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Lung Cancer

Understanding the New Genetics of Responsiveness to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Department of Hematology-Oncology, Istituto Clinico Humanitas, Rozzano, Italy

Key Words. Epidermal growth factor receptor • Tyrosine kinase inhibitors • Gefitinib • Erlotinib • Non-small cell lung cancer

Correspondence: Federico Cappuzzo, M.D., Istituto Clinico Humanitas IRCCS, via Manzoni 56, 20086 Rozzano, Italy. Telephone: +39 (0)2 82248224; Fax: +39-02-82244590; e-mail: federico.cappuzzo{at}humanitas.it

The epidermal growth factor receptor (EGFR) is implicated in cancer progression and development and, being overexpressed in a variety of human malignancies, is an attractive target for selective anticancer therapy. EGFR tyrosine kinase inhibitors (TKIs) have been demonstrated to produce dramatic and durable responses in a fraction of non-small cell lung cancer patients. During the last few years, clinical and biological predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history seemed the most critical factor, probably because of the different spectrum of molecular abnormalities associated with cigarette-smoking exposure. Among biological predictors, several studies indicate that EGFR mutations and increased EGFR gene copy number are implicated in response to TKI therapy, with conflicting results in survival. Mutations in the EGFR gene as well as in K-ras and HER2 genes seemed to impair TKI effects, leading to TKI resistance. Because most available data come from retrospective studies, there is an urgent need to validate these results in prospective trials. Several studies have been recently completed, and these data could indicate how to properly select patients who are candidates for TKI therapy.

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