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12-10-2017 | Colorectal cancer | Article

Protein biomarkers predictive for response to anti-EGFR treatment in RAS wild-type metastatic colorectal carcinoma

Authors:
Astrid Lièvre, Bérèngere Ouine, Jim Canet, Aurélie Cartier, Yael Amar, Wulfran Cacheux, Odette Mariani, Rosine Guimbaud, Janick Selves, Thierry Lecomte, Serge Guyetant, Ivan Bièche, Frédérique Berger, Leanne de Koning

Abstract

Background: Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even amongRAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi)genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways.

Methods: We analysed the expression and activation of proteins involved in cell signalling, using reverse phase protein arrays, on a multicentre French cohort of RAS WT mCRC treated with anti-EGFR treatment.

Results: We identify activated EGFR and HER3 as protein biomarkers predictive for better overall survival. Active EGFR signalling and downstream PI3K, but not MAPK, pathway activation are associated with response to anti-EGFR treatment. Left-sided mCRC displays active ErbB2/3 and Wnt pathways and a better response to anti-EGFR therapy compared to right-sided mCRC.

Conclusions: We identify active EGFR and PI3K signalling as a key factor for response to anti-EGFR treatment in mCRC and highlight the importance of developing these biomarkers in clinical practice for the selection of RAS WT mCRC patients that would benefit from anti-EGFR treatment.

 

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