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.
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.
Salazar
Fernanda
F
Catalan Institute of Oncology, Badalona, Spain.
Molina
Miguel Angel
MA
Sanchez-Ronco
Maria
M
Moran
Teresa
T
Ramirez
Jose Luis
JL
Sanchez
Jose Miguel
JM
Stahel
Rolf
R
Garrido
Pilar
P
Cobo
Manuel
M
Isla
Dolores
D
Bertran-Alamillo
Jordi
J
Massuti
Bartomeu
B
Cardenal
Felipe
F
Manegold
Christian
C
Lianes
Pilar
P
Trigo
Jose Manuel
JM
Sanchez
Jose Javier
JJ
Taron
Miquel
M
Rosell
Rafael
R
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
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