Utility of insulin-like growth factor receptor-1 expression in gefitinib-treated patients with non-small cell lung cancer.

Background: Insulin-like growth factor receptor 1 (IGF1R) is a proposed mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Newer agents targeting this pathway make it of clinical interest. This study evaluates the IGF1R expression in regard to outcomes and molecular markers of EGFR activity in lung cancer patients treated with gefitinib. Materials and Methods: Gefitinib-treated patients with sufficient archived tissue were included. The IGF1R activity was measured by immunohistochemistry and the EGFR by immuno- histochemistry, fluorescent in situ hybridization, and gene mutation testing. Logistic regression and cox proportional hazards models were used. Results: A total of 83 patients were included in the study: 71% were positive for IGF1R expression which was not associated with EGFR parameters or clinical outcomes. Exploratory analyses showed counter- intuitive improved outcomes with co-expression of IGF1R and EGFR. Conclusion: IGF1R expression measured by immunohistochemistry does not appear to be related to gefitinib resistance. Initial phase II trials testing epidermal growth factor receptor tyrosine kinases (EGFR-TKIs) gefitinib and erlotinib, showed objective responses in approximately 10% of patients with non-small cell lung cancer (NSCLC) (1, 2). Subsequently, superior survival was observed with erlotinib in unselected, previously treated patients with NSCLC, and gefitinib was associated with better progression-free survival as well as a trend for longer overall survival (3, 4). EGFR- activating mutations have emerged as important predictors for progression-free survival and response in previously untreated patients with advanced NSCLC (5). Although present in about half of non-smoking-related NSCLCs, the prevalence of activating EGFR mutations in North America and Europe, overall, is only approximately 10% (6). In the phase III trials of gefitinib and erlotinib, however, disease stabilization was observed in approximately 35% of patients with NSCLC treated with an EGFR-TKI, benefiting many EGFR gene mutation-negative patients (3, 4). Molecular profiles that could identify patients most likely to have disease stabilization or rapid progression on EGFR- TKIs would be beneficial by bringing more effective therapies earlier in the treatment course of such patients. The insulin- like growth factor receptor 1 (IGF1R) is a proposed mechanism for resistance to EGFR-TKIs (7-10). IGF1R is a transmembrane tyrosine kinase which, through its downstream signaling, controls the cell size, the growth stimulation and inhibits apoptosis (11). Activation of IGF1R and loss of IGF-binding proteins have been associated with cellular proliferation, survival, transformation, and metastasis (11-15). Recently monoclonal antibodies targeting the IGF1R and the small molecule IGF1R-TKIs have become available. The objective of our retrospective study was to evaluate the potential relationship of the IGF1R expression with the response, progression-free and overall survival in patients with advanced NSCLC treated with gefitinib. Additional objectives included the determination of the relationship of IGF1R expression with EGFR by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) with EGFR-activating mutations. Materials and Methods