The gefitinib long-term responder (LTR)—A cancer stem-like cell story? Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP)

Abstract Background In selected patients with advanced non-small cell lung cancer (NSCLC) the EGFR ( epidermal growth factor receptor ) tyrosine kinase inhibitor (TKI) gefitinib (IRESSA) shows response rates of ≥70% and a significant prolongation of progression free survival (PFS). However, cogent biomarkers predicting long-term response to EGFR -TKIs are yet lacking. Cancer stem-like cells (CSC) are thought to play a pivotal role in tumor regeneration and appear to be influenced by the EGFR -pathway. This makes them a promising candidate for predicting long-term response to EGFR -TKIs. Materials and methods We analyzed pre-therapeutic tissue specimens of a rare and specific subset of previously treated German patients with advanced NSCLC who experienced ≥3 year response to gefitinib within the International IRESSA EAP. 11/20 identified long-term responders (LTRs) had appropriate tissue specimens available. Those were analyzed for EGFR and k-ras ( Kirsten rat sarcoma ) mutations, EGFR and c-met ( met proto-oncogene ) amplifications and protein expression of EGFR , E-cadherin / vimentin and the CSC antigens CD133 and BCRP1 ( breast cancer resistance protein 1 ). The results were compared to primary resistant patients (RPs) and intermediate responders (IRs) showing a median response of 8.6 months. Results Each group consisted of 6 women and 5 men, with 1 squamous cell carcinoma (SCC) and 10 adenocarcinoma (AC). Along the LTRs, all but the SCC had EGFR mutations, whereas the RPs had no EGFR , but k-ras mutations in 5/11 cases. 8/11 IRs had EGFR and 3/11 k-ras mutations, of which 2 occurred concomitantly. One patient of each group had an EGFR and/or c-met amplification. EGFR and E-cadherin / vimentin expression was not different between the groups, whereas CD133 was expressed only in 4/10 LTRs and BCRP1 predominantly in responders. The LTRs showed a substantially longer mean PFS to previous therapies, a substantially lower number of metastatic sites and almost exclusively pulmonary or pleural metastasis. Conclusion LTRs display established properties of EGFR -TKI responders. Antigens characterizing CSC might identify a fraction of LTRs and matter of interest for further evaluation.