The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study
Abstract
:Simple Summary
Abstract
1. Introduction
2. Material and Methods
2.1. Ethics
2.2. Patient Inclusion and Tumour Specimens
2.3. Statistics
3. Results
3.1. Patient Characteristics
3.2. KRAS Mutation Status and Correlations with Clinical Characteristics
3.3. Mutation Status and Survival
3.3.1. Whole Cohort (Stage I–IV)
3.3.2. Curative Surgery
3.3.3. Non-Curative Treatment
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristic | Total | KRAS wt n = 697 | KRAS mut n = 420 | |||
---|---|---|---|---|---|---|
Age (years) | ||||||
<50 | 46 | (4.1) | 29 | (4.2) | 17 | (4.0) |
50–60 | 169 | (15.1) | 104 | (14.9) | 65 | (15.5) |
>60 | 902 | (80.8) | 564 | (80.9) | 338 | (80.5) |
Hospital | ||||||
STO | 622 | (55.7) | 391 | (56.1) | 231 | (55.0) |
UNN | 231 | (20.7) | 144 | (20.7) | 87 | (20.7) |
OUH | 264 | (23.6) | 162 | (23.2) | 102 | (24.3) |
Sex | ||||||
Female | 592 | (53.0) | 353 | (50.6) | 239 | (56.9) |
Male | 525 | (47.0) | 344 | (49.4) | 181 | (43.1) |
Smoking history | ||||||
Never smoker | 126 | (11.3) | 113 | (16.2) | 13 | (3.1) |
Former/current smoker | 991 | (88.7) | 584 | (83.8) | 407 | (96.9) |
Ethnicity | ||||||
Scandinavian/European | 1106 | (99.0) | 686 | (98.4) | 420 | (100.0) |
African | 4 | (0.4) | 4 | (0.6) | 0 | (0.0) |
Asian | 7 | (0.6) | 7 | (1.0) | 0 | (0.0) |
ECOG PS | ||||||
0–1 | 1037 | (92.8) | 650 | (93.3) | 387 | (92.1) |
2 | 59 | (5.3) | 35 | (5.0) | 24 | (5.7) |
3–4 | 21 | (1.9) | 12 | (1.7) | 9 | (2.1) |
Histology | ||||||
Adenocarcinoma | 1063 | (95.2) | 650 | (93.3) | 413 | (98.3) |
Adenosquamous carcinoma | 6 | (0.5) | 6 | (0.9) | 0 | (0.0) |
Large cell carcinoma | 3 | (0.3) | 3 | (0.4) | 0 | (0.0) |
NSCLC-NOS | 36 | (3.2) | 31 | (4.4) | 5 | (1.2) |
MIA | 2 | (0.2) | 2 | (0.3) | 0 | (0.0) |
Other non-squamous NSCLC | 7 | (0.6) | 5 | (0.7) | 2 | (0.5) |
EGFR status | ||||||
No | 948 | (84.9) | 528 | (75.8) | 420 | (100.0) |
Yes | 142 | (12.7) | 142 | (20.4) | 0 | (0.0) |
Not assessed | 27 | (2.4) | 27 | (3.9) | 0 | (0.0) |
ALK rearrangement | ||||||
No | 1011 | (90.5) | 620 | (89.0) | 391 | (93.1) |
Yes | 12 | (1.1) | 12 | (1.7) | 0 | (0.0) |
Not assessed | 94 | (8.4) | 65 | (9.3) | 29 | (6.9) |
ROS1 rearrangement | ||||||
No | 552 | (49.4) | 342 | (49.1) | 210 | (50.0) |
Yes | 3 | (.3) | 3 | (0.4) | 0 | (0.0) |
Not assessed | 562 | (50.3) | 352 | (50.5) | 210 | (50.0) |
Disease stage | ||||||
IA | 227 | (20.3) | 141 | (20.2) | 86 | (20.5) |
IB | 132 | (11.8) | 77 | (11.0) | 55 | (13.1) |
IIA | 40 | (3.6) | 19 | (2.7) | 21 | (5.0) |
IIB | 108 | (9.7) | 75 | (10.8) | 33 | (7.9) |
IIIA | 138 | (12.4) | 83 | (11.9) | 55 | (13.1) |
IIIB | 67 | (6.0) | 42 | (6.0) | 25 | (6.0) |
IIIC | 25 | (2.2) | 16 | (2.3) | 9 | (2.1) |
IVA | 206 | (18.4) | 140 | (20.1) | 66 | (15.7) |
IVB | 174 | (15.6) | 104 | (14.9) | 70 | (16.7) |
Treatment intention | ||||||
Curative | 671 | (60.1) | 414 | (59.4) | 257 | (61.2) |
Palliative | 400 | (35.8) | 251 | (36.0) | 149 | (35.5) |
No treatment | 46 | (4.1) | 32 | (4.6) | 14 | (3.3) |
Variable | PFS | OS | ||||||
---|---|---|---|---|---|---|---|---|
n | HR | 95% CI | p | n | HR | 95% CI | p | |
Age (years) | ||||||||
<50 | 46 | 1 (ref) | 46 | 1 (ref) | ||||
50–60 | 166 | 1.07 | 0.71–1.60) | 0.762 | 169 | 1.49 | (0.90–2.45) | 0.118 |
>60 | 902 | 1.04 | (0.72–1.51) | 0.818 | 902 | 1.68 | (1.06–2.67) | 0.027 |
Sex | ||||||||
Women | 590 | 1 (ref) | 592 | 1 (ref) | ||||
Men | 524 | 1.10 | (0.94–1.27) | 0.233 | 525 | 1.13 | (0.96–1.34) | 0.137 |
Smoking history | ||||||||
Never | 126 | 1 (ref) | 126 | 1 (ref) | ||||
Former/current | 988 | 1.48 | (1.15–1.91) | 0.002 | 991 | 1.59 | (1.19–2.12) | 0.002 |
ECOG PS | ||||||||
0–1 | 1034 | 1 (ref) | 1037 | 1 (ref) | ||||
2 | 59 | 4.30 | (3.24–5.71) | <0.001 | 59 | 6.41 | (4.80–8.56) | <0.001 |
3–4 | 21 | 4.55 | (2.76–7.48) | <0.001 | 21 | 6.91 | (4.18–11.41) | <0.001 |
Stage | ||||||||
I | 359 | 1 (ref) | 359 | 1 (ref) | ||||
II | 148 | 2.15 | (1.61–2.86) | <0.001 | 148 | 2.11 | (1.51–2.95) | <0.001 |
III | 230 | 4.37 | (3.43–5.57) | <0.001 | 230 | 3.89 | (2.93–5.15) | <0.001 |
IV | 377 | 12.74 | (10.01–16.09) | <0.001 | 380 | 12.46 | (9.61–16.14) | <0.001 |
Surgery | ||||||||
No | 534 | 1 (ref) | 534 | 1 (ref) | ||||
Yes | 580 | 0.15 | (0.12–0.17) | <0.001 | 583 | 0.13 | (0.11–0.16) | <0.001 |
Curative RT +/− CT first line | ||||||||
No | 1023 | 1 (ref) | 1023 | 1 (ref) | ||||
Yes | 91 | 1.28 | (0.99–1.64) | 0.060 | 91 | 1.05 | (0.78–1.43) | 0.740 |
Palliative CT and/or RT first line | ||||||||
No | 843 | 1 (ref) | 846 | 1 (ref) | ||||
Yes | 271 | 5.75 | (4.85–6.81) | <0.001 | 271 | 5.54 | ((4.64–6.63)) | <0.001 |
History of TKI (any line) | ||||||||
No | 1025 | 1 (ref) | 1028 | 1 (ref) | ||||
Yes | 89 | 1.56 | (1.22–1.99) | <0.001 | 89 | 1.32 | (0.86–2.03) | 0.198 |
History of ICI (any line) | ||||||||
No | 939 | 1 (ref) | 941 | 1 (ref) | ||||
Yes | 175 | 2.19 | (1.81–2.64) | <0.001 | 176 | 1.39 | ((1.11–1.74)) | 0.006 |
KRAS status | ||||||||
Wild type | 695 | (1 (ref) | 697 | 1 (ref) | ||||
Mutated | 419 | 1.04 | (0.89–1.21) | 0.664 | 420 | 1.01 | (0.85–1.19) | 0.940 |
KRAS G12C status | ||||||||
Wild type | 695 | 1 (ref) | 697 | 1 (ref) | ||||
G12C | 192 | 0.91 | (0.74–1.12) | 0.379 | 193 | 0.91 | (0.72–1.14) | 0.414 |
KRAS non-G12C | 227 | 1.15 | (0.96–1.39) | 0.132 | 227 | 1.10 | (0.89–1.35) | 0.383 |
Raf vs. PI3K preference | ||||||||
Raf | 245 | 1 (ref) | 245 | 1 (ref) | ||||
PI3K | 69 | 1.11 | (0.79–1.55) | 0.554 | 70 | 1.09 | (0.75–1.58) | 0.649 |
Ral A/B vs. PI3K preference | ||||||||
RalA/B | 192 | 1 (ref) | 192 | 1 (ref) | ||||
PI3K | 69 | 1.20 | (0.85–1.70) | 0.312 | 70 | 1.19 | (0.81–1.74) | 0.385 |
Type KRAS mutation | ||||||||
G12A | 30 | 1 (ref) | 30 | 1 (ref) | ||||
G12C | 192 | 0.62 | (0.38–1.00) | 0.050 | 192 | 0.59 | (0.35–0.99) | 0.044 |
G12V | 81 | 0.72 | (0.43–1.21) | 0.220 | 81 | 0.60 | (0.34–1.06) | 0.080 |
G12D | 69 | 0.74 | (0.44–1.26) | 0.274 | 70 | 0.69 | (0.39–1.24) | 0.216 |
Variable | PFS | OS | PFS | OS | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
HR | 95%CI | p | HR | 95%CI | p | HR | 95%CI | p | HR | 95%CI | p | |
Age (years) | 1.01 | (1.00–1.01) | 0.207 | 1.02 | (1.01–1.03) | <0.001 | 1.01 | (1.00–1.01) | 0.214 | 1.02 | (1.01–1.03) | <0.001 |
Sex | ||||||||||||
Women | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Men | 1.09 | (0.93–1.27) | 0.280 | 1.05 | (0.88–1.24) | 0.603 | 1.09 | (0.93–1.27) | 0.283 | 1.05 | (0.89–1.24) | 0.596 |
Smoking history | ||||||||||||
Never | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Former/current | 1.56 | (1.19–2.05) | <0.001 | 1.71 | (1.24–2.33) | 0.001 | 1.56 | (1.19–2.05) | 0.001 | 1.70 | (1.25–2.33) | 0.001 |
ECOG PS | ||||||||||||
0–1 | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
2 | 2.02 | (1.51–2.71) | <0.001 | 2.90 | (2.15–3.92) | <0.001 | 2.01 | (1.50–2.70) | <0.001 | 2.91 | (2.16–3.94) | <0.001 |
3–4 | 4.27 | (2.56–7.14) | <0.001 | 6.51 | (3.83–11.05) | <0.001 | 4.25 | (2.54–7.11) | <0.001 | 6.56 | (3.86–11.14) | <0.001 |
Stage | ||||||||||||
I | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
II | 2.11 | (1.58–2.81) | <0.001 | 2.09 | (1.49–2.92) | <0.001 | 2.11 | (1.58–2.82) | <0.001 | 2.08 | (1.49–2.92) | <0.001 |
III | 3.02 | (2.28–3.99) | <0.001 | 2.67 | (1.92–3.71) | <0.001 | 3.02 | (2.28–3.99) | <0.001 | 2.67 | (1.92–3.72) | <0.001 |
IV | 4.61 | (3.18–6.67) | <0.001 | 4.34 | (2.91–6.47) | <0.001 | 4.61 | (3.19–6.68) | <0.001 | 4.34 | (2.91–6.47) | <0.001 |
Surgery | ||||||||||||
No | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Yes | 0.36 | (0.25–0.52) | <0.001 | 0.25 | (0.11–0.37) | <0.001 | 0.36 | (0.25–0.52) | <0.001 | 0.25 | (0.17–0.37) | <0.001 |
Curative RT +/− CT first line | ||||||||||||
No | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Yes | 0.74 | (0.51–1.09) | 0.127 | 0.47 | (0.31–0.73) | <0.001 | 0.74 | (0.51–1.09) | 0.130 | 0.47 | (0.31–0.73) | 0.001 |
Palliative CT and/or RT first line | ||||||||||||
No | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Yes | 1.49 | (1.19–1.88) | <0.001 | 1.16 | (0.90–1.48) | 0.250 | 1.49 | (1.18–1.87) | 0.001 | 1.16 | (0.91–1.48) | 0.236 |
History of TKI (any line) | ||||||||||||
No | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Yes | 0.78 | (0.58–1.03) | 0.081 | 0.65 | (0.47–0.90) | 0.009 | 0.78 | (0.58–1.03) | 0.081 | 0.65 | (0.47–0.90) | 0.009 |
KRAS status | ||||||||||||
Wild type | 1 (ref) | 1 (ref) | - | - | - | - | - | - | ||||
Mutated | 0.98 | (0.83–1.15) | 0.801 | 0.96 | (0.80–1.15) | 0.678 | - | - | - | - | - | - |
KRAS G12C status | ||||||||||||
Wild type | - | - | - | - | - | - | 1 (ref) | 1 (ref) | ||||
G12C | - | - | - | - | - | - | 0.96 | (0.77–1.19) | 0.691 | 1.00 | (0.79–1.28) | 0.972 |
KRAS non-G12C | - | - | - | - | - | - | 1.00 | (0.82–1.21) | 0.977 | 0.93 | (0.75–1.16) | 0.530 |
Variable | PFS | OS | ||||
---|---|---|---|---|---|---|
HR | 95%CI | p | HR | 95%CI | p | |
Age at time of diagnosis | 1.00 | (0.99–1.02) | 0.820 | 1.01 | (0.99–1.03) | 0.142 |
Sex | ||||||
Women | 1 (ref) | 1/ref) | ||||
Men | 1.16 | (0.89–1.52) | 0.283 | 1.01 | (0.75–1.37) | 0.940 |
Smoking history | ||||||
Never smoker | 1 (ref) | 1 (ref) | ||||
Former/current smoker | 0.93 | (0.40–2.14) | 0.858 | 0.77 | (0.31–1.94) | 0.582 |
ECOG PS | ||||||
0–1 | 1 (ref) | 1 (ref) | ||||
2 | 1.99 | (1.16–3.40) | 0.012 | 2.66 | (1.53–4.61) | 0.001 |
3–4 | 3.82 | (1.64–8.88) | 0.002 | 6.76 | (2.86–16.00) | 0.000 |
Stage | ||||||
I | 1 (ref) | 1 (ref) | ||||
II | 1.66 | (1.01–2.74) | 0.047 | 1.45 | (0.80–2.60) | 0.218 |
III | 2.69 | (1.66–4.35) | 0.000 | 2.02 | (1.13–3.60) | 0.018 |
IV | 2.49 | (1.29–4.82) | 0.007 | 2.06 | (0.99–4.29) | 0.054 |
Surgery | ||||||
No | 1 (ref) | 1 (ref) | ||||
Yes | 0.24 | (0.13–0.46) | 0.000 | 0.17 | (0.08–0.34) | 0.000 |
Curative RT +/− CT first line | ||||||
No | 1 (ref) | 1 (ref) | ||||
Yes | 0.53 | (0.27–1.03) | 0.062 | 0.26 | (0.11–0.59) | 0.001 |
Palliative CT and/or RT first line | ||||||
No | 1 (ref) | 1 (ref) | ||||
Yes | 1.53 | (1.01–2.33) | 0.046 | 1.26 | (0.80–1.99) | 0.314 |
KRAS mutation | ||||||
G12A | 1 (ref) | 1 (ref) | ||||
G12C | 0.76 | (0.45–1.26) | 0.281 | 0.97 | (0.54–1.73) | 0.907 |
G12V | 0.79 | (0.46–1.37) | 0.399 | 0.83 | (0.44–1.56) | 0.561 |
G12D | 0.76 | (0.44–1.33) | 0.333 | 0.87 | (0.46–1.64) | 0.659 |
Variable | PFS | OS | PFS | OS | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
HR | 95%CI | p | HR | 95%CI | p | HR | 95%CI | p | HR | 95%CI | p | |
Age (years) | 1.02 | (1.00–1.03) | 0.070 | 1.02 | (1.00–1.04) | 0.027 | 1.02 | (1.00–1.04) | 0.085 | 1.01 | (0.99–1.03) | 0.200 |
Sex | ||||||||||||
Women | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Men | 1.00 | (0.75–1.35) | 0.981 | 0.88 | (0.63–1.22) | 0.431 | 0.90 | (0.64–1.25) | 0.529 | 0.69 | (0.47–1.01) | 0.054 |
Smoking history | ||||||||||||
Never | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Former/current | 1.02 | (0.36–2.88) | 0.975 | 0.93 | (0.28–3.09) | 0.911 | 1.31 | (0.40–4.33) | 0.653 | 1.34 | (0.31–5.67) | 0.695 |
ECOG PS | ||||||||||||
0–1 | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
2 | 2.23 | (1.32–3.76) | 0.003 | 3.03 | (1.79–5.14) | <0.001 | 2.77 | (1.46–5.23) | 0.002 | 4.89 | (2.49–9.58) | <0.001 |
3–4 | 6.68 | (2.89–15.5) | <0.001 | 9.21 | (3.85–22.02) | <0.001 | 6.02 | (2.41–14.99) | <0.001 | 10.95 | (4.18–28.68) | <0.001 |
Stage | ||||||||||||
I | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
II | 1.55 | (0.88–2.71) | 0.128 | 1.52 | (0.79–2.94) | 0.212 | 1.35 | (0.71–2.58) | 0.363 | 1.03 | (0.47–2.26) | 0.946 |
III | 2.61 | (1.49–4.58) | 0.001 | 2.71 | (1.45–5.06) | 0.002 | 3.21 | (1.77–5.85) | <0.001 | 2.61 | (1.30–5.25) | 0.007 |
IV | 2.74 | (1.36–5.52) | 0.005 | 3.08 | (1.50–6.32) | 0.002 | 3.24 | (1.46–7.19) | 0.004 | 1.94 | (0.80–4.71) | 0.143 |
Surgery | ||||||||||||
No | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Yes | 0.234 | (0.11–0.48) | <0.001 | 0.22 | (0.1–0.48) | <0.001 | 0.28 | (0.13–0.62) | 0.002 | 0.16 | (0.07–0.39) | <0.001 |
Curative RT +/− CT first line | ||||||||||||
No | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Yes | 0.617 | (0.30–1.27) | 0.189 | 0.35 | (0.14–0.83) | 0.017 | 0.57 | (0.26–1.28) | 0.173 | 0.22 | (0.08–0.58) | 0.002 |
Palliative CT and/or RT first line | ||||||||||||
No | 1 (ref) | 1 (ref) | 1 (ref) | 1 (ref) | ||||||||
Yes | 1.56 | (1.00–2.44) | 0.052 | 1.27 | (0.77–2.09) | 0.350 | 1.15 | (0.94–2.48) | 0.089 | 1.32 | (0.78–2.24) | 0.302 |
PI3K vs. Raf | ||||||||||||
Raf | 1 (ref) | 1 (ref) | - | - | - | - | - | - | ||||
PI3K | 0.903 | (0.64–1.28) | 0.570 | 0.89 | (0.60–1.30) | 0.530 | - | - | - | - | - | - |
PI3K vs. RalA/B | ||||||||||||
RalA/B | - | - | - | - | - | - | 1 (ref) | 1 (ref) | ||||
PI3K | - | - | - | - | - | - | 0.94 | (0.65–1.35) | 0.720 | 0.86 | (0.58–1.29) | 0.474 |
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Wahl, S.G.F.; Dai, H.Y.; Emdal, E.F.; Berg, T.; Halvorsen, T.O.; Ottestad, A.L.; Lund-Iversen, M.; Brustugun, O.T.; Førde, D.; Paulsen, E.-E.; et al. The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study. Cancers 2021, 13, 4294. https://doi.org/10.3390/cancers13174294
Wahl SGF, Dai HY, Emdal EF, Berg T, Halvorsen TO, Ottestad AL, Lund-Iversen M, Brustugun OT, Førde D, Paulsen E-E, et al. The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study. Cancers. 2021; 13(17):4294. https://doi.org/10.3390/cancers13174294
Chicago/Turabian StyleWahl, Sissel Gyrid Freim, Hong Yan Dai, Elisabeth Fritzke Emdal, Thomas Berg, Tarje Onsøien Halvorsen, Anine Larsen Ottestad, Marius Lund-Iversen, Odd Terje Brustugun, Dagny Førde, Erna-Elise Paulsen, and et al. 2021. "The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study" Cancers 13, no. 17: 4294. https://doi.org/10.3390/cancers13174294