Page 8 - Read Online
P. 8

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

               Table 2. Promising future pharmacogenomics biomarkers
                Biomarker                       Description  Potential predictive value               Ref.
                CMS1     Microsatellite instability immune (14%):  Response to anti-VEGF          [181-186]
                         - high TML
                         -MSI
                         -CIMP+
                         -BRAF mutation
                         -strong immune activation
                         -right sided
                CMS2     Canonical (37%):                   Response to anti-EGFRs                [181-186]
                         -epithelial signature              Response to anti-HER2
                         -WNT-β-catenin and MYC activation  Chemo-sensitivity
                         -CIN
                         -left sided
                CMS3     Metabolic (13%):                   -                                     [181-186]
                         -metabolic dysregulation
                CMS4     Mesenchymal (23%):                 Resistance to anti-EGFRs              [181-186]
                         -TGF-β activation                  Lack of benefit from 5-FU and oxaliplatin
                         -stromal invasion
                         -angiogenesis
                Liquid biopsy Mutational analysis of circulating tumor DNA  Identification of predictive mutations for targeted treatments at  [187-191]
                                                            baseline
                                                            Dynamic monitoring
                                                            Early detection of secondary resistance
                MiRNA    Micro RNA: noncoding single-stranded RNA molecules,   Response/resistance to chemotherapy and targeted agents  [195]
                         < 200 nucleotides, with post-transcriptional regulatory
                         functions
               TML: tumor mutational load; EGFR: epidermal growth factor receptor; 5-FU: 5-fluorouracil; MSI: microsatellite instability; TGF: transforming
               growth factor; VEGF: vascular endothelial growth factor

               More recently, KRAS mutations have been shown to be associated with suppressed Th1/cytotoxic immunity
               in CRC, irrespective of mismatch repair (MMR) status, tumor location, neoantigen load and transcriptional
               subtype, with a differential effect modulated by the underlying tumor consensus molecular subtypes (CMS,
               discussed more extensively in section 4) . These findings may have a role in explaining the heterogeneity
                                                 [31]
               of treatment response and outcomes in RAS mutated tumors and provide a rationale for novel treatment
               strategies in these patients.

               BRAF
               The serine/threonine protein kinase BRAF is another player in the EGFR-mediated signaling pathway which
               is well-known to be implicated as an oncogenic driver in CRC. In normal cells, MEK, ERK and RAF are
               part of a tyrosine kinase signaling cascade activated by RAS, which affects cell proliferation, growth and
               differentiation, and regulates key cellular function such as apoptosis, cell migration and survival . Mutations
                                                                                               [32]
               in BRAF can be found in approximately 8%-10% of CRCs , the majority of which (about 80%) involve the
                                                                [33]
               substitution of glutamic acid for valine at residue 600 within the protein kinase domain (V600E). BRAF
               constitutive activation resulting from V600E mutation promotes signaling transduction through the MEK-
               ERK-MAP kinase pathway even in absence of RAS-mediated signals. RAS and BRAF V600E mutations, as
               they work through the same pathway, are considered mutually exclusive, and their concomitant detection is
               extremely rare (< 0.001%) .
                                    [34]
               The negative prognostic value of BRAF V600E mutation in mCRC has been extensively described in several
               univariate and multivariate models. Life expectancy for this subgroup of patients is poor when compared to
               BRAF WT ones. When retrospectively evaluated, in fact, metastatic BRAF-mutated patients were showed to
               have a median OS ranging from 10 to 19 months across multiple series, even when treated with association
               therapies [35-38] . Additionally,  BRAF V600E-mutated tumors share distinct clinicopathological features:
               they are more frequent in women, elderly, and are often right-sided; they more often present a mucinous
               histology, poor differentiation and high microsatellite instability (MSI-H); more often are diagnosed as
               advanced disease with preferential spread to lymph nodes and peritoneum [39-41] . When oligo-metastatic liver
   3   4   5   6   7   8   9   10   11   12   13