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Page 2 of 25                         Battaglin et al. J Cancer Metastasis Treat 2018;4:12  I  http://dx.doi.org/10.20517/2394-4722.2018.04

               INTRODUCTION
               Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the western world and ranks
                                                                           [1]
               third among the most frequent malignancies in both men and women . Although still unsatisfactory, the
               median overall survival (OS) of patients with metastatic CRC (mCRC) has notably increased in the past 20
                                                                      [2,3]
               years, reaching around 30 months in recent phase III clinical trials , thanks to the introduction of innovative
               medical and surgical treatment strategies. The availability of new drugs and treatment combinations, both
               in terms of cytotoxic chemotherapy regimens and new targeted therapies, has been crucial in order to reach
               this result. However, patients’ outcome and response to treatment can be highly heterogeneous, thus an
               extensive effort has been directed towards the identification of reliable predictive biomarkers to aid clinical
               management of patients and identify subgroups more likely to benefit from different treatment strategies.

               Pharmacogenomics represents an irreplaceable tool in order to tailor patients treatment to an individualized
               approach based on germline and somatic acquired genetic variations able to predict drugs response and
               risk of toxicities . Moving from early studies exploring the genetic bases of individual predisposition to
                             [4]
               severe toxicities from chemotherapy agents [i.e. 5-fluorouracil (5-FU) or irinotecan] in mCRC patients, the
               introduction of targeted agents such as anti-epidermal growth factor receptor (EGFR) drugs, has prompted
               the discovery of predictive molecular biomarkers (i.e. RAS mutational status) which are now tested as part
               of routine clinical practice . Over time, additional mechanisms of primary and secondary resistance to
                                      [5]
               targeted agents have emerged as promising novel predictive biomarkers and potentially actionable target
               of treatment, although validation is still an issue in most cases, and many steps forward have been made
               in the biological understanding and molecular characterization of CRC . Finally, new perspectives have
                                                                             [6]
               been recently opened following innovative results of immunotherapy treatment, and the development of
               new analytical techniques which allow dynamic tumor profiling and a sensitive detection of coexisting
               alterations underlying tumor heterogeneity, such as liquid biopsy .
                                                                      [7]
               In this review, we present an overview of current pharmacogenomic biomarkers validated in clinical practice
               and future perspectives of pharmacogenomics in CRC [Tables 1 and 2], in an evolving scenario moving
               from a single drug-gene interactions approach to a more comprehensive genome-wide approach, comprising
               genomics and epigenetics.



               CURRENT PHARMACOGENOMIC BIOMARKERS IN CLINICAL PRACTICE
               RAS
               EGFR signaling pathway plays a crucial role in the regulation of cellular responses to growth signals and its
               constitutive activation is one of the main actor promoting CRC growth and proliferation through the KRAS/
                                                     [8]
               RAF/MAPK and the PI3K/AKT/mTOR axes . EGFR inhibitors are nowadays well-established therapeutic
               agents incorporated into standard care for mCRC [9,10] . To date, two anti-EGFR monoclonal antibodies have
               been approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the
               treatment of mCRC: Cetuximab (Erbitux®, Merck KGaA/Lilly USA) and Panitumumab (Vectibix®, Amgen
               Inc). At the time when the efficacy of these drugs was first proven in advanced lines of treatment [11,12] , no
               predictive biomarker was available, although a subgroup effect on the activity of these agents was evident.
               KRAS is a small GTPase member of the RAS protein family , and somatic gene mutations can lead to its
                                                                   [13]
               constitutive activation resulting in independent cell proliferation and survival . KRAS mutations, more
                                                                                   [14]
                                       [15]
               frequently involving exon 2 , can be found in approximately 40% to 50% of mCRCs. The identification
               of KRAS exon 2 (codons 12 and 13) mutations as a negative predictive marker of response to anti-EGFRs
               represented the turning point on biomarker selection for anti-EGFR treatment.


                                                                                                        [16]
               First evidence of the negative predictive role of KRAS exon 2 mutation came from retrospective series
               and was then confirmed through post-hoc analyses of randomized phase III trials [11,17-20] . Moving from these
               data, in 2008 FDA and EMA restricted the use of anti-EGFR drugs to patients with KRAS exon 2 wild-
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