Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease

Abstract

Purpose: EGFR-mutant lung cancer was first described as a new clinical entity in 2004. Here, we present an update on new controversies and conclusions regarding the disease.

Methods: This article reviews the clinical implications of EGFR mutations in lung cancer with a focus on epidermal growth factor receptor tyrosine kinase inhibitor resistance.

Results: The discovery of EGFR mutations has altered the ways in which we consider and treat non-small-cell lung cancer (NSCLC). Patients whose metastatic tumors harbor EGFR mutations are expected to live longer than 2 years, more than double the previous survival rates for lung cancer.

Conclusion: The information presented in this review can guide practitioners and help them inform their patients about EGFR mutations and their impact on the treatment of NSCLC. Efforts should now concentrate on making EGFR-mutant lung cancer a chronic rather than fatal disease.

Fig 1.

Distribution of EGFR mutations in lung cancer. Schematic of the kinase domain of epidermal growth factor receptor showing exons 18 to 21. Activating drug-sensitive mutations are shown on the top, and tyrosine kinase inhibitor (TKI) –resistant mutations are depicted on the bottom (red: acquired resistant mutations). The most common activating mutations in EGFR are a point mutation in exon 21, which substitutes an arginine for a leucine (L858R), and a small deletion in exon 19 that removes four amino acids (LREA). Together, these account for approximately 85% of the TKI-sensitive mutations observed in EGFR-mutant tumors. Many rare mutations have also been reported.

Fig 2.

Impact of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on survival in patients with lung cancers harboring EGFR mutations. (A) The graph depicts the overall survival (OS) rates achieved in various prospective trials conducted in the United States/Europe (left panel) and East Asia (right panel) before and after the introduction of EGFR TKIs. After 2006, OS was consistently longer than 18 months in patients with EGFR-mutant tumors.^, Five trials^–,, were conducted in unselected patients with non–small-cell lung cancer (NSCLC), and the other trials were performed in patients with EGFR-mutant tumors.^,, One trial was for never- or light former smokers; the OS data were from the subgroup of patients with EGFR-mutated lung cancers treated with erlotinib. (B) Age-adjusted 12-month survival rates in patients with metastatic NSCLC in the SEER database. The rate increases especially in the Asian population from 2003 to 2004 onward. The thick lines are the trends for the years 1998 to 2003, and the thin lines are the predicted improvement in 12-month survival, given the 1998 to 2003 trends. (C) Age-adjusted incidence and prevalence (per 100,000 people in the United States) of NSCLC in the SEER database. The incidence decreases starting from 2002, whereas the prevalence displays a small increase. (A to C) Arrows indicate years in which drugs were approved.

Fig 3.

Schematic representation of the epidermal growth factor receptor (EGFR) signaling pathway and molecules that may affect drug resistance. Gold star indicates mutations in EGFR. Red star indicates genes found to be mutated in tumor samples from patients with acquired resistance to EGFR tyrosine kinase inhibitors. HGF, hepatocyte growth factor; mTOR, mammalian target of rapamycin.

Fig 4.

Mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Multiple mechanisms have been elucidated in human samples and preclinical models. Some factors may overlap. HGF, hepatocyte growth factor; IL-6, interleukin-6.