Systematic Reviews
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 14, 2016; 22(30): 6944-6954
Published online Aug 14, 2016. doi: 10.3748/wjg.v22.i30.6944
Prognostic and predictive biomarkers in metastatic colorectal cancer anti-EGFR therapy
Cristiana Lo Nigro, Vincenzo Ricci, Daniela Vivenza, Cristina Granetto, Teresa Fabozzi, Emanuela Miraglio, Marco C Merlano
Cristiana Lo Nigro, Vincenzo Ricci, Daniela Vivenza, Cristina Granetto, Emanuela Miraglio, Marco C Merlano, Department of Oncology, S. Croce and Carle Teaching Hospital, 12100 Cuneo, Italy
Teresa Fabozzi, Department of Oncology, San Raffaele Institute, 20132 Milan, Italy
Author contributions: Lo Nigro C and Ricci V equally contributed to the ideation of the topic of the review and to the frame of the review; Merlano MC supervised their work and stimulated discussion; Ricci V reviewed all the main clinical studies; Fabozzi T helped with the revision of the scientific literature; Lo Nigro C, Ricci V and Vivenza D were in charge of the manuscript writing; Granetto C, Miraglio E and Merlano CM reviewed the manuscript.
Conflict-of-interest statement: Merlano MC received honoraria as consultant from Merckgroup; The other authors have no financial and personal conflict of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Cristiana Lo Nigro, PhD, Laboratory of Cancer Genetics and Translational Oncology, Department of Oncology, S. Croce and Carle Teaching Hospital, via Carle 25, 12100 Cuneo, Italy. lonigro.c@ospedale.cuneo.it
Telephone: +39-0171-616338 Fax: +39-0171-616331
Received: March 24, 2016
Peer-review started: March 25, 2016
First decision: May 12, 2016
Revised: May 27, 2016
Accepted: July 6, 2016
Article in press: July 6, 2016
Published online: August 14, 2016
Abstract

AIM: To reviewing genetic and epigenetic make-up of metastatic colorectal cancers (mCRCs) addicted to epidermal growth factor receptor (EGFR) signalling.

METHODS: The present study summarizes the potential value of prognostic and predictive biomarkers in selecting mCRC patients treated with anti-EGFR therapy. A meta-analysis was performed using a systematic search of PubMed, Medline and Web of Science to identify eligible papers until March 21st, 2016 using these following terms: ‘‘colorectal cancer’’, “predictive biomarkers’’, “anti-EGFR therapy”, “KRAS”, “NRAS’’, “PIK3CA”, “TP53”, “PTEN”, ‘‘EGFR”, “MET”, “HER2”, “epiregulin”, “amphiregulin”, “prognostic biomarkers”, “BRAF”, “miRNA” and “antibody-dependent cell-mediated cytotoxicity (ADCC) activity”. Two investigators independently evaluated and extracted data from each identified studies based on selected criteria of inclusion and exclusion.

RESULTS: The introduction of agents targeting EGFR such as cetuximab and panitumumab increased overall survival of mCRCs. Nevertheless, it has firstly became evident that response rates to cetuximab regimens in unselected patient populations were typically lower than 30%. Clinical data confirmed the predictive value of RAS mutations for resistance to cetuximab and panitumumab leading to the license of these monoclonal antibodies exclusively for the management of patients with RAS-wild type colorectal cancers. So far the identification of predictive biomarkers have generated interesting, though preliminary and, at times, conflicting data on the importance of tumour mRNA levels of EGFR ligands, of activating mutations in other genes such as NRAS and PIK3CA. The prognostic value of selected microRNAs level and ADCC activity is under investigation, while the prognostic impact of BRAF status remains controversial.

CONCLUSION: This review focuses on the personalized treatment of mCRC and discusses the potential of new prognostic and predictive biomarkers in selecting patients treated with anti-EGFR therapy.

Keywords: Metastatic colorectal cancer, Anti-epidermal growth factor receptor therapy, KRAS, Biomarkers, Antibody-dependent cell-mediated cytotoxicity

Core tip: This review focuses on progress in the metastatic colorectal cancer (mCRC) personalized treatment and on the role of prognostic and predictive biomarkers available for selecting patients treated with anti-epidermal growth factor receptor (EGFR) therapy. Not only the KRAS mutational status but also BRAF, NRAS, PIK3CA, TP53 and PTEN alterations might be useful in selecting patients who likely will respond to anti-EGFR treatments. In particular, we focused on the following points: (1) predictive biomarkers of response to anti-EGFR therapy; (2) prognostic biomarkers; and (3) new prognostic value of antibody-dependent cell-mediated cytotoxicity activity induced by cetuximab in mCRC.