The gefitinib long-term responder (LTR) - a cancer stem-like cell story?

• Verfasst von: Gottschling, Sandra [VerfasserIn]
• Verfasst von: Herpel, Esther [VerfasserIn]
• Verfasst von: Eberhardt, Wilfried E. E. [VerfasserIn]
• Verfasst von: Köhne, Claus-Henning [VerfasserIn]
• Verfasst von: Kuhnt, Thomas [VerfasserIn]
• Verfasst von: Muley, Thomas [VerfasserIn]
• Verfasst von: Meister, Michael [VerfasserIn]
• Verfasst von: Bischoff, Helge [VerfasserIn]
• Verfasst von: Schnabel, Philipp Albert [VerfasserIn]
• Verfasst von: Thomas, Michael [VerfasserIn]
• Verfasst von: Penzel, Roland [VerfasserIn]
• Titel: The gefitinib long-term responder (LTR) - a cancer stem-like cell story?
• Titelzusatz: Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP)
• Verf.angabe: Sandra Gottschling, Esther Herpel, Wilfried E. E. Eberhardt, David F. Heigener, Jürgen R. Fischer, Claus-Henning Köhne, Cornelius Kortsik, Thomas Kuhnt, Thomas Muley, Michael Meister, Helge G. Bischoff, Peter Klein, Ines Moldenhauer, Philipp A. Schnabel, Michael Thomas, Roland Penzel
• E-Jahr: 2012
• Jahr: July 2012
• Umfang: 9 S.
• Fussnoten: Gesehen am 17.04.2018
• Titel Quelle: Enthalten in: Lung cancer
• Ort Quelle: Amsterdam [u.a.] : Elsevier, 1985
• Jahr Quelle: 2012
• Band/Heft Quelle: 77(2012), 1, Seite 183-191
• ISSN Quelle: 1872-8332
• DOI: doi:10.1016/j.lungcan.2012.03.003
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Biomarker
• Sach-SW: Cancer stem-like cell
• Sach-SW: Long-term response
• Sach-SW: Non-small cell lung cancer
• Sach-SW: tyrosine kinase inhibitor
• K10plus-PPN: 1572070404

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.