Bjørn H Grønberg1, Marius Lund-Iversen, Erik H Strøm, Odd Terje Brustugun, Helge Scott. 1. *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.
Abstract
INTRODUCTION: 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.
INTRODUCTION: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.
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