original articles 19. Bendell JC, Meluch A, Peyton J et al. A phase II trial of preoperative concurrent chemotherapy/radiation plus bevacizumab/erlotinib in the treatment of localized esophageal cancer. Clin Adv Hematol Oncol 2012; 10: 430–437. 20. Dias-Santagata D, Akhavanfard S, David SS et al. Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine. EMBO Mol Med 2010; 2: 146–158. 21. Roh MS, Colangelo LH, O’Connell MJ et al. Preoperative multimodality therapy improves disease-free survival in patients with carcinoma of the rectum: NSABP R03. J Clin Oncol 2009; 27: 5124–5130. 22. Aschele C, CIonini L, Lonardi S et al. Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol 2011; 29: 2773–2780. 23. Gerard JP, Azria D, Gourgou-Bourgade S et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige2. J Clin Oncol 2010; 28: 1638–1644. 24. Kennecke H, Berry S, Wong R et al. Preoperative bevacizumab, capecitabine, oxaliplatin and radiation among patients with locally advanced or low rectal cancer. Eur J Cancer 2012; 48: 37–45.
Annals of Oncology 25. Valentini V, De Paoli A, Gambacorta MA et al. Infusional 5-fluorouracil and ZD1839 (Gefininib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II trial (1839IL/0092). Int J Radiat Oncol Biol Phys 2008; 72: 644–649. 26. Czito BG, Willett CG, Bendal JC et al. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J Clin Oncol 2006; 24: 656–662. 27. Van Triest B, Kuenen B, Ghotra V et al. Feasibility study of erlotinib plus radiotherapy in patients with locally advanced or recurrent rectal carcinoma. Int J Radiat Oncol Biol Phys. 2008; 72: 69s (suppl: abstr 153). 28. Tournigand C, Samson B, Sheithauer W et al. Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients ( pts) with metastatic colorectal cancer (mCRC): efficacy and safety result so of the international GERCOR DREAM phase III trial. J Clin Oncol 2012; 30 (suppl;abstr LBA3500). 29. Roh MS, Yothers GA, O’Connell MJ et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin Oncol 2011; 29 (suppl;abstr 3503).
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-Faller1,2,3*, N. Prim4,5, A.-M. Ruppert3,6,7, I. Nanni-Metéllus8, R. Lacave9, L. Lacroix10, F. Escande11, S. Lizard12, J.-L. Pretet13, I. Rouquette14, P. de Crémoux15, J. Solassol16, F. de Fraipont17, I. Bièche18, A. Cayre19, E. Favre-Guillevin20, P. Tomasini21, M. Wislez3,6,7, B. Besse3,22, M. Legrain1, A.-C. Voegeli1, L. Baudrin3, F. Morin3, G. Zalcman3,23, E. Quoix3,4, H. Blons24 & J. Cadranel3,6,7 1 Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, Strasbourg; 2Research Unit EA 3430 and Translational Medicine Federation, Strasbourg University, Strasbourg; 3French Thoracic Intergroup (IFCT), Paris; 4Department of Chest, Strasbourg University Hospital, Strasbourg; 5EA 4438 and Translational Medicine Federation, Strasbourg University, Strasbourg; 6Department of Chest, Tenon University Hospital, AP-HP, Paris; 7GRC Theranoscan, P&M Curie University, Paris; 8Department of Biochemistry and Molecular Biology, Marseille University Hospital, Marseille; 9Department of Biochemistry and Molecular Biology, Tenon University Hospital, Paris; 10Department of Biochemistry and Molecular Biology, Gustave-Roussy Institute, Villejuif; 11Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille; 12Department of Biochemistry and Molecular Biology, GF Leclerc Center, Dijon; 13Department of Biochemistry and Molecular Biology, Besançon University Hospital, Besançon; 14Department of Pathology, Toulouse University Hospital, Toulouse; 15Department of Biochemistry and Molecular Biology, Curie Institute, Paris; 16Department of Biochemistry and Molecular Biology, Montpellier University Hospital, Montpellier; 17Department of Biochemistry and Molecular Biology, Grenoble University Hospital, Grenoble; 18Department of Biochemistry and Molecular Biology, René Huguenin Center, Saint-Cloud; 19Department of Biochemistry and Molecular Biology, Clermont-Ferrand University Hospital, Clermont-Ferrand; 20Department of Chest, Georges Pompidou European Hospital, Paris; 21Department of Chest, Marseille University Hospital, Marseille; 22Department of Chest, Gustave-Roussy Institute, Villejuif; 23Department of Chest, Caen University Hospital, Caen; 24Department of Biochemistry and Molecular Biology, Georges Pompidou European Hospital, Paris, France
Received 15 February 2013; revised 21 August 2013; accepted 2 September 2013
Background: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations.
*Correspondence to: Dr Michelle Beau-Faller, Molecular Biology Laboratory, Strasbourg University Hospital, 1, avenue Molière, 67098 Strasbourg, France. Tel: +33-1-12-84-57; Fax: +33-1-12-75-35; E-mail: [email protected]
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Seton Hall on September 25, 2014
Annals of Oncology 25: 126–131, 2014 doi:10.1093/annonc/mdt418 Published online 26 November 2013
original articles
Annals of Oncology
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 < 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. Key words: epidermal growth factor receptor mutations, exon 18 mutations, exon 20 mutations, non-small-cell lung cancer, tyrosine-kinase inhibitors
In 2004, identification of somatic mutations in the epidermal growth factor receptor (EGFR) provided a clinically relevant driver oncogene of non-small-cell lung cancer (NSCLC) [1–3]. About 10%–15% of all NSCLC in Western Europeans and 30% in East Asians are EGFR mutated. The most common (85%– 90%) EGFR mutations are in-frame deletions around the LeuArgGluAla motifs (LREA residues 746–750) of exon 19 (45%–50%) and the Leu858Arg (L858R) substitution in exon 21 (40%–45%) [4]. They result in the preferential binding of EGFR tyrosine kinase inhibitors (TKIs), i.e., gefitinib, erlotinib, or afatinib, leading to >60% overall response rates (ORR), median progression-free survival (PFS) >9 months, and overall survival (OS) of >20 months, better than with chemotherapy [5–10]. Epidemiological data, correlations with clinical characteristics, EGFR-TKI response, and prognostic value remain unclear in NSCLC cases with uncommon EGFR mutations [11–19]. Therefore, the ERMETIC-IFCT network decided to report its results of EGFR exon 18 and 20 mutations based on 10 117 analyses carried out between 2008 and 2011 [20].
methods centres and molecular analysis Centres and technics are detailed in supplementary data, available at Annals of Oncology online [21, 22] (supplementary Table S1, available at Annals of Oncology online). Rare EGFR mutations were defined as mutations at exon 18 and/or 20; complex mutations were defined as mutations at more than one exon: double mutation at exon 18 and 20 or one mutation at exon 18 or 20 with one mutation in another exon (19 or 21) and were compared with COSMIC (Catalog of Somatic Mutations in Cancer) [23], somaticmutationsEGFR.org [4] and PubMed.
clinical data French National Cancer Institute [24] required that clinical data be collected for testing, such as demographic information, clinical staging [25], and lung cancer histology (WHO classification) [26]. Never smokers were defined as
Annals of Oncology 25. Valentini V, De Paoli A, Gambacorta MA et al. Infusional 5-fluorouracil and ZD1839 (Gefininib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II trial (1839IL/0092). Int J Radiat Oncol Biol Phys 2008; 72: 644–649. 26. Czito BG, Willett CG, Bendal JC et al. Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J Clin Oncol 2006; 24: 656–662. 27. Van Triest B, Kuenen B, Ghotra V et al. Feasibility study of erlotinib plus radiotherapy in patients with locally advanced or recurrent rectal carcinoma. Int J Radiat Oncol Biol Phys. 2008; 72: 69s (suppl: abstr 153). 28. Tournigand C, Samson B, Sheithauer W et al. Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients ( pts) with metastatic colorectal cancer (mCRC): efficacy and safety result so of the international GERCOR DREAM phase III trial. J Clin Oncol 2012; 30 (suppl;abstr LBA3500). 29. Roh MS, Yothers GA, O’Connell MJ et al. The impact of capecitabine and oxaliplatin in the preoperative multimodality treatment in patients with carcinoma of the rectum: NSABP R-04. J Clin Oncol 2011; 29 (suppl;abstr 3503).
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-Faller1,2,3*, N. Prim4,5, A.-M. Ruppert3,6,7, I. Nanni-Metéllus8, R. Lacave9, L. Lacroix10, F. Escande11, S. Lizard12, J.-L. Pretet13, I. Rouquette14, P. de Crémoux15, J. Solassol16, F. de Fraipont17, I. Bièche18, A. Cayre19, E. Favre-Guillevin20, P. Tomasini21, M. Wislez3,6,7, B. Besse3,22, M. Legrain1, A.-C. Voegeli1, L. Baudrin3, F. Morin3, G. Zalcman3,23, E. Quoix3,4, H. Blons24 & J. Cadranel3,6,7 1 Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, Strasbourg; 2Research Unit EA 3430 and Translational Medicine Federation, Strasbourg University, Strasbourg; 3French Thoracic Intergroup (IFCT), Paris; 4Department of Chest, Strasbourg University Hospital, Strasbourg; 5EA 4438 and Translational Medicine Federation, Strasbourg University, Strasbourg; 6Department of Chest, Tenon University Hospital, AP-HP, Paris; 7GRC Theranoscan, P&M Curie University, Paris; 8Department of Biochemistry and Molecular Biology, Marseille University Hospital, Marseille; 9Department of Biochemistry and Molecular Biology, Tenon University Hospital, Paris; 10Department of Biochemistry and Molecular Biology, Gustave-Roussy Institute, Villejuif; 11Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille; 12Department of Biochemistry and Molecular Biology, GF Leclerc Center, Dijon; 13Department of Biochemistry and Molecular Biology, Besançon University Hospital, Besançon; 14Department of Pathology, Toulouse University Hospital, Toulouse; 15Department of Biochemistry and Molecular Biology, Curie Institute, Paris; 16Department of Biochemistry and Molecular Biology, Montpellier University Hospital, Montpellier; 17Department of Biochemistry and Molecular Biology, Grenoble University Hospital, Grenoble; 18Department of Biochemistry and Molecular Biology, René Huguenin Center, Saint-Cloud; 19Department of Biochemistry and Molecular Biology, Clermont-Ferrand University Hospital, Clermont-Ferrand; 20Department of Chest, Georges Pompidou European Hospital, Paris; 21Department of Chest, Marseille University Hospital, Marseille; 22Department of Chest, Gustave-Roussy Institute, Villejuif; 23Department of Chest, Caen University Hospital, Caen; 24Department of Biochemistry and Molecular Biology, Georges Pompidou European Hospital, Paris, France
Received 15 February 2013; revised 21 August 2013; accepted 2 September 2013
Background: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations.
*Correspondence to: Dr Michelle Beau-Faller, Molecular Biology Laboratory, Strasbourg University Hospital, 1, avenue Molière, 67098 Strasbourg, France. Tel: +33-1-12-84-57; Fax: +33-1-12-75-35; E-mail: [email protected]
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
Downloaded from http://annonc.oxfordjournals.org/ at Seton Hall on September 25, 2014
Annals of Oncology 25: 126–131, 2014 doi:10.1093/annonc/mdt418 Published online 26 November 2013
original articles
Annals of Oncology
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 < 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. Key words: epidermal growth factor receptor mutations, exon 18 mutations, exon 20 mutations, non-small-cell lung cancer, tyrosine-kinase inhibitors
In 2004, identification of somatic mutations in the epidermal growth factor receptor (EGFR) provided a clinically relevant driver oncogene of non-small-cell lung cancer (NSCLC) [1–3]. About 10%–15% of all NSCLC in Western Europeans and 30% in East Asians are EGFR mutated. The most common (85%– 90%) EGFR mutations are in-frame deletions around the LeuArgGluAla motifs (LREA residues 746–750) of exon 19 (45%–50%) and the Leu858Arg (L858R) substitution in exon 21 (40%–45%) [4]. They result in the preferential binding of EGFR tyrosine kinase inhibitors (TKIs), i.e., gefitinib, erlotinib, or afatinib, leading to >60% overall response rates (ORR), median progression-free survival (PFS) >9 months, and overall survival (OS) of >20 months, better than with chemotherapy [5–10]. Epidemiological data, correlations with clinical characteristics, EGFR-TKI response, and prognostic value remain unclear in NSCLC cases with uncommon EGFR mutations [11–19]. Therefore, the ERMETIC-IFCT network decided to report its results of EGFR exon 18 and 20 mutations based on 10 117 analyses carried out between 2008 and 2011 [20].
methods centres and molecular analysis Centres and technics are detailed in supplementary data, available at Annals of Oncology online [21, 22] (supplementary Table S1, available at Annals of Oncology online). Rare EGFR mutations were defined as mutations at exon 18 and/or 20; complex mutations were defined as mutations at more than one exon: double mutation at exon 18 and 20 or one mutation at exon 18 or 20 with one mutation in another exon (19 or 21) and were compared with COSMIC (Catalog of Somatic Mutations in Cancer) [23], somaticmutationsEGFR.org [4] and PubMed.
clinical data French National Cancer Institute [24] required that clinical data be collected for testing, such as demographic information, clinical staging [25], and lung cancer histology (WHO classification) [26]. Never smokers were defined as
