Med Oncol (2016)33:1 DOI 10.1007/s12032-015-0714-8
ORIGINAL PAPER
EGFR mutations are associated with higher incidence of distant metastases and smaller tumor size in patients with non-small-cell lung cancer based on PET/CT scan Jian Guan1 • Min Chen1 • Nanjie Xiao1 • Lu Li1 • Yue Zhang1 • Qinyang Li1 Mi Yang1 • Laiyu Liu2 • Longhua Chen1
•
Received: 20 October 2015 / Accepted: 3 November 2015 Ó Springer Science+Business Media New York 2015
Abstract The study aimed to explore the correlation of epidermal growth factor receptor (EGFR) mutation with tumor node metastasis (TNM) stage in patients with nonsmall-cell lung cancer (NSCLC) who underwent positron emission tomography/computed tomography (PET/CT) scan. Patients diagnosed with NSCLC who underwent EGFR mutation status testing and PET/CT or PET/CT plus brain magnetic resonance imaging scan at initial diagnosis in Nanfang Hospital between July 2010 and June 2014 were consecutively enrolled. The correlation of EGFR mutation status with TNM stage and distant metastasis organs including brain, bone, liver, pleural, adrenals and contralateral lobe of lung were analyzed. A total of 401 patients were enrolled. Tumor size in EGFR mutation group was significantly smaller than the wild-type group (P \ 0.001). Further, patients with EGFR mutations were demonstrated significantly more frequent in patients with distant metastasis than non-metastasis (45.7 vs 32.2 %, P = 0.007). The rates of bone (32.2 vs 22.8 %, P = 0.007) and brain (16.3 vs 9.4 %, P = 0.008) metastasis were significantly higher in EGFR mutation group than the wild-
Jian Guan and Min Chen have contributed equally to this work. & Laiyu Liu
[email protected] & Longhua Chen
[email protected] 1
Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
2
Chronic Airways Diseases Laboratory, Department of Respiratory and Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
type group. In the subgroup of 199 metastatic NSCLC patients, patients with EGFR mutation were significantly associated with a smaller tumor size (P = 0.013) and earlier N stage (P = 0.033). Of note, compared with the EGFR wild-type group, patients had a higher likelihood of developing brain plus bone metastases at initial diagnosis of EGFR mutation group (20.9 vs 7.5 %, P = 0.018). Taken together, we identify that EGFR mutations might associate with more aggressive tumor progression than the wild types in NSCLC. In addition, patients with tumor having EGFR mutation had a smaller tumor size than without mutation. Keywords Non-small-cell lung cancer EGFR mutation Tumor size TNM stage Bone metastasis Brain metastasis
Introduction Lung cancer is the most common cancer and the leading cancer-related deaths worldwide [1]. Non-small-cell lung cancer (NSCLC) accounts for approximately 85 % of lung cancer cases [2]. For patients with advanced NSCLC harbored an activating mutation in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR), targeted treatment of the EGFR-TK inhibitors (TKIs) such as gefitinib and erlotinib has been shown to be effective [3–5]. Patients who harbored a sensitive EGFR mutation showed a dramatic response to EGFR-TKIs, however, whether EGFR mutations associated with more aggressive clinical characteristics was still unknown, which was important for clinicians to make diagnostic and preventive strategies. Several studies have tried to explore the
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relationship between EGFR mutation and imaging manifestations including brain metastasis, bone metastases or lymph node, respectively [6–9]. However, all the previous studies could focus only on one or two organs of metastasis owing to that the distributing metastasis in patients was difficult to fully evaluate—there are patients having asymptomatic metastases maybe unsuspected or undiagnosed—in some organs. To our knowledge, none of the previous studies gave an overview of the correlation of EGFR mutations with the tumor-node-metastasis (TNM) stage and common metastasis organs such as brain, bone, liver and adrenals [10]. However, positron emission tomography/computed tomography (PET/CT) has been demonstrated to be effective in finding unsuspected–unknown metastasis [11]. Hence, using PET/CT scan at initial diagnosis, we could make a relatively complete and accurate evaluation of imaging manifestations in NSCLC patients [10, 12]. In this study, we enrolled the NSCLC patients who underwent PET/CT scan to evaluate the whole-body image, and tried to explore the correlation of EGFR mutation status with TNM stage.
Methods Patients We consecutively enrolled 401 patients diagnosed with NSCLC who underwent EGFR mutation status testing and PET/CT or PET/CT plus brain magnetic resonance imaging (MRI) at initial diagnosis in Nanfang Hospital between July 2010 and June 2014. Patients’ EGFR mutation status, clinical characteristics, TNM stages (American Joint Committee on Cancer, 7th edition.) and all the metastases including brain, bone, liver, pleural, adrenal, contralateral lobe of lung and other organs had been evaluated at initial diagnosis. Patients with brain metastases were verified by brain MRI. According to the smoking history, patients were categorized as smokers, never smokers and former smokers (stopped smoking at least 1 year before the diagnosis of lung cancer). Tumor histology and TNM stages of patients were confirmed by at least two relevant experts who did not know the EGFR mutation status.
Med Oncol (2016)33:1
2013) or amplification refractory mutation system (ARMS) (March 2013 to June 2014). Statistical methods Dichotomous variables were analyzed using the v2 test or Fisher’s exact test as appropriate. The relationship between numerical and categorical variables was compared using the Wilcoxon signed-rank test. P \ 0.05 was considered statistically significant. All analyses were performed on SPSS 20.0 software.
Result Demographic and baseline characteristics Patient demographic and baseline characteristics are shown in Table 1. A total of 401 Chinese NSCLC patients (280 males and 121 females) with a median age of 60 (range 24–98 years) were consecutively enrolled in our study; 206 (51.4 %) of the patients were current or former smoker, among which three were females, and 209 (52.1 %) patients had EGFR-mutant detection in Sanger sequencing and 192 (47.9 %) in ARMS. EGFR mutations were found in 39.7 % of the patients (159 out of 401), of which 80 patients in exon 19, 60 patients in exon 21, three patients in exon 18, eight patients in exon 20, seven patients in dual, and one in triple exons of mutation. EGFR mutation status and clinical characteristics Comparison of the demographic and clinical characteristics between patients with EGFR mutations and those with wild-type EGFR is listed in Table 1. 39.7 % patients harbored EGFR mutations. EGFR mutations were found preferentially in females (63.5 vs 28.6 %, P \ 0.001), never smokers (59.5 vs 20.9 %, P \ 0.001) and adenocarcinomas [46.1 % (adenocarcinoma) vs 18.3 % (nonadenocarcinoma), P \ 0.001]. Of note, data showed that the distribution of EGFR mutation rates in the different TNM stage was unequal (P = 0.001). Difference in EGFR mutation rate between patients detected by the methods of Sanger sequence and ARMS was not significant (43.5 vs 35.4 %, P = 0.097).
EGFR mutation status testing EGFR mutation status testing was performed on tumor specimens obtained from surgical resection, bronchoscopic biopsy or CT-guided core biopsy, before the initiation of therapy. The EGFR mutation status was analyzed using the methods of Sanger sequencing (July 2010 to February
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Correlation of EGFR mutation status with TNM stage in patients with non-small-cell lung cancer Table 2 showed the result of comparison of the EGFR mutation status with the TNM stages. We observed that the distribution of T and N stages between different EGFR
Med Oncol (2016)33:1 Table 1 Correlation of EGFR mutation status with clinical characteristics
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Variable
Total
EGFR mutation status
P
Mutation (n = 159)
Wild type (n = 242)
No. of patients
No. of patients
%
%
Age (years) Media (range)
0.593 60 (24–98)
60 (30–98)
60 (24–87)
Male
280
80
28.6
200
71.4
Female
121
79
65.3
42
34.7
43 116
20.9 59.5
163 79
79.1 40.5
\0.001
Sex
\0.001
Smoking history Current or former smoker 206 Never smoker 195
\0.001
Histological type SCC
62
10
16.1
52
ADC
308
142
46.1
166
83.9 53.9
LCC
8
1
12.5
7
76.5
Others
23
6
26.1
17
73.9
TNM stage
0.001
I
86
38
44.2
48
55.8
II
32
8
25.0
24
75.0
III
84
20
23.8
64
76.2
IV
199
93
46.7
106
53.3
Sanger sequencing
209
91
43.5
118
56.5
ARMS
192
68
35.4
124
64.6
Methods of EGFR detection
0.097
EGFR epidermal growth factor receptor, SCC squamous cell carcinoma, ADC adenocarcinoma, LCC large cell carcinoma, mutation patients with EGFR mutation, wild-type patients with wild-type EGFR
mutation status was similar (T: P = 0.468; N: P = 0.168). However, data showed that the tumor size in EGFR mutation group was significantly smaller than the wild-type group (P \ 0.001). Further, patients with EGFR mutations were demonstrated significantly more frequent in patients with distant metastasis than non-metastasis (46.0 vs 33.2 %, P = 0.008). Further, data showed that patients had a higher rate of distant metastasis in patients with EGFR mutations than the wild type (58.5 vs 45.0 %, P = 0.008). Of note, the rates of distant metastases in bone (34.6 vs 24.8 %, P = 0.034) and brain (15.7 vs 6.6 %, P = 0.003) were higher in patients with EGFR mutations than the wild type. However, data showed that distant metastases rates were similar in lung (16.4 vs 12.4 %, P = 0.264), pleural (16.4 vs 13.6 %, P = 0.453), liver (6.3 vs 7.9 %, P = 0.555) and adrenal metastasis (8.8 vs 10.7 %, P = 0.526; Fig. 1). Correlation of EGFR mutation status with TNM stage in IV stage NSCLC patients Next, analyses were performed to explore the relationship between TNM stage and EGFR mutation status in stage IV
NSCLC patients. Data showed that patients in EGFR mutation group had smaller tumor size and earlier N stage than the wild-type group, similar to the data we acquired in 401 NSCLC patients (Table 3). In the 199 stage IV patients in our study, 58 (29.2 %) had at least three organs of metastases, 59 (29.6 %) patients had two organs of metastases, and 82 (41.2 %) patients had only one organ of metastases. In the massive disordered data, we mainly did analysis in patients with brain, bone, liver or adrenals metastases (the most common extrathoracic metastases for NSCLC [10] which could not find by chest CT scan) to explore the difference between EGFR mutations and wild type. 73.9 % (147 out of 199) of the patients had brain, bone, liver or adrenals metastases, and the overall situation is shown in Fig. 2, and 59 patients had more than two organs metastases. Further, data showed that 20.9 % of the patients with EGFR mutation had metastases in brain and bone, while the data in wild-type group were 7.5 % (P = 0.018). There was no similar result found in bone plus liver (P = 0.385), bone plus adrenals (P = 0.826), brain plus liver (P = 0.796), brain plus adrenals (P = 0.355) and liver plus adrenals (P = 0.523; Table 4).
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Table 2 Correlation of EGFR mutation status with TNM stage
Med Oncol (2016)33:1
Variable
Total
EGFR mutation status Mutation (n = 159)
TNM stage
No. of patients
P Wild type (n = 242)
%
No. of patients
% 0.468w
Tumor T1
87
39
44.8
48
T2
163
62
38.0
101
55.2 62.0
T3
52
19
36.5
33
63.5
T4
99
39
39.4
60
60.6 \0.001w
Tumor size B2 cm [2 cm, B3 cm
72 108
35 54
48.6 50.0
37 54
51.4 50.0
[3 cm, B 5 cm
130
53
40.8
77
59.2
[5 cm, B7 cm
54
10
18.5
44
81.5
[7 cm
37
7
18.9
30
81.1 0.168w
Node N0
152
66
43.4
86
56.6
N1
29
13
44.8
30
55.2
N2
100
37
37.0
113
63.0
N3
120
43
35.8
119
64.2 0.008f
Metastasis M0
199
66
33.2
133
66.8
M1
202
93
46.0
109
54.0
EGFR epidermal growth factor receptor, mutation patients with EGFR mutation, wild-type patients with wild-type EGFR, TNM tumor, node and metastasis classification w
Wilcoxon signed-rank test
f
v2 test
Fig. 1 Percentage of distant metastases in different organs according to different EGFR mutation status. EGFR epidermal growth factor receptor, NS not significant
Discussion Our present study demonstrated that EGFR-mutant NSCLCs showed higher likelihood of suffering distant metastases especially bone and brain metastases, but smaller tumor size compared with the wild types. In
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addition, for metastatic NSCLC, EGFR mutation group had a smaller tumor size and a tendency to earlier N stage than the wild-type group. In this study, we identified 39.7 % of the patients harboring EGFR mutations, which was similar to the results of the previous reports [3, 4]. In addition, EGFR mutations were more prevalent in females, never smokers and patients with adenocarcinoma in our study, which was consistent with the previous reports [13–15]. Data showed that EGFR mutation was significantly associated with distant metastasis (P \ 0.001). In the present study, 58.7 % of the EGFR-mutant NSCLC had distant metastasis, while the rate in wild types was 44.6 %. Previous preclinical study had demonstrated that EGFR active mutation associated with tumor metastasis, and the possible mechanisms may be the activation of HER signaling pathway networks including Ras/Raf/MAPK and PI3K/Akt pathways [16–19]. We firstly demonstrated this finding in NSCLC patients which suggested that clinicians should pay more attention on evaluation of distant metastases site when making diagnostic strategy and follow up the patients. Lung cancer is the third common cancer to develop bone metastasis [20]. In the present study, bone metastases
Med Oncol (2016)33:1 Table 3 Correlation of EGFR mutation status with TNM stage in stage IV NSCLC patients
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Variable
Total
EGFR mutation status Mutation (n = 92)
TNM stage
No. of patients
P Wild type (n = 107)
%
No. of patients
% 0.802w
Tumor T1
25
11
44.0
14
56.0
T2
67
30
44.8
37
55.2
T3
29
15
51.7
14
48.3
T4
78
36
46.2
42
53.8 0.013w
Tumor size B2 cm [2 cm, B3 cm
32 50
16 30
50.0 60.0
16 20
50.0 40.0
[3 cm, B5 cm
69
31
44.9
38
55.1
[5 cm, B7 cm
26
9
34.6
17
65.4
[7 cm
22
6
27.3
16
72.7 0.033w
Node N0
39
24
61.5
15
38.5
N1
11
7
63.6
4
36.4
N2
53
22
41.2
31
58.5
N3
96
39
40.6
57
59.4 0.384f
Metastasis M1a
36
19
52.8
17
47.2
M1b
163
73
44.8
90
55.2
EGFR epidermal growth factor receptor, mutant patients with EGFR mutation, wild-type patients with wildtype EGFR, TNM tumor, node, metastasis w
Wilcoxon signed-rank test
f
v2 test
Fig. 2 Four-set Venn diagram of single and multiple metastases of brain, bone, liver and adrenal
developed in 28.7 % NSCLC patients at initial diagnosis. Of note, EGFR signaling system is an important mediator of the pathogenesis of bone metastases [21]. Many studies
had demonstrated that EGFR mutation was associated with bone metastasis in advanced prostate cancer and NSCLC [6, 22, 23], and Lu et al. [24] gave a possible mechanism that EGFR signaling pathway acts an important role in bone metastasis. In our study, data showed that the rates of bone metastasis in EGFR-mutant group were significantly higher than the wild-type group (32.2 vs 22.8 %, P = 0.007), which indicated that clinicians should pay more attention to the early diagnosis of EGFR-mutant NSCLC. As bone metastasis was significantly associated with bad prognosis and reduced overall survival [23, 25] and many new strategies were applied to reduce the morbidity of skeletal-related events (SREs) [26, 27], our finding suggested that EGFR mutation may be an useful predictor for clinicians to monitor bone metastasis and to develop strategies to improve the quality of life for patients early. NSCLC patients had a poor outcome when developed brain metastases. Our data also showed that NSCLC patients with EGFR mutation had a higher rate of brain metastasis than those without mutation. Although the mechanism was still unknown, the reports from Japan and Korea showed the similar results with us [6, 7]. This
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Table 4 Correlation of EGFR mutation status with metastatic organs cross in stage IV NSCLC patients
Med Oncol (2016)33:1
Variable
Total
EGFR mutation status
P
Mutation (n = 92) No. of patients
Wild type (n = 107) %
No. of patients
%
Metastatic cross Bone ? brain
20
14
20.9
6
7.5
0.018
Bone ? liver
24
9
13.4
15
18.8
0.385
Bone ? adrenals
23
10
14.9
13
16.2
0.826 0.796
Brain ? liver
8
4
6.0
4
5.0
Brain ? adrenals
12
7
10.4
5
6.2
0.355
Adrenals ? liver
11
4
6.0
7
8.8
0.523
EGFR epidermal growth factor receptor, mutant patients with EGFR mutation, wild-type patients with wildtype EGFR
finding may be useful to remind clinicians to evaluate the brain metastasis more carefully and find brain metastasis early. A meta-analysis reported that prophylactic cranial irradiation (PCI) may be effective in reducing brain metastasis in NSCLC [28]. Considering the poor prognosis of brain metastases, NSCLC patients with EGFR mutation might be more needed to receive a PCI and to monitor brain metastasis more regularly. In addition, EGFR-TKIs had shown a good efficacy in EGFR-mutant NSCLC patients with brain metastasis [29–31]. Of note, EGFRTKIs-combined whole-brain radiotherapy (WBRT) increased the response rate of brain metastasis than treated with EGFR-TKIs alone for EGFR-mutant NSCLC patients [29, 32, 33]. O’Brien M et al. hold the opinion that EGFRTKIs-combined WBRT was feasible in treatment of brain metastasis and EGFR-TKIs may act as radiosensitizers in EGFR-mutant NSCLC [34]. Therefore, early diagnosis of brain metastasis is shown to be important to develop treatment strategy for EGFR-mutant NSCLC. Further, patients showed higher likelihood of developing brain plus bone metastases in EGFR mutation group than the wild types. This result had never been reported before, and the certain mechanism was unknown. However, it remained us to pay more attention to suspect the possibility of another organ of metastasis when we found a metastasis in brain or bone for NSCLC patients. In addition, patients with three or four organs of metastasis cannot be analyzed because of the small sample. Further study with larger samples was needed to confirm and deepen our findings. It is interesting that patients with EGFR mutation had a smaller tumor size than the wild types. In addition, in the stage IV NSCLC patients, the similar result was obtained. Moreover, for stage IV NSCLC, EGFR mutation group had a tendency to earlier N stage than the wild-type group. A previous study was consistent with our study that EGFR mutations were predominantly seen in smaller primary tumors [35]. The other study showed that EGFR mutation
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was associated with early N stage in advanced NSCLC. Although the mechanism of all these findings was uncertain, its value on clinical application needs to be further considered. A limitation of this study was that not every patient underwent brain MRI scan. MRI should be conducted to evaluate the brain lesions because of the limited septicity in diagnosis of brain metastases using PET/CT [12]. However, every patient diagnosed with brain metastasis was comforted by brain MRI scan in our study.
Conclusion In conclusion, we found that EGFR mutations showed higher likelihood of suffering distant metastases, especially bone and brain metastases compared with the wild types in NSCLC. Of note, brain plus bone metastases were found more frequently in EGFR mutation group than the wildtype group at initial diagnosis, which suggested that clinicians should pay more attention on evaluation of distant metastases, especially in brain and bone when making diagnostic and preventive strategies for EGFR-mutant NSCLCs. Acknowledgments This work was supported by National Natural Science Foundation of China (81300029); Science and technology projects in Guangdong Province (2012B031800262); Natural Science Foundation of Guangdong Province (S2013040013505); President Foundation of Nanfang Hospital, Southern Medical University (2013Z010); President Foundation of Nanfang Hospital, Southern Medical University (2012Z002). Compliance with ethical standards Conflict of interest of interest.
The authors declare that they have no conflict
Ethical approval Ethical approval was given by the Ethics Committee of the Nanfang Hospital of Southern Medical University (No.
Med Oncol (2016)33:1 NFEC-2015-11). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.
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