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Page 2 of 16 Cidon. J Unexplored Med Data 2018;3:8 I http://dx.doi.org/10.20517/2572-8180.2018.03

After the initial emotion with the adoption of new drugs, namely bevacizumab or cetuximab into the
armamentarium of metastatic disease, systemic options have remained stationary and fluorouracil-based
cytotoxic chemotherapy continues to be the standard. Moreover, patients stop responding to the therapy at
[4]
some point, due to intrinsic or acquired resistance to these agents , and disease progression after two lines
[5]
of treatment entails a short survival of about 4-6 months with best supportive care only .
However, some patients are still able to receive further treatment and the choice of an option will depend
on previously used treatments, the patient thoughts and performance status and the tumour biology. In this
scenario, strategic trials are relevant to ascertain the best therapeutic sequence but new agents are urgently
needed. It is in this context when the appearance of immunotherapies has enabled a hopeful new therapeutic
approach.

These novel agents were accepted immediately due to the good results seen with the use of immune
checkpoint inhibitor drugs.

It is a fact that several gastrointestinal neoplasias showed positive outcomes but unfortunately colonic
tumours are not one of them. However, emerging data show that there are some patients who may benefit
from these agents.

This article will discuss the current situation of immunotherapy treatment in colon cancer by reviewing the
ongoing and already published trials.

MOLECULAR ALTERATIONS IN COLON CANCER: A KEY POINT TO KNOW
Colon cancer origins from a collection of genetic modifications, and most of them appear to originate from
adenomas which evolve to carcinoma following a pathway of oncogene activation and loss of suppressor
[6]
genes. RAS mutations have been detected in about 60% of adenomas smaller than 1 cm .

Wnt/B-catenin route seems to be deregulated due to inactivation of APC (a gene that abolish tumours) which
is a crucial step but not sufficient to generate cancer and in fact to allow tumor progression other mutations
[7]
are needed .

RAS mutations have been documented in more than half of these cancers and BRAF is present in about 5%
[8,9]
[10]
to 10% while Her-2amplifications have been detected in 2%-5% of them but all of those play a role in
this neoplasia progression and behaviour.
Genomic instability is a key factor in an early phase of tumorigenesis and this creates a tolerant environment
[11]
that allows a cell to transform into a neoplastic cell . There are two relevant classes of genomic instability:
[12]
microsatellite instability or MSI and chromosome instability or CINMSI which is present in 15% of the
cases. This is due to a malfunctioning mismatch repair (MMR) system which is caused by MMR mutations
or hypermethylation of mutL homologue 1 (the MLH1) promoter.

[13]
MSI which appears in > 90% of Lynch syndrome colonic tumours , stimulates the formation of tumours
through promotion of gene alterations in crucial genes, i.e., transforming growth factor-beta (TGF-β) and
[14]
[13]
BAX . In sporadic MSI-positive colon cancers, hypermethylation of MLH1 promoter seems to be present
as well.
CIN is another form of genomic instability, which is in fact, the one that causes the majority of colon
[15]
neoplasias and seems to be produced by errors in the mitosis either in the process or in the apparatus, that
[15]
will lead to mitotic failures .