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

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• 作者：Sandra Gottschling^a ; ^{sandra.gottschling@thoraxklinik-heidelberg.de} ; Esther Herpel^b ; Wilfried E.E. Eberhardt^c ; David F. Heigener^d ; Jü ; rgen R. Fischer^e ; Claus-Henning K&ouml ; hne^f ; Cornelius Kortsik^g ; Thomas Kuhnt^h ; Thomas Muleyⁱ ; Michael Meisterⁱ ; Helge G. Bischoff^a ; Peter Klein^j ; Ines Moldenhauer^k ; Philipp A. Schnabel^b ; Michael Thomas^a ; Roland Penzel^b
• 关键词：Non-small cell lung cancer ; Epidermal growth factor receptor tyrosine kinase inhibitor ; Long-term response ; Biomarker ; Cancer stem-like cell
• 刊名：Lung Cancer
• 出版年：2012
• 期刊代码：187_01695002
• 类别：med
• 出版时间：July, 2012
• 卷：77
• 期：1
• 页码：183-191
• 文件大小：1175 K

摘要

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 鈮?0%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 鈮? 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.