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Figure legends
Fig. 1. (A) mRNA expression levels of vascular endothelial growth factor A (VEGFA) in nonsquamous non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor
receptor (EGFR) mutation with stage I (N=29), with stage II (N=17), with stage III (N=12), and
with stage IV (N=4) (B) mRNA expression levels of VEGFA in NSCLC patients harboring EGFR
wild-type with stage I (N=228), with stage II (N=96), with stage III (N=70), and with stage IV
(N=19). (C) mRNA expression levels of VEGFA and IL-6 in advanced non-squamous NSCLC
patients harboring EGFR mutation (N=16) and wild-type (N=89). p-values were calculated by
Mann-Whitney U test. Spearman correlation was used to assess the correlation between two
variables.
Fig. 2. Kaplan-Meier plot of progression-free survival (PFS) in the total number of patients (A),
in the patients treated with bevacizumab plus carboplatin and pemetrexed chemotherapy
(BevCPem) (B), and in the patients treated with carboplatin and pemetrexed chemotherapy
(CPem) (C).
Supplementary Fig. 1. mRNA expression levels of ANGPT2, CXCL12, FGF2, IL-1B, IL-8,
PDGFB, PIGF, VEGFB, VEGFC, VEGFD, VEGFR1, and VEGFR2 in advanced non-squamous
NSCLC patients with EGFR mutation (N=16) and wild-type (N=89). P-values were calculated
by Mann-Whitney U test. ANGPT2: angiopoietin 2, CXCL12: C-X-C motif chemokine ligand 12,
FGF2: fibroblast growth factor 2, IL-1B: interleukin 1 beta, IL-8: interleukin 8, PDGFB: platelet
derived growth factor subunit B, PIGF: phosphatidylinositol glycan anchor biosynthesis class F,
VEGFB: vascular endothelial growth factor B, VEGFC: vascular endothelial growth factor C,
VEGFD: vascular endothelial growth factor D, VEGFR1: vascular endothelial growth factor
receptor 1, and VEGFR2: vascular endothelial growth factor receptor 2
Supplementary Fig. 2.
Flowchart of patient selection in this cohort.
Supplementary Fig. 3.
Kaplan-Meier plot of overall survival in the patients with stage IV, treated with bevacizumab plus
carboplatin and pemetrexed chemotherapy (BevCPem), and carboplatin and pemetrexed
chemotherapy (CPem).
Supplementary Fig. 4.
(A) mRNA expression levels of IL-6 in NSCLC patients, characterized as non-smokers (N=75),
with current smokers (N=118), and with former smokers (N=301). (B) mRNA expression levels
of IL-6 in NSCLC patients harboring EGFR wild-type with non-smokers (N=41), with current
smokers (N=103), and with former smokers (N=260). p-values were calculated by Mann-Whitney
U test.
Table 1. Clinical characteristics of 159 NSCLC patients with EGFR mutations or EGFR wild type
BevCPem
CPem
EGFR wild
n (%)
33 (60.0)
P‡
55
EGFR mutation
n (%)
22 (40.0)
EGFR wild
n (%)
73 (70.2)
P‡
104
EGFR mutation
n (%)
31 (29.8)
62.0
62.2 (47-74)
61.9 (41-80)
0.9095
65.3
67.8 (40-76)
64.2 (27-79)
0.0768
31
24
9 (29.0)
13 (54.2)
22 (71.0)
11 (45.8)
0.0954
71
33
12 (16.9)
19 (57.6)
59 (83.1)
14 (42.4)
<0.0001
12
25
18
4 (33.3)
9 (36.0)
9 (50.0)
8 (66.7)
16 (64.0)
9 (50.0)
0.5658
28
37
36
3 (10.7)
5 (13.5)
22 (61.1)
25 (89.3)
32 (86.5)
14 (38.9)
<0.0001
40
15
17 (42.5)
5 (33.3)
23 (57.5)
10 (66.7)
0.7582
57
47
21 (36.8)
10 (21.3)
36 (63.2)
37 (78.7)
0.0910
IIIA
IIIB
IV
Recurrence
34
18
1 (50.0)
0 (0.0)
16 (47.1)
5 (27.8)
1 (50.0)
1 (100.0)
18 (52.9)
13 (72.2)
0.4617
11
62
25
1 (16.7)
4 (36.4)
17 (27.4)
9 (36.0)
5 (83.3)
7 (63.6)
45 (72.6)
16 (64.0)
0.7177
53
22 (41.5)
0 (0.0)
0 (0.0)
31 (58.5)
0 (0.0)
2 (10.0)
Not Available
91
10
31 (34.1)
0 (0.0)
0 (0.0)
60 (65.9)
3 (100.0)
10 (100.0)
0.0427
Characteristic
Total
Total
Median Age (Range)
Total
Gender
Male
Female
Smoking status*
Current
Former
Never
PS
Stage
Subtype
Adenocarcinoma
Large cell carcinoma
NSCLC
‡P values were calculated by T-Test, Fisher’s exact test or Chi-square test.
*Information was not available for 3 cases
Table 2. Response to BevCPem or CPem in advanced NSCLC patients
BevCPem
EGFR mutation
N=22
CPem
EGFR wild
EGFR mutation
EGFR wild
N=33
N=31
N=73
Best response
CR
0.0
0.0
0.0
1.4
PR
12
54.5
12
36.4
11
35.5
22
27.4
SD
40.9
15
45.4
16
51.6
27
38.3
PD
4.5
18.2
12.9
23
32.9
ORRs
12
54.5
12
36.4
11
35.5
23
28.8
DCRs
21
95.5
27
81.8
27
87.1
50
67.1
CR; complete response, PR; partial response, SD; stable disease, PD; progression disease,
ORR; overall response rate, DCR; disease control rate
Figure 1
1A
Patients with EGFR mutation
VEGFA mRNA expression
p = 0.0009
r = 0.3901
p = 0.2217
p = 0.0012
II
III
IV
Stage
1B
Patients with EGFR wild-type
VEGFA mRNA expression
p = 0.9063
r = 0.02439
p = 0.2522
p = 0.6216
II
III
Stage
IV
IL-6 mRNA expression
VEGFA mRNA expression
Figure 1
1C
p = 0.0476
p = 0.0065
Figure 2
2A
N=55
N=104
p = 0.0028 (Wilcoxon)
p = 0.0485 (Log-rank)
2B
BevCPem
N=22
N=33
p = 0.0278 (Wilcoxon)
p = 0.0730 (Log-rank)
2C
CPem
N=31
N=73
p = 0.1822 (Wilcoxon)
p = 0.5081 (Log-rank)
IL-8 mRNA expression
PDGFB mRNA expression
PIGF mRNA expression
VEGFB mRNA expression
VEGFC mRNA expression
VEGFD mRNA expression
VEGFR2 mRNA expression
VEGFR1 mRNA expression
IL-1B mRNA expression
FGF2 mRNA expression
CXCL12 mRNA expression
ANGPT2 mRNA expression
Supplementary Figure 1
Supplementary Figure 2
Medical records of NSCLC patients
between January 2004 and June 2018 (N=1678)
Patients enrolled for this study were selected
based on the following Eligibility criteria (N=174)
(1) Diagnosed as having stage III/IV or recurrent nonsquamous NSCLC as confirmed by histological or
cytological examination
(2) Performance status 0–1
(3) Receiving BevCPem or CPem
Excluded: N=15
non-target region: N=6
no available data: N=9
BevCPem
N=55
EGFR mutation
N=22
EGFR wild
N=33
CPem
N=104
EGFR mutation
N=31
EGFR wild
N=73
Supplementary Figure 3
N=16
N=18
p = 0.7724 (Wilcoxon)
p = 0.8117 (Log-rank)
N=18
N=49
p = 0.2499 (Wilcoxon)
p = 0.2383 (Log-rank)
Supplementary Figure 4
IL-6 mRNA expression
4A
All cases
4B
EGFR wild
p = 0.0379
p = 0.1732
p = 0.0439
p = 0.2383
...
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