Ca colon

Adjuvant therapy for stage 2

• Mismatch repair (MMR) proteins are responsible for correcting
mistakes made by DNA polymerase during DNA synthesis. MMR
protein deficiency leads to MSI, which is an accumulation of errors
within short repetitive sequences of DNA, called microsatellites. MSI
status is checked by either immunohistochemistry (IHC) staining for
the mismatch repair pro- teins or by polymerase chain reaction to
detect instable and shortened microsatellites. MSI-high tumors would
have missing MMR protein(s) by IHC and shortened/instable
microsatellites. MMR protein deficiency is caused by either germline
mutation of the MMR genes (hereditary Lynch syndrome) or sporadic
silencing of the MMR genes.
• Monoclonal antibodies have been developed to target either the
VEGF ligand itself or the VEGF receptors (VEGFR).
• Bevacizumab (Avastin) is a monoclonal antibody that binds the ligand
VEGF-A, and the first biologic agent to be approved in the treatment
of metastatic colorectal cancer (mCRC).
• The EGFR pathway plays an important role in colorectal
carcinogenesis. EGFR is a member of the human epidermal growth
factor family of receptor tyrosine kinases. EGFR is expressed on
colorectal cancers, and it can lead to activation of signaling pathways
such as the RAS-RAF mitogen-activated protein kinase (MAPK),
phospha- tidylinositol 3-kinase (PI3K), and phospholipase C pathways
that lead to tumor prolif- eration, metastasis, and survival.
• KRAS, NRAS, and BRAF proteins are downstream of EGFR in the MAPK
pathway.

• KRAS and NRAS mutations lead to constitutive activation of the MAPK

signaling pathway down- stream of EGFR; thus inhibition of EGFR by
cetuximab and panitumumab upstream to KRAS and NRAS is not
effective.

• Anti-EGFR antibody therapy is most efficacious in patients with tumors

that are KRAS/NRAS wild-type and left-sided.
• The PD-1 pathway negatively regulates the cytotoxic immune response to
cancer cells. Thus, tumors that have upregulation of PD-1 and programmed-
death ligand-1 (PD-L1) escape the host immune system. Because of DNA
mismatch repair defi- ciencies, MSI-high tumors have increased amounts of
mutations and neoantigens, and are also found to have increasing tumor
infiltrating lymphocytes (TILs) which have higher expression of PD-1, PDL-1,
and checkpoint ligands such as cytotoxic T lymphocyte-associated 4 (CTLA-
4). Thus, it is hypothesized that when PD-1 inhibitors activate the host
immune response toward cancer cells, they are especially effective in MSI-
high cancers because of the high number of neoantigens, TILs, and
associated immune infiltrate at the tumor-invasive fronts.
• currently available epidemiologic evidence indicates positive associations
between red/processed meat and CRC risk, although it does not rule out
contributions from other confounding factors, such as higher fat intake
and lack of physical activity. The associations tend to be stronger for
rectal cancer than colon cancer and for pro- cessed meat than red meat
as well as for men than women. Potential underlying mech- anisms of the
elevated CRC risk by red/processed meat include carcinogenic chemical
byproducts made during cooking and processing, such as heterocyclic
amines, polycy- clic aromatic hydrocarbons, and N-nitroso compounds.
Controlled studies, however, need to delineate the mechanisms of action
of these carcinogenic chemicals.
• Fish consumption may decrease the risk of CRC development, partially
because fish con- tains high levels of polyunsaturated fatty acids
(PUFAs).

• Whole grains and cereals are major sources of dietary fiber, and
accumulating evidence suggests that high fiber intake from whole
grains and cereals associates with a lower risk of CRC
• Fiber includes heterogeneous plant material composed of cellulose,
hemicellulose, and pectin.10 Its potential protective effects include
reducing fecal transit time, diluting fecal carcinogens, affecting bile
acid metabolism, maintaining colonic epithelial cell integrity,
absorbing heterocyclic amines, and stimulating bacte- rial anaerobic
fermentation to promote the production of short-chain fatty acids
(SCFAs).10,16 SCFAs, such as acetate, propionate, and butyrate, have
been shown to decrease colonic pH44,45 and inhibit colon
carcinogenesis
• Fruit and vegetables, which are rich in polyphenol compounds,
flavonoids, soluble fi- ber, vitamins, and minerals, have been highly
recommended for CRC prevention, although the results of
epidemiologic studies are weak, possibly because of the vari- ability
within the category “fruit and vegetable