Background
Methods
Patients
Molecular analysis
Statistical analysis
Results
Variable | Study population | Variable | Study population |
---|---|---|---|
(n = 469) | (n = 469) | ||
Age (years) | 64.1 ± 11.4 | N stage | |
Gender | N0 | 117 (24.9) | |
Male | 235 (50.1) | N1 | 65 (13.9) |
Female | 234 (49.9) | N2 | 134 (28.6) |
Smoking status | N3 | 153 (32.6) | |
Never smokers | 115 (24.5) | Extrathoracic metastasis/−es | 213 (45.4) |
Ex-smokers | 160 (34.1) | M stage | |
Current smokers | 194 (41.4) | M0 | 168 (35.8) |
Clinical stage | M1a | 88 (18.8) | |
I | 34 (7.2) | M1b | 72 (15.4) |
II | 36 (7.7) | M1c | 141 (30.1) |
III | 100 (21.3) | Localization | |
IV | 299 (63.8) | Right upper lobe | 121 (25.8) |
T stage | Right lower lobe | 65 (13.9) | |
T1 | 68 (14.5) | Middle lobe | 19 (4.1) |
T1a | 9 (1.9) | Left upper lobe | 88 (18.8) |
T1b | 28 (6.0) | Left lower lobe | 73 (15.6) |
T1c | 31 (6.6) | Lingula | 14 (3.0) |
T2 | 120 (25.6) | Involvement of two lobes | 89 (19.0) |
T2a | 81 (17.3) | Distribution | |
T2b | 39 (8.3) | Central | 96 (20.5) |
T3 | 93 (19.8) | Peripheral | 323 (68.9) |
T4 | 188 (40.1) | Central and peripheral | 50 (10.7) |
Lymph node metastasis/−es | 352 (75.1) | Size (mm) | 45 ± 25 |
EGFR mutation analysis
cDNA change | Amino acid change | Frequency | Percentage | |
---|---|---|---|---|
Exon 21 | c.2573 T > G | p.L858R | 35 | 38.9 |
Exon 19 | c.2235_2249del/c.2236_2250dela | p.E746_A750del | 33 | 36.7 |
Exon 19 | c.2240_2257del | p.L747_P753delinsS | 6 | 6.7 |
Exon 19 | c.2254_2277del | p.S752_I759del | 3 | 3.3 |
Exon 19 | c.2239_2253del | p.L747_T751del | 2 | 2.2 |
Exon 19 | c.2239_2248delinsC | p.L747_A750delinsP | 2 | 2.2 |
Exon 19 | c.2238_2252delinsGCA | p.L747_T751delinsQ | 1 | 1.1 |
Exon 19 | c.2239_2256del | p.L747_S752del | 1 | 1.1 |
Exon 19 | c.2237_2255delinsT | p.E746_S752delinsV | 1 | 1.1 |
Exon 18 | c.2126A > C | p.E709A | 2 | 2.2 |
Exon 18 | c.2126A > G | p.E709G | 1 | 1.1 |
Exon 18 | c.2156G > C | p.G719A | 1 | 1.1 |
Exon 18 | c.2155G > T | p.G719C | 1 | 1.1 |
Exon 20 | c.2303G > T | p.S768I | 2 | 2.2 |
Exon 20 | c.2320G > A | p.V774 M | 1 | 1.1 |
Exon 21 | c.2497 T > G | p.L833 V | 1 | 1.1 |
Exon 21 | c.2560A > G | p.T854A | 1 | 1.1 |
Variable | EGFR wt (n = 379) | EGFR mt (n = 90) | p-value |
---|---|---|---|
Age (years) | 64.1 ± 10.9 | 64.2 ± 13.1 | 0.946 |
Gender |
0.020
| ||
Male | 200 (52.8) | 35 (38.9) | |
Female | 179 (47.2) | 55 (61.1) | |
Smoking status | |||
Never smokers | 46 (12.1) | 69 (76.7) |
< 0.001
|
Ex-smokers | 150 (39.6) | 10 (11.1) |
< 0.001
|
Current smokers | 183 (48.3) | 11 (12.2) |
< 0.001
|
Clinical stage | |||
I | 25 (6.6) | 9 (10.0) | 0.263 |
II | 32 (8.4) | 4 (4.4) | 0.200 |
III | 88 (23.2) | 12 (13.3) |
0.040
|
IV | 234 (61.7) | 65 (72.2) | 0.063 |
T stage | |||
T1 | 55 (14.5) | 13 (14.4) | 0.987 |
T1a | 7 (1.8) | 2 (2.2) | 0.685 |
T1b | 26 (6.9) | 2 (2.2) | 0.095 |
T1c | 22 (5.8) | 9 (10.0) | 0.150 |
T2 | 90 (23.7) | 30 (33.3) | 0.061 |
T2a | 55 (14.5) | 26 (28.9) |
0.001
|
T2b | 35 (9.2) | 4 (4.4) | 0.139 |
T3 | 77 (20.3) | 16 (17.8) | 0.587 |
T4 | 157 (41.4) | 31 (34.4) | 0.224 |
LN metastasis/−es | 289 (76.3) | 63 (70.0) | 0.218 |
N stage | |||
N0 | 90 (23.7) | 27 (30.0) | 0.218 |
N1 | 57 (15.0) | 8 (8.9) | 0.129 |
N2 | 114 (30.1) | 20 (22.2) | 0.138 |
N3 | 118 (31.1) | 35 (38.9) | 0.158 |
Extrathoracic metastasis−/es | 164 (43.3) | 49 (54.4) | 0.056 |
M stage | |||
M0 | 143 (37.7) | 25 (27.8) | 0.077 |
M1a | 72 (19.0) | 16 (17.8) | 0.790 |
M1b | 60 (15.8) | 12 (13.3) | 0.555 |
M1c | 104 (27.4) | 37 (41.1) |
0.011
|
Localization | |||
Right upper lobe | 95 (25.1) | 26 (28.9) | 0.456 |
Right lower lobe | 57 (15.0) | 8 (8.9) | 0.129 |
Middle lobe | 15 (4.0) | 4 (4.4) | 0.770 |
Left upper lobe | 72 (19.0) | 16 (17.8) | 0.790 |
Left lower lobe | 60 (18.8) | 13 (14.4) | 0.744 |
Lingula | 13 (3.4) | 1 (1.1) | 0.487 |
Involvement of two lobes | 67 (17.7) | 22 (24.4) | 0.141 |
Distribution | |||
Central | 74 (19.5) | 22 (24.4) | 0.298 |
Peripheral | 267 (70.4) | 56 (62.2) | 0.130 |
Central and peripheral | 38 (10.0) | 12 (13.3) | 0.361 |
Size (mm) | 45.5 ± 26.3 | 44.7 ± 20.3 | 0.744 |
Univariate logistic regression | Multivariate logistic regression | |||||||
---|---|---|---|---|---|---|---|---|
OR | 95% CI | Beta | p-value | OR | 95% CI | Beta | p-value | |
Sex | 0.019 | 0.033 | ||||||
Male | 1.00 | 1.00 | ||||||
Female | 1.756 | 1.10–2.81 | 0.563 | 1.328 | 0.75–2.37 | 0.284 | ||
Smoking status | < 0.001 | < 0.001 | ||||||
Ever smokers | 1.00 | 1.00 | ||||||
Never smokers | 23.786 | 13.35–42.38 | 3.169 | 23.069 | 12.92–41.20 | 3.139 |
KRAS mutation analysis
cDNA change | Amino acid change | Frequency | Percentage | |
---|---|---|---|---|
Codon 12/Exon 2 | c.34G > T | p.G12C | 72 | 45.3 |
Codon 12/Exon 2 | c.35G > T | p.G12 V | 26 | 16.4 |
Codon 12/Exon 2 | c.35G > A | p.G12D | 20 | 12.6 |
Codon 12/Exon 2 | c.35G > C | p.G12A | 15 | 9.4 |
Codon 12/Exon 2 | c.34_35del | p.G12F | 3 | 1.9 |
Codon 12/Exon 2 | c.34G > C | p.G12R | 2 | 1.3 |
Codon 12/Exon 2 | c.34G > A | p.G12S | 1 | 0.6 |
Codon 13/Exon 2 | c.37G > T | p.G13C | 10 | 6.3 |
Codon 13/Exon 2 | c.37G > A | p.G13S | 2 | 1.3 |
Codon 13/Exon 2 | c.38G > A | p.G13D | 2 | 1.3 |
Codon 13/Exon 2 | c.37G > C | p.G13R | 1 | 0.6 |
Codon 61/Exon 3 | c.183A > C | p.Q61H | 3 | 1.9 |
Codon 61/Exon 3 | c.182A > T | p.Q61L | 2 | 1.3 |
Variable | KRAS wt (n = 284) | KRAS mt (n = 159) | p-value |
---|---|---|---|
Age (years) | 64.7 ± 12.0 | 63.3 ± 9.4 | 0.193 |
Gender | 0.108 | ||
Male | 153 (53.9) | 73 (45.9) | |
Female | 131 (46.1) | 86 (54.1) | |
Smoking status | |||
Never smokers | 83 (29.2) | 7 (4.4) |
< 0.001
|
Ex-smokers | 99 (34.9) | 61 (38.4) | 0.461 |
Current smokers | 102 (35.9) | 91 (57.2) |
< 0.001
|
Clinical stage | |||
I | 19 (6.7) | 11 (6.9) | 0.927 |
II | 24 (8.5) | 10 (6.3) | 0.412 |
III | 60 (21.1) | 38 (23.9) | 0.500 |
IV | 181 (63.7) | 100 (62.9) | 0.860 |
T stage | |||
T1 | 39 (13.7) | 26 (16.4) | 0.455 |
T1a | 7 (2.5) | 2 (1.3) | 0.499 |
T1b | 16 (5.6) | 11 (6.9) | 0.588 |
T1c | 16 (5.6) | 13 (8.2) | 0.299 |
T2 | 78 (27.5) | 30 (18.9) |
0.043
|
T2a | 51 (18.0) | 18 (11.3) | 0.065 |
T2b | 27 (9.5) | 12 (7.5) | 0.485 |
T3 | 52 (18.3) | 37 (23.3) | 0.211 |
T4 | 115 (40.5) | 66 (41.5) | 0.835 |
LN metastasis/−es | 212 (74.6) | 121 (76.1) | 0.734 |
N stage | |||
N0 | 72 (25.4) | 38 (23.9) | 0.734 |
N1 | 33 (11.6) | 27 (17.0) | 0.114 |
N2 | 82 (28.9) | 48 (30.2) | 0.771 |
N3 | 97 (34.2) | 46 (28.9) | 0.259 |
Extrathoracic metastasis/−es | 124 (43.7) | 74 (46.5) | 0.559 |
M stage | |||
M0 | 101 (35.6) | 59 (37.1) | 0.746 |
M1a | 59 (20.8) | 26 (16.4) | 0.257 |
M1b | 37 (13.0) | 30 (18.9) | 0.100 |
M1c | 87 (30.6) | 44 (27.7) | 0.512 |
Localization | |||
Right upper lobe | 71 (25.0) | 44 (27.7) | 0.538 |
Right lower lobe | 45 (15.8) | 17 (10.7) | 0.134 |
Middle lobe | 11 (3.9) | 6 (3.8) | 0.958 |
Left upper lobe | 52 (18.3) | 31 (19.5) | 0.759 |
Left lower lobe | 33 (11.6) | 34 (21.4) |
0.006
|
Lingula | 11 (3.9) | 3 (1.9) | 0.252 |
Involvement of two lobes | 61 (21.5) | 24 (15.1) | 0.102 |
Distribution | |||
Central | 64 (22.5) | 27 (17.0) | 0.165 |
Peripheral | 189 (66.5) | 117 (73.6) | 0.124 |
Central and peripheral | 31 (10.9) | 15 (9.4) | 0.624 |
Size (mm) | 45.8 ± 25.8 | 45.6 ± 25.8 | 0.937 |
Univariate logistic regression | Multivariate logistic regression | |||||||
---|---|---|---|---|---|---|---|---|
OR | 95% CI | Beta | p-value | OR | 95% CI | Beta | p-value | |
Sex | 0.108 | 0.016 | ||||||
Male | 1.00 | 1.00 | ||||||
Female | 1.376 | 0.93–2.03 | 0.319 | 1.660 | 1.10–2.51 | 0.507 | ||
Smoking status | < 0.001 | < 0.001 | ||||||
Ever smokers | 1.00 | 1.00 | ||||||
Never smokers | 0.112 | 0.05–0.25 | −2.194 | 0.102 | 0.05–0.23 | −2.285 |
ALK rearrangement analysis
Variable | ALK neg. (n = 348) | ALK pos. (n = 28) | p-value |
---|---|---|---|
Age (years) | 64.4 ± 11.2 | 61.7 ± 14.1 | 0.229 |
Gender | 0.920 | ||
Male | 183 (52.6) | 15 (53.6) | |
Female | 165 (47.4) | 13 (46.4) | |
Smoking status | |||
Never smokers | 72 (20.7) | 12 (42.9) |
0.007
|
Ex-smokers | 124 (35.6) | 9 (32.1) | 0.710 |
Current smokers | 152 (43.7) | 7 (25.0) | 0.054 |
Clinical stage | |||
I | 22 (6.3) | 2 (7.1) | 0.697 |
II | 29 (8.3) | 2 (7.1) | 0.822 |
III | 67 (19.3) | 10 (35.7) |
0.038
|
IV | 230 (66.1) | 14 (50.0) | 0.086 |
T stage | |||
T1 | 47 (13.5) | 6 (21.4) | 0.258 |
T1a | 8 (2.3) | 0 (0.0) | 0.263 |
T1b | 19 (5.5) | 5 (17.9) |
0.025
|
T1c | 20 (5.7) | 1 (3.6) | 0.608 |
T2 | 88 (25.3) | 7 (25.0) | 0.973 |
T2a | 59 (17.0) | 4 (14.3) | 0.711 |
T2b | 29 (8.3) | 3 (10.7) | 0.721 |
T3 | 70 (20.1) | 4 (14.3) | 0.455 |
T4 | 143 (41.1) | 11 (39.3) | 0.852 |
LN metastasis/−es | 259 (74.4) | 24 (85.7) | 0.183 |
N stage | |||
N0 | 89 (25.6) | 4 (14.3) | 0.183 |
N1 | 50 (14.4) | 1 (3.6) | 0.151 |
N2 | 93 (26.7) | 15 (53.6) |
0.003
|
N3 | 116 (33.3) | 8 (28.6) | 0.606 |
Extrathoracic metastasis/−es | 161 (46.3) | 7 (25.0) | 0.029 |
M stage | |||
M0 | 116 (33.3) | 14 (50.0) | 0.074 |
M1a | 71 (20.4) | 7 (25.0) | 0.564 |
M1b | 56 (16.1) | 0 (0.0) |
0.013
|
M1c | 105 (30.2) | 7 (25.0) | 0.565 |
Localization | |||
Right upper lobe | 96 (27.6) | 0 (0.0) |
0.001
|
Right lower lobe | 51 (14.7) | 5 (17.9) | 0.587 |
Middle lobe | 11 (3.2) | 4 (14.3) |
0.019
|
Left upper lobe | 66 (19.0) | 6 (21.4) | 0.750 |
Left lower lobe | 43 (12.4) | 6 (21.4) | 0.236 |
Lingula | 11 (3.2) | 1 (3.6) | 0.611 |
Involvement of two lobes | 70 (20.1) | 6 (21.4) | 0.868 |
Distribution | |||
Central | 70 (20.1) | 8 (28.6) | 0.288 |
Peripheral | 244 (70.1) | 16 (57.1) | 0.153 |
Central and peripheral | 34 (9.8) | 4 (14.3) | 0.508 |
Size (mm) | 44.5 ± 24.4 | 46.0 ± 31.7 | 0.761 |
Univariate logistic regression | Multivariate logistic regression | |||||||
---|---|---|---|---|---|---|---|---|
OR | 95% CI | Beta | p-value | OR | 95% CI | Beta | p-value | |
Sex | 0.920 | 0.669 | ||||||
Male | 1.00 | 1.00 | ||||||
Female | 0.961 | 0.44–2.08 | −0.040 | 0.842 | 0.38–1.85 | −0.172 | ||
Smoking status | 0.009 | 0.008 | ||||||
Ever smokers | 1.00 | 1.00 | ||||||
Never smokers | 2.875 | 1.30–6.35 | 1.056 | 2.948 | 1.32–6.57 | 1.081 |
Study population (n = 469) | Patients testeda | |
---|---|---|
EGFR
| 90/469 (19.2) | 90/469 (19.2) |
KRAS
| 159/469 (33.9) | 159/443 (35.9) |
ALK
| 28/469 (6.0) | 28/376 (7.4) |
BRAF
| 12/469 (2.6) | 12/309 (3.9) |
ERBB2
| 9/469 (1.9) | 9/286 (3.1) |
MET
| 9/469 (1.9) | 9/234 (3.8) |
PIK3CA
| 7/469 (1.5) | 7/163 (4.3) |
RET
| 4/469 (0.8) | 4/208 (1.9) |
ROS1
| 8/469 (1.7) | 8/248 (3.2) |
EGFR, KRAS and ALK comparative analyses
Other mutations and rearrangements
cDNA change | Amino acid change | Frequency | Percentage | |
---|---|---|---|---|
Exon 15 | c.1799 T > A | p.V600E | 9 | 75.0 |
Exon 15 | c.1781A > G | p.D594G | 1 | 8.3 |
Exon 11 | c.1406G > T | p.G469 V | 1 | 8.3 |
Exon 11 | c.1406G > C | p.G469A | 1 | 8.3 |
ERBB2 mutation type | Mutation | Alternate nomenclature (based on HGVS guidelines) | Frequency | Percentage |
---|---|---|---|---|
Exon 20 insertion | p.A775_G776insYVMA (c.2324_2325ins12) | p.Y772_A775dup (c.2313_2324dup) | 5 | 55.6 |
Exon 20 insertion | p.P780_Y781insGSP (c.2339_2340insGGCTCCCCA) | p.G778_P780dup (c.2331_2339dup) | 1 | 11.1 |
Exon 20 insertion | p.G776 > VC (c.2326_2327insTGT) | p.G776delinsVC (c.2326_2327insTGT) | 1 | 11.1 |
Exon 8 missense mutation | p.Q527* (c.1579C > T) | p.Gln527Ter (c.1579C > T) | 1 | 11.1 |
Exon 13 nonsense mutation | p.S310Tyr (c.929C > A) | p.Ser310Tyr (c.929C > A) | 1 | 11.1 |