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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