The role of IGF-1R in EGFR TKI resistance in NSCLC using IHC and AQUA technology

10556 Background: Epidermal growth factor receptor (EGFR) mutations predict benefit from EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC), however, only 70-80% will respond. Ultimately, all patients (pts) develop drug resistance. The insulin-like growth factor-1 (IGF-1) pathway may have a role in EGFR TKI resistance. We assessed IGF-1R protein expression and its association to progressive disease (PD) and outcome in EGFR TKI treated NSCLC pts using immunohistochemistry (IHC) and automated quantitative fluorescence analysis technology (AQUA). Methods: IGF-1R protein expression (Ventana Medical Systems, Inc, Tucson, AZ) was analyzed in 98 and 70/98 gefitinib-treated Japanese NSCLC pts, respectively, with IHC and AQUA (HistoRx Inc, New Haven, CT). IHC scoring was performed with the H-scoring method evaluating membrane or cytoplasm only and membrane + cytoplasm. Results: IGF-1R expression was significantly higher in pts with PD vs disease control (CR+PR+SD) using any method of assessment. Using ROC curve analyses, the best discrimination of PD vs DC was obtained with IHC scoring of membrane + cytoplasm and a cutoff of 165, with an accuracy of 72%, sensitivity and specificity of 68% and 73% with an area under the curve of 0.75 (p=0.0006). Overall survival (OS) from gefitinib was worse in pts with high IGF-1R using cutoff 165 (median 14.7 vs 29.1 months (ms), p=0.0175) or by an arbitrary cutoff of 40 (16.2 vs 43.6 ms, p=0.0138). Progression free survival (PFS) was shorter in high IGF-1R pts with a 165 (4.6 vs 12.0 ms, p=0.0065) or 40 cutoff (8.7 vs 28.7 ms, p=0.0296). Prediction of PD and shorter PFS by high IGF-1R IHC membrane + cytoplasm scoring remained significant in the adenocarcinomas (n=78) and EGFR mutations (n=49) subgroups. High IGF-1R expression evaluated by AQUA was also predictive of PD (p=0.033) and shorter PFS (p=0.0496) in a 70 pt subset. Conclusions: High IGF-1R protein expression, evaluated both by IHC and AQUA, predicted primary resistance to gefitinib therapy in NSCLC and was associated with worse OS and shorter PFS. Thus, IGF-1R protein expression appears to be a clinically relevant biomarker to identify NSCLC pts with intrinsic EGFR TKI resistance, even in pts having EGFR mutations.