New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?

// Giuseppe Bronte 1,* , Nicola Silvestris 2,* , Marta Castiglia 1 , Antonio Galvano 1 , Francesco Passiglia 1 , Giovanni Sortino 1 , Giuseppe Cicero 1 , Christian Rolfo 3 , Marc Peeters 3 , Viviana Bazan 1 , Daniele Fanale 1 , Antonio Giordano 4,5 and Antonio Russo 1 1 Department of Surgical, Oncological and Oral Sciences, University of Palermo, Palermo, Italy 2 Medical Oncology Unit,National Cancer Institute “Giovanni Paolo II”, Bari, Italy 3 Department of Oncology, University Hospital of Antwerp, Edegem, Belgium 4 Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA 5 Department of Medicine, Surgery & Neuroscience, University of Siena, Siena, Italy * These authors equally contributed to this work Correspondence to: Antonio Russo, email: // Keywords : RAS, colorectal cancer, epidermal growth factor receptor, cetuximab, panitumumab Received : May 18, 2015 Accepted : July 04, 2015 Published : July 22, 2015 Abstract Anti-epidermal growth factor receptor therapy with the monoclonal antibodies cetuximab and panitumumab is the main targeted treatment to combine with standard chemotherapy for metastatic colorectal cancer. Many clinical studies have shown the benefit of the addition of these agents for patients without mutations in the EGFR pathway. Many biomarkers, including KRAS and NRAS mutations, BRAF mutations, PIK3CA mutations, PTEN loss, AREG and EREG expression, and HER-2 amplification have already been identified to select responders to anti-EGFR agents. Among these alterations KRAS and NRAS mutations are currently recognized as the best predictive factors for primary resistance. Liquid biopsy, which helps to isolate circulating tumor DNA, is an innovative method to study both primary and acquired resistance to anti-EGFR monoclonal antibodies. However, high-sensitivity techniques should be used to enable the identification of a wide set of gene mutations related to resistance.

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