Cell Line Derived 5-FU and Irinotecan Drug-Sensitivity Profiles Evaluated in Adjuvant Colon Cancer Trial Data

PLoS One. 2016 May 12;11(5):e0155123. doi: 10.1371/journal.pone.0155123. eCollection 2016.

Abstract

Purpose: This study evaluates whether gene signatures for chemosensitivity for irinotecan and 5-fluorouracil (5-FU) derived from in vitro grown cancer cell lines can predict clinical sensitivity to these drugs.

Methods: To test if an irinotecan signature and a SN-38 signature could identify patients who benefitted from the addition of irinotecan to 5-FU, we used gene expression profiles based on cell lines and clinical tumor material. These profiles were applied to expression data obtained from pretreatment formalin fixed paraffin embedded (FFPE) tumor tissue from 636 stage III colon cancer patients enrolled in the PETACC-3 prospective randomized clinical trial. A 5-FU profile developed similarly was assessed by comparing the PETACC-3 cohort with a cohort of 359 stage II colon cancer patients who underwent surgery but received no adjuvant therapy.

Results: There was no statistically significant association between the irinotecan or SN-38 profiles and benefit from irinotecan. The 5-FU sensitivity profile showed a statistically significant association with relapse free survival (RFS) (hazard ratio (HR) = 0.54 (0.41-0.71), p<1e-05) and overall survival (HR = 0.47 (0.34-0.63), p<1e-06) in the PETACC-3 subpopulation. The effect of the 5-FU profile remained significant in a multivariable Cox Proportional Hazards model, adjusting for several relevant clinicopathological parameters. No statistically significant effect of the 5-FU profile was observed in the untreated cohort of 359 patients (relapse free survival, p = 0.671).

Conclusion: The irinotecan predictor had no predictive value. The 5-FU predictor was prognostic in stage III patients in PETACC-3 but not in stage II patients with no adjuvant therapy. This suggests a potential predictive ability of the 5-FU sensitivity profile to identify colon cancer patients who may benefit from 5-FU, however, any biomarker predicting benefit for adjuvant 5-FU must be rigorously evaluated in independent cohorts. Given differences between the two study cohorts, the present results should be further validated.

MeSH terms

  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Camptothecin / therapeutic use
  • Cell Line, Tumor
  • Chemotherapy, Adjuvant
  • Clinical Trials as Topic*
  • Cohort Studies
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Disease-Free Survival
  • Drug Evaluation, Preclinical*
  • Fluorouracil / pharmacology
  • Fluorouracil / therapeutic use*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Irinotecan
  • Prognosis

Substances

  • Irinotecan
  • Fluorouracil
  • Camptothecin

Grant support

The work was partially supported by grant SNF 320030_135421 of the Swiss National Science Foundation. The Danish Cancer Society provided a scholarship for Ida K. Buhl and financial support to the project grant 31176.