjuvant therapy

Tumor Biol. (2014) 35:24372444

2441

Table 2 EGFR mutation type and frequency in 136 NSCLC brain

metastases
EGFR mutation

Frequency (%)

P1

P2

P3

L858R
19-Del
19-Del/L858R
G719X/L861Q

26 (36.1 %)
36 (50.0 %)
6 (8.3 %)
1 (1.4 %)

0.032
0.013
0.004

0.032

0.011
0.002

0.013
0.011

0.421

19-Del/G719X
19-DeL/20-Ins
L861Q

1 (1.4 %)
1 (1.4 %)
1 (1.4 %)

0.003
0.002
0.004

0.001
0.001
0.002

0.381
0.293
0.492

P1 EGFR mutations vs. L858R EGFR mutation, P2 EGFR mutations vs.

19-Del EGFR mutation, P3 EGFR mutations vs. 19-Del/L858R EGFR
mutation

with Platinum, Taxanes or/and Pemetrexed. Seven (5.1 %)

patients were administered with EGFR TKI during the course
of the disease.
EGFR mutation status in BM and primary lung lesions
of the NSCLC patients
EGFR mutation status of 136 brain metastatic samples in
NSCLC patients is presented in Table 2. EGFR mutation
was detected in 72 (52.9 %) patients. Sixty-two (86.1 %)
patients carried either leucine-to-arginine mutation in exon
21 (L858R, 26/72, 36.1 %) or deletion in exon 19 (19-Del,
36/72, 50.0 %). Six (8.3 %) patients had 19-Del&L858R

double mutations. The remaining four patients had

G719X&L861Q, 19-Del&G719X, 19-Del&Ins-20, and
L861Q, respectively. The statistical analysis among the
different EGFR mutations are also listed in Table 2.
EGFR mutation status comparison between primary
NSCLC and the corresponding BM was also analyzed, and
is shown in Table 3. EGFR mutation status was classified as:
(1) EGFR wild-type in both primary tumor and BM (n =7,
46.7 %), (2) EGFR mutation in primary tumor (n =0, 0.0 %)
or in BM (n =1, 6.7 %), and (3) EGFR mutation in both
primary tumor and metastasis (n =7, 46.7 %). Overall, EGFR
mutation status showed a concordance rate of 93.3 % (14 of
15 patients) between the primary lung lesions and
corresponding BMs. No statistically significant difference
(McNemar's test, P =1.000; Kappa test, =0.867, P =0.000)
was observed between these two groups. The positive
prediction value (PPV) of testing primary lung lesions for
BM EGFR mutation status is 100.0 % (7/7), and the negative
prediction value (NPV) is 87.5 % (7/8). On the other hand, the
PPV of testing BM lesions for primary lung lesion EGFR
mutation is 87.5 % (7 out of 8) and the NPV is 100.0 % (7/7)
(see Table 4).
The EGFR mutation status of 136 BMs with 15 primary
lung lesions is presented in Table 5. The EGFR mutation rate
in primary NSCLC lesions was 46.7 % (7/15 patients). No
statistical significance of EGFR mutation rate (Pearson Chisquare test, 2 =0.213, P =0.644) was seen between the
primary lung lesions and BMs in those NSCLC patients.

Table 3 Comparison of EGFR mutation between the primary lung lesions and paired brain metastases in 15 NSCLC patients
Case

Sex

Age

Smoking history

Pathology diagnosis

EGFR mutation

Primary

BM

Primary

BM

38

Never

SCC

SCC

WT

WT

2
3
4
5
6
7
8
9
10
11
12
13
14
15

M
M
M
M
M
M
M
F
F
M
F
M
M
M

47
43
55
74
68
63
44
45
59
67
59
50
48
55

Active
Active
Active
Active
Never
Active
Active
Never
Never
Active
Never
Never
Active
Active

AC
Mixed SCC-AC
AC
Mixed SCC-AC
AC
AC
Mixed SCC-AC
AC
AC
AC
Mixed SCC-AC
SCC
AC
AC

AC
Mixed SCC-AC
AC
Mixed SCC-AC
AC
Poorly differentiated NSCLC
AC
AC
AC
AC
AC
Mixed SCC-AC
AC
AC

WT
WT
L858R
19-del
WT
WT
19-del
L858R
WT
L858R
19-del
WT
19-del
WT

WT
WT
L858R
19-del
WT
19-del
19-del
L858R
WT
L858R
19-del
WT
19-del
WT

EGFR epidermal growth factor receptor, WT wild-type, SCC squamous cell carcinoma, AC adenocarcinoma, NSCLC non-small-cell lung cancer, BM
brain metastases

2442

Tumor Biol. (2014) 35:24372444

Table 4 Combined analysis of EGFR mutation in the primary NSCLC

and paired brain metastases
EGFR mutation, no. (%)
Primary

EGFR wt
EGFR mt
Total

BM

Total

EGFR WT

EGFR MT

7 (87.5 %)
0 (.0 %)
7 (46.7 %)

1 (12.5 %)
7 (100.0 %)
8 (53.3 %)

8
7
15

EGFR epidermal growth factor receptor, WT wild type, MT mutant,

NSCLC non-small-cell lung cancer, BM brain metastases

Correlation of EGFR mutation with survival outcomes

of the patients
PFS was not significantly different between the wild-type
group versus the mutant group (P =0.594) with median PFS
of 12 months (95 % confidence interval, 6.36217.638) and
10 months (95 % confidence interval, 7.42812.572) (Fig. 1),
respectively.
OS was not significantly different between the mutant
group and the wild-type group (P =0.248). Median OS was
24.5 months in the wild-type group (95 % confidence interval,
17.00731.993) and 15 months in the mutant group (95 %
confidence interval, 9.66720.333) (Fig. 2).

Discussion
To our best knowledge, this is the largest cohort of BM lesions
analyzed for EGFR mutation and its clinical implications in
Chinese NSCLC patients. Our results showed a similar level
of EGFR mutation frequency in BMs (52.9 %, 72/136) as in
the primary NSCLC tumors (46.7 %, 7/15) (P =0.644). In
addition, a high concordance rate (93.3 %) of EGFR mutation
status was shown between the primary lung and
corresponding brain lesions. Recently, two other studies in
East Asian NSCLC patients were reported with similar
findings although the sample sizes were smaller. Matsumoto
et al. [12] found EGFR mutations in 63 % (12/19) of BMs

Fig. 1 KaplanMeier survival curves for progression free survival

between mutation group and wild-type group. EGFR epidermal growth
factor receptor, WT wild-type, MT mutation

from Japanese NSCLC patients. Moreover, six of eight pairs

of cases were positive for EGFR mutation and the
concordance rate was 100 %. Gow et al. [13] identified
44 % (11/25) of EGFR mutation rate in BMs of NSCLC
patients from Taiwan [13]. The concordance rate between
the primary lung tumor and BMs was increased from 68 %
to 84 % when a more sensitive method (SARMS) was used as
compared to direct DNA sequencing. In Caucasian
population, three studies evaluated the EGFR mutation in
BM of NSCLCs and identified only 02 % of EGFR mutation
rate in both the primary lung tumors and the BMs [1416].

Table 5 EGFR mutation frequency in primary lung lesions and brain

metastasis
EGFR mutation, no. (%)

Primary
Metastasis

EGFR WT
8 (53.3 %)
64 (47.1 %)

EGFR MT
7 (46.7 %)
72 (52.9 %)

Total
15
136

EGFR epidermal growth factor receptor, WT wild-type, MT mutant type,

NSCLC non-small-cell lung cancer

Fig. 2 KaplanMeier survival curves for overall survival between

mutant group and wild-type group. EGFR epidermal growth factor
receptor, WT wild-type, MT mutation

Tumor Biol. (2014) 35:24372444

The biased population with predominant smokers and males

might explain the far lower EGFR mutation rate than the
previously reported 10 % in Caucasian patients [8].
In our study, one out of the 15 patients with paired samples
was detected to be wild-type EGFR in the primary lung lesion
and 19-Del in the corresponding BMs. This might be
attributed to the potential heterogeneity of primary lung tumor
tissue [17]. Considering the high concordance of EGFR
mutation status between primary lung tumor and BMs, EGFR
mutation detected at one site (lung or brain) could be used as a
predictor for the status of another site (brain or lung). The PPV
of testing primary lung lesions for BM EGFR mutation status
is 100.0 %, and the negative prediction value is 87.5 %.
Similar prediction value is to be obtained by testing BM
samples for primary lung EGFR mutation status. For the
advanced NSCLC patients, whose BMs were not clinically
eligible for surgery or biopsy due to the health condition of
patients or the characters of BM lesions, such as miliary
metastases, the primary lung lesion could be used as surrogate
samples to predict the EGFR mutation status in the BM
lesions. Under some other circumstances, brain lesions were
found at presentation before primary lung cancer is detectable.
In our study, 108/136 (79.4 %) patients were initially admitted
with a variety of craniocerebral disorders without any
pulmonary symptoms at presentation. Resection of BMs
may become the first step in treatment for symptomatic
reasons and/or to prolong survival. Therefore, for these
patients, brain lesions might be the only available tissue for
determination of EGFR status, and the status might help to
predict the patients' response to EGFR-TKI therapy.
Heimberger et al. reported that TKIs did not readily cross
the bloodbrain barrier (BBB) [18]. The study by Zhang et al.
[19] had found that the concentration of gefitinib in the CSF
was low, and increase in the doses of gefitinib was effective
for the new intracranial lesions. It was also shown that
continuous administration of EGFR-TKI following
radiotherapy after progressive disease in isolated metastasis
appeared to be a valid treatment option [20]. Therefore, when
using EGFR-TKI to control the BMs, the high dose might
have helped to increase the TKI concentration in CSF and
improve curative effect. Hence, a new generation of EGFRTKI with better BBB penetration property would be attractive
for treatment of NSCLC patients with BM with the foundation
that the EGFR mutation status of the BM is mostly the same
as primary lung lesion in NSCLC patients.
We also conducted a comprehensive analysis of the
characteristics of the NSCLC patients as well as their
BM lesions stratified by the EGFR mutation status.
Similar to the reports on primary tumors, EGFR mutations
in the BM occur more frequently in females and neversmokers. No significant difference was found in terms of the
number or the size of the BM in the patients with or without
EGFR mutations.

2443

The reports about the relationship between the EGFR

mutation status and patients' survival have been controversial.
It was reported that the presence of EGFR mutations was an
independent prognostic factor in patients with BMs and was
associated with longer survival [21]. In our study, however,
EGFR mutations showed no significant effect on PFS or OS.
The study by Nose et al. [22] showed similar findings to ours.
They found that mutant or wild-type EGFR had no influence
on the PFS of 393 Japanese patients with stage IIV lung
adenocarcinoma that underwent complete resection. On the
other hand, Lee et al. [23] have reported that tumors harboring
EGFR mutations had lower risk of recurrence than those
harboring the wild-type EGFR in curatively resected lung
adenocarcinoma. There might be several factors that led to
the inconsistent findings. The major one could be the use of
EGFR-TKI therapy in different cohorts. It is reported that
patients who received EGFR-TKI at any time after diagnosis
of BMs survived longer than those who did not [21, 24]. Thirtytwo out of 73 recurred patients in the report by Lee et al. had
been receiving salvage therapy with EGFR-TKIs. However,
only seven of 136 patients had TKI therapy in our study.
In conclusion, EGFR mutations occur in more than half of
the NSCLC BM lesions with preference for females and
never-smokers. More than 90 % of the NSCLC patients have
the same EGFR mutations between the primary lung tumors
and the corresponding BM lesions. The EGFR mutation
frequency of BM is largely consistent with that of primary
lesion in these NSCLC patients. Therefore, the primary lung
tumor samples could be used as surrogate tissues to assess the
EGFR mutation status in the BM lesions, vice versa.
Moreover, EGFR mutations showed no significant effect on
the PFS and OS in the NSCLC patients with BM. However,
well-controlled prospective studies with paired primary
NSCLC and BMs are needed to further validate the prognostic
significance of EGFR mutation.
Conflicts of interest None

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