Epidermal growth factor receptor mutations are linked to skip N2 lymph node metastasis in resected non-small-cell lung cancer adenocarcinomas.
The impact of skip N2 metastases (i.e. N2 lymph node metastases without N1) on survival in surgically resected non-small lung cancer remains an intriguing and rarely investigated topic. The goal of our study was to elucidate (i) skip N2 influence on overall survival (OS) and time to recurrence (TTR) in patients with resected lung adenocarcinoma and (ii) its link with epidermal growth factor receptor ( EGFR ) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations.



A retrospective analysis of 279 consecutive patients with lung pN2 adenocarcinoma, operated in two institutions between 2003 and 2013, was conducted. OS and TTR were calculated using the Kaplan-Meier method. Crude and multivariable-adjusted comparisons by skip N2 for OS and TTR were performed using the Cox method with shared frailty (accounting for the within-centre correlation). Associations between skip N2 metastasis, clinicopathological characteristics and EGFR and KRAS mutations were investigated using the Fisher exact test and Cramér's V -test.



The mean age at the time of surgery was 63 years (±12), and the median follow-up time was 36 months (min 3; max 101). Skip N2 was observed in 54 patients (19%). EGFR mutations were observed in 38 patients (14%); KRAS mutations were seen in 86 patients (31%). Patients with skip N2 metastasis were predominantly non-smokers ( P  =   0.001), underwent segmentectomy or limited resections ( P  =   0.004) and were not submitted to adjuvant therapy ( P  =   0.022). Moreover, there was a correlation between EGFR mutations and skip N2 (Cramér's V : 0.25, P  <   0.001). Indeed, EGFR mutations were significantly more frequent in skip N2 tumours (33%) compared with non-skip tumours (10%), P  <   0.001. No correlation between skip N2 and KRAS mutations was observed (Cramér's V : 0.05, P  =   0.46). The multivariable-adjusted model showed a significant skip N2 protective effect on OS (hazard ratio, HR 0.503; P  =   0.014; 95% confidence interval, CI: 0.291-0.8704) but not on TTR (HR 0.788; P  =   0.446; 95% CI: 0.427-1.454).



In our series, lung adenocarcinoma skip N2 metastasis demonstrated a favourable prognosis. The presence of EGFR mutations could have significance in the better survival and in the specific anatomic pathway of lymphatic metastases exhibited by skip N2 tumours.
Department of Thoracic Surgery, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.|Department of Thoracic Surgery, Strasbourg University Hospital, Strasbourg, France.
Francesco
F
Guerrera
Department of Thoracic Surgery, Strasbourg University Hospital, Strasbourg, France.|EA3430, Tumoral Progression and Microenvironment, Epidemiological and Translational Approaches, Strasbourg University, Strasbourg, France.
Stéphane
S
Renaud
Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Torino, Torino, Italy.|Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
Fabrizio
F
Tabbó
Department of Molecular Biology, Strasbourg University Hospital, Strasbourg, France.
Anne-Claire
AC
Voegeli'
Department of Thoracic Surgery, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Pier Luigi
PL
Filosso
Department of Molecular Biology, Strasbourg University Hospital, Strasbourg, France.
Michèle
M
Legrain
Department of Medical Sciences, Allergology and Immunology, University of Torino, Torino, Italy.
Monica
M
Boita
Department of Biostatistics, Strasbourg University Hospital, Strasbourg, France.
Mickaël
M
Schaeffer
EA3430, Tumoral Progression and Microenvironment, Epidemiological and Translational Approaches, Strasbourg University, Strasbourg, France.|Department of Molecular Biology, Strasbourg University Hospital, Strasbourg, France.
Michèle
M
Beau-Faller
Department of Thoracic Surgery, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Enrico
E
Ruffini
Department of Thoracic Surgery, Strasbourg University Hospital, Strasbourg, France.
Pierre-Emmanuel
PE
Falcoz
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.|Department of Pathology and NYU Cancer Center, New York University School of Medicine, New York, NY, USA.
Giorgio
G
Inghirami
Department of Thoracic Surgery, Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.
Alberto
A
Oliaro
Department of Thoracic Surgery, Strasbourg University Hospital, Strasbourg, France.
Gilbert
G
Massard
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000556:secondary* / Q000601:surgery; D000077192:Adenocarcinoma of Lung; D000368:Aged; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary* / Q000601:surgery; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011013:Pneumonectomy / Q000379:methods; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis
C117307:KRAS protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
EGFR; KRAS; Lung adenocarcinoma; Lymph node; NSCLC; Skip N2; Survival