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© Research
Publication : The journal of pathology. Clinical research

A 12-gene signature to distinguish colon cancer patients with better clinical outcome following treatment with 5-fluorouracil or FOLFIRI

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in The journal of pathology. Clinical research - 09 Apr 2015

Paquet ER, Cui J, Davidson D, Pietrosemoli N, Hassan HH, Tsofack SP, Maltais A, Hallett MT, Delorenzi M, Batist G, Aloyz R, Lebel M

Link to Pubmed [PMID] – 27499901

J Pathol Clin Res 2015 Jul;1(3):160-72

Currently, there is no marker in use in the clinical management of colon cancer to predict which patients will respond efficiently to 5-fluorouracil (5-FU), a common component of all cytotoxic therapies. Our aim was to develop and validate a multigene signature associated with clinical outcome from 5-FU therapy and to determine if it could be used to identify patients who might respond better to alternate treatments. Using a panel of 5-FU resistant and sensitive colon cancer cell lines, we identified 103 differentially expressed genes providing us with a 5-FU response signature. We refined this signature using a clinically relevant DNA microarray-based dataset of 359 formalin-fixed and paraffin-embedded (FFPE) colon cancer samples. We then validated the final signature in an external independent DNA microarray-based dataset of 316 stage III FFPE samples from the PETACC-3 (Pan-European Trails in Alimentary Tract Cancers) clinical trial. Finally, using a drug sensitivity database of 658 cell lines, we generated a list of drugs that could sensitize 5-FU resistant patients using our signature. We confirmed using the PETACC-3 dataset that the overall survival of subjects responding well to 5-FU did not improve with the addition of irinotecan (FOLFIRI; two-sided log-rank test p = 0.795). Conversely, patients who responded poorly to 5-FU based on our 12-gene signature were associated with better survival on FOLFIRI therapy (one-sided log-rank test p = 0.039). This new multigene signature is readily applicable to FFPE samples and provides a new tool to help manage treatment in stage III colon cancer. It also provides the first evidence that a subgroup of colon cancer patients can respond better to FOLFIRI than 5-FU treatment alone.

https://www.ncbi.nlm.nih.gov/pubmed/27499901