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DOI: 10.1055/s-2007-959174
Erfolgreiche individualisierte zielgerichtete Gefitinib-Therapie beim NSCLC nach prädiktiver Mutationsanalyse des EGF Rezeptors
Successful Individualized and Targeted Therapy of an NSCLC Patient with Gefitinib Based on a Predictive Assessment of the EGF-Receptor Mutation StatusPublikationsverlauf
eingereicht 19.10.2006
akzeptiert 10.1.2007
Publikationsdatum:
24. April 2007 (online)
Zusammenfassung
Hintergrund: Molekulare Veränderungen in der Tyrosinkinase- (TK) Domäne des menschlichen epidermalen Wachstumsfaktor-Rezeptors (EGFR) korrelieren beim Nicht-kleinzelligen Lungenkarzinom (NSCLC) nach Behandlung mit dem TK-Inhibitor Gefinitib mit einer Tumorremission. Wir haben retrospektiv den Zusammenhang zwischen dem Auftreten von Mutationen im EGFR und einer klinischen Response untersucht. Aufgrund dieser Ergebnisse haben wir eine prospektive molekulare Analyse als Grundlage für die Behandlung einer Patientin durchgeführt. Methode: Unter 62 in einem Expanded Access Programm mit Gefitinib behandelten Patienten wurden bei 11 Patienten (10 Responder, 1 Nonresponder) Mutationsanalysen des EGFR durchgeführt. Ergebnisse: Aktivierende Mutationen wurden bei 8 von 11 Proben nachgewiesen (Punktmutationen in den Exons 18 und 21, Deletionen im Exon 19). Alle molekularen Veränderungen betrafen Adeno- oder bronchioloalveoläre Karzinome. Zwei männliche Responder mit Plattenepithelkarzinomen zeigten Wildtypsequenz oder trugen eine Nonsense-Mutation. Bei einer Patientin zeigte sich nach prospektiver EGFR Mutationsanalyse eine Tumorremission nach Behandlung mit Gefitinib, sodass die Analyse als prädiktiv angesehen werden kann. Schlussfolgerungen: Das Auftreten der Mutationen in der TK-Domäne des EGFR korrelierte mit der Kontrolle des Tumorwachstums. Deshalb kann die prospektive Untersuchung des EGFR Mutationsstatus bei der Entscheidung für eine Behandlung mit Gefitinib in bestimmten Fällen hilfreich sein. Gleichwohl können Patienten mit Wildtypsequenz im EGFR ebenfalls auf Gefitinib ansprechen.
Abstract
Background: Molecular alterations in the tyrosine kinase (TK) domain of the human epidermal growth factor receptor (EGFR) have been correlated with tumour remission upon treatment with the TK inhibitor Gefitinib in non-small cell lung cancer (NSCLC). We have retrospectively investigated the correlation of point mutations with clinical response and, based on our retrospective results, used predictive molecular assessment as the basis for treatment in one patient. Methods: Mutational analysis was performed in 11 NSCLC-patients (10 responders, 1 non-responder) among 62 patients treated with Gefitinib within an expanded access program. Results: Activating molecular alterations were found in 8/11 investigated samples (point mutations in exons 18 and 21, deletions in exon 19). All molecular changes were found in adenocarcinoma or bronchioloalveolar carcinoma. The tumours of two male responders with squamous cell carcinoma showed either a wild-type sequence or carried a nonsense mutation. In one patient treatment with Gefitinib after prospective assessment of mutations resulted in tumour remission and thus proved to be predictive. Conclusions: Mutations in the EGFR TK domain correlate with the clinical response to Gefitinib. The predictive assessment of molecular alterations may thus be helpful for treatment decisions in selected cases. A clinical response to Gefitinib is nevertheless also found in patients with wild-type EGFR.
Literatur
- 1 Ritter C A, Arteaga C A. The epidermal growth factor receptor kinase: a promising therapeutic target in solid tumors. Sem Oncol. 2003; 30 S1 3-11
- 2 Baselga J, Arteaga C L. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol. 2005; 23 2445-2459
- 3 Giaccone G. Epidermal growth factor receptor inhibitiors in the treatment of non-small cell lung cancer. J Clin Oncol. 2005; 23 3235-3242
- 4 Pastorino U, Andreola S, Tagliabue E. et al . Immunocytochemical markers in stage I lung cancer: relevance to prognosis. J Clin Oncol. 1997; 15 2858-2865
- 5 Fontanini G, Vignati S, Bigini D. et al . Epidermal growth factor recptor (EGFr) expression in non-small cell lung carcinomas correlates with metastatic involvement of hilar and mediastinal lymph nodes in the squamous subtype. Eur J Cancer. 1995; 31A 178-183
- 6 Volm M, Koomagi R, Mattern J. et al . Expression profile of genes in NSCLC from long-term surviving patients. Clin Cancer Res. 2002; 8 1843-1848
- 7 Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res. 2001; 7 2958-2970
- 8 Bell D W, Lynch T J, Haserlat S M. et al . Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol. 2005; 23 8081-8092
- 9 Miller V A, Kris M G, Shah N. et al . Bronchioloalvelar pathologic subtype and smoking history predict sensitivity to gefinitib in advanced non-small-cell lung cancer. J Clin Oncol. 2004; 22 1103-1109
- 10 Paez J G, Jänne P A, Lee J C. et al . EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304 1497-1500
- 11 Lynch T J, Bell D W, Sordella R. et al . Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small cell lung cancer to Gefitinib. N Engl J Med. 2004; 350 29-39
- 12 Pao W, Miller V, Zakowski M. et al . EGF receptor gene mutations are common in lung cancer from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004; 101 13 306-13 311
- 13 Huang S F, Liu H P, Li L H. et al . High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan. Clin Cancer Res. 2004; 10 8195-8203
- 14 Shigematsu H, Lin L, Takahashi T. et al . Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst. 2005; 97 339-346
- 15 Marchetti A, Martella C, Felicioni L. et al . EGFR mutations in non-small cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol. 2005; 23 857-865
- 16 Taron M, Ichinose Y, Rosell R. et al . Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in Gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res. 2005; 11 5878-5885
- 17 Eberhard D A, Johnson E J, Amler L C. et al . Mutations in the epidermal growth factor receptor and KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and combination with erlotinib. J Clin Oncol. 2005; 23 5900-5909
- 18 Tsao M S, Sakurada A, Cutz J C. et al . Erlotinib in lung cancer - molecular and clinical predictors of outcome. New Engl J Med. 2004; 353 133-144
- 19 Sordella R, Bell D W, Haber D A. et al . Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science. 2004; 305 1163-1167
- 20 Tracy S, Mukohara S, Hansen M. et al . Gefitinib induces apoptosis in the EGFR L858R non-small cell lung cancer cell line H3255. Cancer Res. 2004; 64 7241-7244
- 21 Pao W, Miller V A, Politi K A. et al . Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005; 2 e73
- 22 Kobayashi S, Boggon T J, Dayaram T. et al . EGFR mutation and resistance of non-small cell lung cancer to gefitinib. New Engl J Med. 2005; 352 786-792
- 23 Sasaki H, Shimizu S, Endo K. et al . EGFR and ErbB2 mutation status in Japanese lung cancer patients. Int J Cancer. 2006; 118 180-184
- 24 Cappuzzo F, Hirsch F R, Rossi E. et al . Epidermal growth factor receptor gene and protein and Gefitinib sensitivity in Non-Small-Cell Lung Cancer. J Natl Cancer Inst. 2005; 9 643-655
- 25 Hirsch F R, Varella-Garcia M, McCoy J. et al . Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: a southwest oncology group study. J Clin Oncol. 2005; 28 6838-6845
- 26 Cappuzzo F, Magrini E, Ceresoli G L. et al . Akt phosphorylation and gefitinib efficacy in patients with advanced non-small cell lung cancer. J Natl Cancer Inst. 2004; 96 1133-1141
- 27 Amador M L, Oppenheimer D, Perea S. et al . An epidermal growth factor receptor intron 1 polymorphism mediates response to epidermal growth factor receptor inhibitors. Cancer Res. 2004; 64 9139-9143
- 28 Pao W, Wang T Y, Riely G J. et al . KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PloS Med. 2005; 2 e17
PD Dr. Jürgen R. Fischer
Medizinische Klinik II Onkologie Klinik Löwenstein gGmbH
Im Geisshölzle 62
74245 Löwenstein
eMail: jr.fischer@klinik-loewenstein.de