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Page 10 of 17                     Spallanzani et al. J Cancer Metastasis Treat 2018;4:28 I http://dx.doi.org/10.20517/2394-4722.2018.31

               Table 3. Transcriptomic pathways envolved and potential treatment strategies for each molecular subtypes
                Molecular     Transcriptomic   Potential treatment   Stroma-immune   Strategies for immunotherapy
                subtypes        pathways         strategies   microenvironment
                CMS1 (14%)   Immune activation  (1) Immune   Highly         Immune checkpoint inhibition (anti PD1/
                            JAK-STAT activation   checkpoint   immunogenic   PDL-1/ anti-CTLA-4/anti-IDO)
                                             inhibition
                                             (2) Anti PD-1 + anti
                                             CTLA-4/anti-IDO
                CMS2 (37%)   WNT targets     (1) Pan-RAS +   Poorly         (1) Combined EGFR pathway
                            MYC activation   BRAF + PI3K wt:   immunogenic   inhibition and immune
                            EGFR activation   polichemotherapy +            checkpoint inhibition
                            VEGF or VEGFR    anti-EGFR                      (2) Combined HDAC inhibitors
                            activation       (2) BRAF mutated:              and immune checkpoint
                                             BRAF inhibitor +
                            Integrins activation   anti-EGFR + MEK-         inhibition
                            TGFβ activation   inhibitor                     (3) Immuno-chemotherapy
                CMS3 (13%)   DNA damage repair   (3) HER-2 amplified:   Poorly   (1) Combined MEK-inhibitor and
                            Glutaminolysis   anti-HER2 + anti-  immunogenic   immune checkpoint inhibition
                                             EGFR
                            Lipidogenesis    (4) KRAS or                    (2) Combined HDAC inhibitors
                            Cell cycle       NRAS mutated:                  and immune checkpoint
                                             polichemotherapy +             inhibition
                                             anti-VEGF                      (3) Immuno-chemotherapy
                CMS4 (23%)   Mesenchymal     (1) Polichemotherapy   Inflamed (immune   (1) Combined TGF pathway
                            transition       + anti-VEGF     tollerant)     inhibition and immune
                            Complement       (2) Chemotherapy +             checkpoint inhibition
                            activation       anti-TGFR                      (2) Combined anti-VEGF
                            Immunosuppression                               and immune checkpoint
                                                                            inhibitors
                                                                            (3) Anti-T-reg and/or anti-MDSCs
                                                                            treatment

               CMS: consensus molecular subtypes; EGFR: epidermal growth factor receptor; JAK: Janus kinase; STAT: signal transducer and activator
               of transcription; TGFβ: transforming growth factor-β; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; PD1: programmed
               death protein 1; CTLA4: cytotoxic T-lymphocyte-associated protein 4; IDO1: indoleamine-pyrrole 2,3-dioxygenase; HDAC: histone
               deacetylase; MEK: mitogen-activated protein kinase (MAPK) kinase; MDSCs: myeloid derived suppressor cells


               that dysbiosis might affect the therapeutic efficacy of immune check-point inhibitors, they explored
               the composition of gut microbioma of these patients and observed that Akkermansia muciniphila was
               overrepresented in the faeces of patients who later benefited from PD-1 inhibition.

               Furthermore, they observed improving CPIs efficacy and increasing CCR9+CXCR3+CD4+ TILs levels when
               they transplanted faecal microbiota from cancer patients who responded to immunotherapy into antibiotic-
                       [80]
               free mice .

               MOLECULAR DRIVEN THERAPEUTIC HYPOTESIS
               With the CMS classification system, approximately 85% of colorectal cancers could be molecularly classified.
               The evolution of precision medicine should be based on association of molecular information (mutations,
               methylation status, gene regulation), biological and clinical characteristics of the tumour [Table 3].


               Early-stage patients with CMS1 tumours and in particular MSI tumours (most CMS1 cancers) have good
               prognosis with low recurrence rate. No adjuvant therapy should be considered for stage II tumours, while for
               stage III MSI-H CRC it is plausible that the addition of oxaliplatin could overcome the potential detrimental
                                                  [81]
               effect of fluoropyirimide monotherapy . For these subgroups of patients with MSI, hypermutated,
               hypermethylated cancers characterized by strong infiltration of immune cells, the usefulness of immune
                                                                                                        [82]
               check-point inhibitors as the main treatment of advanced disease should be considered. Recently Shin et al.
               identified acquired mutations in 4 patients treated with pembrolizumab with previous clinical benefit: these
               mutations caused mistakes in antigen presentation and immune escape of cancer cells. New efforts should
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