jlc Journal of Lung Cancer J Lung Cancer 1598-7809 Korean Association for the Study of Lung Cancer 10.6058/jlc.2009.8.1.13 jlc-8-13 Original Article The Prognostic and Predictive Value of EGFR and HER-2 in Advanced Non-small Cell Lung Cancer Patients Who Are Treated with Cisplatin and Paclitaxel YooJinyoungM.D. 1 ShimByoung YongM.D. 2 KangSeok JinM.D. 1 Departments of Pathology Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea Address for correspondence Seok Jin Kang, M.D. Department of Pathology, St. Vincent's Hospital, The Catholic University of Korea, 93, Ji-dong, Paldal-gu, Suwon 442-723, Korea Tel: 82-31-249-7591 Fax: 82-31-244-6786 E-mail: sjkang@catholic.ac.kr

This work was supported by a 2008 research grant from St.Vincent's Hospital.

 01 2009 10 01 2009 8 1 13 20 10022009 08042009 Copyright © 2009 Korean Association for the Study of Lung Cancer 2009 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Purpose

Although both platinum-based drugs and third-generation drugs are commonly used as first-line therapy for patients with advanced, unresectable non-small cell lung cancer, their effectiveness and clinical outcomes vary. We investigated whether epidermal growth factor receptor (EGFR) and HER-2 were correlated with the chemoresponse and survival after treatment with a cisplatin plus paclitaxel regimen.

 Materials and Methods

Forty-nine tumors were analyzed by chromogenic in situ hybridization (CISH) for EGFR and HER-2 gene amplification.

 Results

Twenty-eight patients (57%) achieved a partial response (PR), 13 (27%) showed stable disease (SD) and 8 (16%) had progressive disease (PD). EGFR and HER-2 amplification was identified in 43% and 57% of the tumors, respectively. EGFR amplification revealed no association with either a chemoresponse or survival, whereas HER-2 was amplified more frequently in the patients with PD (88% vs. 54%, respectively, p=0.06) and in the patients with shorter survival (12 months vs. 20 months respectively, p=0.027).

 Conclusion

The evaluation of HER-2 gene amplification is a promising approach for identifying those patients who are most likely to benefit from combination chemotherapy with cisplatin and paclitaxel.

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EGFR (A) and HER-2 (B) gene amplification by chromogenic in situ hybridization. A typical gene amplification appears as a cluster of multiple individual gene copies (CISH, ×400). EGFR: epidermal growth factor receptor.

 Tables

Clinicopathologic Features and Their Relationship with Tumor Response to Chemotherapy

Variables No. (%) Responder (%) Non-responder (%) p value
Age (years)        
  Mean 59.5±9.5     0.114
  <60 23 (47) 12 (52) 11 (48)  
  ≥60 26 (53) 16 (62) 10 (38)  
Gender       0.138
  Male 30 (61) 19 (63) 11 (37)  
  Female 19 (39) 9 (48) 10 (52)  
Smoking       0.148
  Never-smoker 14 (29) 6 (42) 8 (58)  
  Current or ex-smoker 35 (71) 22 (63) 13 (37)  
T       0.291
  T2, T3 21 (43) 12 (57) 9 (43)  
  T4 28 (57) 16 (57) 12 (43)  
N       0.894
  N0 3 (6) 2 (67) 1 (33)  
  N1∼3 46 (94) 26 (57) 20 (43)  
Stage       0.114
  IIIB 15 (31) 11 (73) 4 (27)  
  IV 34 (69) 17 (50) 17 (50)  
Histology       0.053
  Squamous cell carcinoma 20 (41) 16 (80) 4 (20)  
  Adenocarcinoma 24 (49) 9 (38) 15 (62)  
  Large cell carcinoma 5 (10) 3 (60) 2 (40)  
Differentiation       0.462
  Well differentiated 4 (8) 3 (75) 1 (25)  
  Moderately differentiated 23 (47) 10 (43) 13 (57)  
  Poorly differentiated 22 (45) 15 (68) 7 (32)  
Total 49 28 (57) 21 (43)  

Association between Clinicopathologic Variables and Gene Amplification of EGFR and HER-2

Variables EGFR HER-2
  Amplified (%) p value Amplified (%) p value
Age (years)   0.876   0.646
  ＜60 (n=23) 11 (48)   14 (61)  
  ≥60 (n=26) 10 (38)   14 (54)  
Gender   0.956   0.62
  Male (n=30) 13 (43)   18 (60)  
  Female (n=19) 8 (42)   10 (53)  
Smoking   0.943   0.533
  Never-smoker (n=14) 6 (43)   7 (50)  
  Current or ex-smoker (n=35) 15 (43)   21 (60)  
T   0.227   0.529
  T2, T3 (n=21) 10 (48)   11 (52)  
  T4 (n=28) 11 (39)   17 (61)  
N   0.276   0.4
  N0 (n=3) 1 (33)   2 (67)  
  N1∼3 (n=46) 20 (43)   26 (57)  
Stage   0.718   0.112
  IIIB (n=15) 6 (40)   6 (40)  
  IV (n=34) 15 (44)   22 (65)  
Histology   0.575   0.8
  Squamous cell carcinoma (n=20) 8 (40)   11 (55)  
  Adenocarcinoma (n=24) 11 (46)   14 (58)  
  Large cell carcinoma (n=5) 2 (40)   3 (60)  
Differentiation   0.102   0.135
  Well differentiated (n=4) 2 (50)   2 (50)  
  Moderately differentiated (n=23) 7 (30)   11 (48)  
  Poorly differentiated (n=22) 12 (55)   15 (68)  
Tumor response   0.204   0.06
  Partial response (n=28) 13 (46)   15 (54)  
  Stable disease (n=13) 5 (38)   6 (46)  
  Progressive disease (n=8) 3 (38)   7 (88)  
Total 21 (43)   28 (57)  

Association between Clinicopatholgic Variables and Median Survival

Variables Median survival ±SD (months) 95% CI p value
Age (years)     0.269
  ＜60 17±4.372 8.098∼25.235  
  ≥60 14±2.214 9.496∼18.174  
Gender     0.361
  Male 14±1.881 10.314∼17.686  
  Female 20±3.119 13.888∼26.112  
Smoking     0.227
  Never-smoker 18±3.165 11.796∼24.204  
  Current or ex-smoker 15±2.098 10.887∼19.113  
T     0.16
  T2 12±2.980 6.158∼17.842  
  T3 14±3.879 6.396∼21.604  
  T4 20±2.980 14.158∼25.842  
N     0.889
  N0 20±9.798 0.796∼39.204  
  N1 12±3.286 5.559∼18.441  
  N2 14±4.866 4.463∼23.537  
  N3 15±2.882 9.350∼20.650  
Stage     0.058
  IIIB 16±4.508 6.163∼23.837  
  IV 12±2.325 10.443∼19.557  
Histology     0.036
  Squamous cell carcinoma 18±4.837 8.519∼27.481  
  Adenocarcinoma 14±2.078 9.927∼18.073  
  Large cell carcinoma 8±0.816 6.400∼9.600  
Differentiation     0.366
  Well differentiated 24±14.697 0.000∼52.806  
  Moderately differentiated 16±2.695 10.717∼21.283  
  Poorly differentiated 14±4.297 5.578∼22.422  
Tumor response     0.013
  Partial response 20±8.490 3.359∼36.641  
  Stable disease 15±1.708 11.653∼18.347  
  Progressive disease 10±3.933 2.292∼17.708  
EGFR     0.438
  Not-amplified 13±2.735 7.639∼18.361  
  Amplified 15±2.950 9.218∼20.782  
HER-2     0.027
  Not-amplified 20±4.218 11.732∼28.268  
  Amplified 12±2.851 6.412∼17.588  

SD: standard deviation, CI: confidence interval, EGFR: epidermal growth factor receptor

Univariate and Multivariate Analyses of Cox Proportional Hazard Model

Variables Level Hazard ratio 95% CI p value
a) Univariate analysis        
   Age (in years) ≥60 vs. ＜60 0.988 0.950∼1.029 0.565
   Smoking Current or ex-smoker vs. Never-smoker 1.298 0.565∼2.983 0.539
   Stage IV vs. IIIB 1.137 0.581∼2.214 0.708
   Histology Non-squamous vs. Squamous 1.714 0.943∼3.114 0.077
   Tumor response PR or SD vs. PD 0.323 0.129∼0.809 0.016
   EGFR Amplified vs. Not amplified 0.996 0.781∼1.269 0.971
   HER-2 Amplified vs. Not amplified 1.718 0.888∼2.326 0.108
b) Multivariate analysis        
   Age (in years) ≥60 vs ＜60 0.994 0.952∼1.038 0.792
   Smoking Current or ex-smoker vs. Never-smoker 1.837 0.667∼5.133 0.246
   Stage IV vs. IIIB 1.018 0.283∼1.438 0.279
   Histology Non-squamous vs. Squamous 2.036 0.977∼4.242 0.058
   Tumor response PR or SD vs. PD 0.332 0.129∼0.809 0.031
   EGFR Amplified vs. Not amplified 1.084 0.827∼1.419 0.56
   HER-2 Amplified vs. Not amplified 1.744 0.810∼3.756 0.155

CI: confidence interval, PR: partial response, SD: stable disease, PD: progressive disease, EGFR: epidermal growth factor receptor