Erfolgreiche individualisierte zielgerichtete Gefitinib-Therapie beim NSCLC nach prädiktiver Mutationsanalyse des EGF Rezeptors

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.

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