Associations between TS, TTF-1, FR-α, FPGS, and overall survival in patients with advanced non-small-cell lung cancer receiving pemetrexed plus carboplatin or gemcitabine plus carboplatin as first-line chemotherapy.
BACKGROUND
Pemetrexed is effective in the treatment of non-small-cell lung cancer, mainly in nonsquamous cell carcinomas. Inhibition of thymidylate synthase (TS) is considered the key mechanism of action. Folate receptor-α facilitates uptake of pemetrexed. Polyglutamation by folylpolyglutamate synthetase enhances activity and prolongs cellular retention of pemetrexed. Thyroid transcription factor-1 (TTF-1) is mainly positive in nonsquamous cell carcinoma and has been proposed as a marker for sensitivity to pemetrexed. The aim was to investigate associations between these biomarkers and survival in patients who participated in a phase III trial comparing pemetrexed plus carboplatin with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer (n = 436). In this study, there was no difference in overall survival between the two regimens.


METHODS
Formalin-fixed, paraffin-embedded biopsies were collected. Percentages of tumor cells positive and highly positive for the biomarkers were assessed using immunohistochemistry (IHC) and an IHC score was calculated (range, 0-200).


RESULTS
Two hundred thirty-six biopsies were analyzed (pemetrexed plus carboplatin: n = 114, gemcitabine plus carboplatin: n = 122). There was a significant difference in overall survival between those with TTF-1-positive and -negative tumors (10.4 versus 6.0 months; p < 0.001) and those with a low and a high TS IHC score (9.7 versus 6.2 months; p < 0.001). Folate receptor-α and folylpolyglutamate synthetase were not significant prognostic factors. In multivariate analyses adjusting for established prognostic characteristics, TS (p = 0.002) and TTF-1 (p = 0.003) remained significant. There were no differences in survival between the treatment arms depending on biomarker scores.


CONCLUSIONS
TTF-1 positivity and low TS level were associated with prolonged survival. The associations between the biomarkers and overall survival were similar for both chemotherapy regimens.
*The Cancer Clinic, St. Olavs Hospital-Trondheim University Hospital, Trondheim, Norway; †European Palliative Care Research Centre, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway; Departments of ‡Pathology, ‖Oncology, Oslo University Hospital, Oslo, Norway; and §Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Bjørn H
BH
Grønberg
Marius
M
Lund-Iversen
Erik H
EH
Strøm
Odd Terje
OT
Brustugun
Helge
H
Scott
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage; D018287:Carcinoma, Large Cell / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D058975:Folate Receptor 1 / Q000378:metabolism*; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D010453:Peptide Synthases / Q000378:metabolism*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D013940:Thymidylate Synthase / Q000378:metabolism*; D046888:Tissue Array Analysis; D014157:Transcription Factors; D000093542:Gemcitabine
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D058975:Folate Receptor 1; D005971:Glutamates; C504003:TTF1 protein, human; D014157:Transcription Factors; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D016190:Carboplatin; D013940:Thymidylate Synthase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D000093542:Gemcitabine