title: First-line therapy and methylation status of CHFR in serum influence outcome to chemotherapy versus EGFR tyrosine kinase inhibitors as second-line therapy in stage IV non-small-cell lung cancer patients.
abstract: The potential differential effect of first-line treatment and molecular mechanisms on survival to second-line chemotherapy or EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) has not been fully investigated. In particular, CHFR is frequently methylated in NSCLC and may influence outcome. We analyzed the outcome of second-line chemotherapy or EGFR TKIs in 179 of 366 patients who had been treated in an ERCC1 mRNA-based customized cisplatin trial and correlated the results with CHFR methylation status. CHFR methylation in circulating DNA was examined by methylation-specific assay. A panel of seven human EGFR wild-type NSCLC cell lines was characterized for their sensitivity to sequential treatment with cisplatin and erlotinib, and the results were correlated with CHFR. Patients who had received first-line docetaxel/cisplatin attained an overall survival of 19.2 months when treated with second-line EGFR TKIs, in comparison with 10.7 months when treated with second-line chemotherapy (P = 0.0002). However, for patients who had received first-line docetaxel/gemcitabine, overall survival was 14.8 months with EGFR TKIs and 10.8 months with chemotherapy (P = 0.29). For patients with unmethylated CHFR overall survival to EGFR TKIs was 21.4 months, and 11.2 months for those with treated with chemotherapy (P = 0.0001). In the only lung tumor cell line not expressing CHFR, pretreatment with cisplatin was antagonistic to erlotinib, while it was synergistic in the other six lines. Second-line EGFR TKIs improved survival in patients receiving first-line cisplatin-based treatment. Unmethylated CHFR predicts increased survival to EGFR TKIs.
authors: Catalan Institute of Oncology, Badalona, Spain.
authors: Fernanda
authors: F
authors: Salazar
authors: Miguel Angel
authors: MA
authors: Molina
authors: Maria
authors: M
authors: Sanchez-Ronco
authors: Teresa
authors: T
authors: Moran
authors: Jose Luis
authors: JL
authors: Ramirez
authors: Jose Miguel
authors: JM
authors: Sanchez
authors: Rolf
authors: R
authors: Stahel
authors: Pilar
authors: P
authors: Garrido
authors: Manuel
authors: M
authors: Cobo
authors: Dolores
authors: D
authors: Isla
authors: Jordi
authors: J
authors: Bertran-Alamillo
authors: Bartomeu
authors: B
authors: Massuti
authors: Felipe
authors: F
authors: Cardenal
authors: Christian
authors: C
authors: Manegold
authors: Pilar
authors: P
authors: Lianes
authors: Jose Manuel
authors: JM
authors: Trigo
authors: Jose Javier
authors: JJ
authors: Sanchez
authors: Miquel
authors: M
authors: Taron
authors: Rafael
authors: R
authors: Rosell
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008745:Methylation; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D000075223:Poly-ADP-Ribose Binding Proteins; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C412002:CHFR protein, human; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; D002945:Cisplatin