Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network

M. Beau-Faller (1) , N. Prim (2) , A. M. Ruppert (3) , I. Nanni-Metellus (4) , R. Lacave (3) , L. Lacroix (5) , F. Escande (6) , S. Lizard (7) , J. L. Pretet (8) , I. Rouquette (9) , P. De Cremoux (10) , Jérôme Solassol (11) , F. De Fraipont (12) , I. Bieche (13) , A. Cayre (14) , E. Favre-Guillevin (15) , P. Tomasini (4) , M. Wislez (3, 16) , B. Besse (17) , M. Legrain (2) , A. C. Voegeli (2) , L. Baudrin (17) , F. Morin (17) , G. Zalcman (18, 17) , E. Quoix (2, 17) , H. Blons (15) , J. Cadranel (17, 3)

1 Progression tumorale et microenvironnement. Approches translationnelles et épidémiologie
2 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
3 CHU Tenon [AP-HP]
4 CHU Marseille
5 Département de biologie et pathologie médicales [Gustave Roussy]
6 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
7 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
8 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
9 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
10 Institut Curie [Paris]
11 IRCM - U896 Inserm - UM1 - Institut de recherche en cancérologie de Montpellier
12 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
13 Hôpital René Huguenin [Saint-Cloud]
14 CHU Clermont-Ferrand
15 CIC 1418 - CIC - HEGP
16 Theranoscan
17 IFCT - Intergroupe Francophone de Cancérologie Thoracique [Paris]
18 CHU Caen

BACKGROUND: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS: EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS: Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P \textless 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS: Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.

Mots clés: Humans; Female; Middle Aged; Adult; Male; Young Adult; Aged; 80 and over; Receptor; Epidermal Growth Factor/antagonists & inhibitors/*genetics; Disease-Free Survival; Proportional Hazards Models; Antineoplastic Agents/pharmacology/therapeutic use; Adenocarcinoma/drug therapy/*genetics/mortality; Carcinoma; Non-Small-Cell Lung/drug therapy/*genetics/mortality; Drug Resistance; Neoplasm/genetics; Exons; Gene Frequency; Genetic Association Studies; Lung Neoplasms/drug therapy/*genetics/mortality; Protein Kinase Inhibitors/pharmacology/therapeutic use

Domaines: Cancer

M. Beau-Faller, N. Prim, A. M. Ruppert, I. Nanni-Metellus, R. Lacave, et al.. Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Annals of Oncology, 2014, 25, pp.126--31. ⟨10.1093/annonc/mdt418⟩. ⟨hal-02181347⟩