Documentos de Académico
Documentos de Profesional
Documentos de Cultura
(2014) 35:24372444
DOI 10.1007/s13277-013-1323-9
RESEARCH ARTICLE
Received: 11 September 2013 / Accepted: 14 October 2013 / Published online: 7 November 2013
# International Society of Oncology and BioMarkers (ISOBM) 2013
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
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
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
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
2441
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
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
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
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
Primary
Metastasis
EGFR WT
8 (53.3 %)
64 (47.1 %)
EGFR MT
7 (46.7 %)
72 (52.9 %)
Total
15
136
2443
References
1. Han KY, Gu X, Wang HR, Liu D, Lv FZ, Li JN. Overexpression of
MAC30 is associated with poor clinical outcome in human nonsmall-cell lung cancer. Tumor Biol. 2013;34(2):8215.
2. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin.
2010;60(5):277300.
3. Merchut MP. Brain metastases from undiagnosed systemic
neoplasms. Arch Intern Med. 1989;149(5):107680.
4. Sorensen JB, Hansen HH, Hansen M, Dombernowsky P. Brain
metastases in adenocarcinoma of the lung: frequency, risk groups,
and prognosis. J Clin Oncol. 1988;6(9):147480.
5. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N.
Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma.
N Engl J Med. 2009;361(10):94757.
2444
6. Porta R, Sanchez-Torres JM, Paz-Ares L, Massuti B, Reguart N,
Mayo C, et al. Brain metastases from lung cancer responding to
erlotinib: the importance of EGFR mutation. Eur Respir J.
2011;37(3):62431.
7. Paz-Ares L, Soulieres D, Melezinek I, Moecks J, Keil L, Mok T, et al.
Clinical outcomes in non-small-cell lung cancer patients with EGFR
mutations: pooled analysis. J Cell Mol Med. 2010;14(12):5169.
8. Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al.
Screening for epidermal growth factor receptor mutations in lung
cancer. N Engl J Med. 2009;361(10):95867.
9. Kim JE, Lee DH, Choi Y, Yoon DH, Kim SW, Suh C, et al.
Epidermal growth factor receptor tyrosine kinase inhibitors as a
first-line therapy for never-smokers with adenocarcinoma of the lung
having asymptomatic synchronous brain metastasis. Lung Cancer.
2009;65(3):3514.
10. Ni SS, Zhang J, Zhao WL, Dong XC, Wang JL. ADAM17 is
overexpression in non-small-cell lung cancer and its expression
correlates with poor patients survival. Tumor Biol. 2013;34(3):18138.
11. Edge SB, Compton CC. The American Joint Committee on Cancer:
the 7th edition of the AJCC cancer staging manual and the future of
TNM. Ann Surg Oncol. 2010;17(6):14714.
12. Matsumoto S, Takahashi K, Iwakawa R, Matsuno Y, Nakanishi Y,
Kohno T, et al. Frequent EGFR mutations in brain metastases of lung
adenocarcinoma. Int J Cancer. 2006;119(6):14914.
13. Gow CH, Chang YL, Hsu YC, Tsai MF, Wu CT, Yu CJ, et al.
Comparison of epidermal growth factor receptor mutations between
primary and corresponding metastatic tumors in tyrosine kinase
inhibitor-naive non-small-cell lung cancer. Ann Oncol. 2009;20(4):
696702.
14. Cortot AB, Italiano A, Burel-Vandenbos F, Martel-Planche G,
Hainaut P. KRAS mutation status in primary nonsmall cell lung
cancer and matched metastases. Cancer. 2010;116(11):26827.
15. Daniele L, Cassoni P, Bacillo E, Cappia S, Righi L, Volante M, et al.
Epidermal growth factor receptor gene in primary tumor and
metastatic sites from non-small cell lung cancer. J Thorac Oncol.
2009;4(6):6848.