title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  LTRs display established properties of EGFR-TKI responders. Antigens characterizing CSC might identify a fraction of LTRs and matter of interest for further evaluation.
authors.affiliation: Department of Thoracic Oncology, Thoraxklinik/University of Heidelberg, Amalienstr 5, 69126 Heidelberg, Germany. sandra.gottschling@thoraxklinik-heidelberg.de
authors.forename: Sandra
authors.initials: S
authors.lastname: Gottschling
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.forename: Wilfried E E
authors.initials: WE
authors.lastname: Eberhardt
authors.forename: David F
authors.initials: DF
authors.lastname: Heigener
authors.forename: Jürgen R
authors.initials: JR
authors.lastname: Fischer
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: Cornelius
authors.initials: C
authors.lastname: Kortsik
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuhnt
authors.forename: Thomas
authors.initials: T
authors.lastname: Muley
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.forename: Helge G
authors.initials: HG
authors.lastname: Bischoff
authors.forename: Peter
authors.initials: P
authors.lastname: Klein
authors.forename: Ines
authors.initials: I
authors.lastname: Moldenhauer
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Schnabel
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
mesh_terms: D000071916:AC133 Antigen; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D000077156:Gefitinib; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use*; D017741:Survivors; D018631:ras Proteins / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D000071916:AC133 Antigen; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006023:Glycoproteins; C117307:KRAS protein, human; C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606025:Prom1 protein, rat; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib