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

J Thorac Oncol. 2013 Oct;8(10):1255-64. doi: 10.1097/JTO.0b013e3182a406a3.

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.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / mortality
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / metabolism*
  • Carboplatin / administration & dosage
  • Carcinoma, Large Cell / drug therapy
  • Carcinoma, Large Cell / metabolism
  • Carcinoma, Large Cell / mortality
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / mortality
  • DNA-Binding Proteins / metabolism*
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Female
  • Folate Receptor 1 / metabolism*
  • Follow-Up Studies
  • Glutamates / administration & dosage
  • Guanine / administration & dosage
  • Guanine / analogs & derivatives
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Pemetrexed
  • Peptide Synthases / metabolism*
  • Prognosis
  • Retrospective Studies
  • Survival Rate
  • Thymidylate Synthase / metabolism*
  • Tissue Array Analysis
  • Transcription Factors

Substances

  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Folate Receptor 1
  • Glutamates
  • TTF1 protein, human
  • Transcription Factors
  • Pemetrexed
  • Deoxycytidine
  • Guanine
  • gemcitabine
  • Carboplatin
  • Thymidylate Synthase
  • Peptide Synthases
  • folylpolyglutamate synthetase