Pathophysiology of colon cancer

CRC usually does not produce symptoms in early stages of the disease. If symptoms are present, they
usually depend on the site of the primary tumor. Cancers of the proximal colon tend to grow larger
before symptoms appear than those in the left colon and rectum. The first symptoms of colon cancer
may be iron-deficiency anemia and bleeding due to abnormal vasculature in the tumor and trauma from
the fecal stream. The bleeding is usually occult in early stages. Tumors of the anus, sigmoid colon, and
rectum may lead to hematochezia.

Later stages of the disease may be associated with obstruction of the colonic lumen, abdominal
distension, pain, nausea, and vomiting. Obstruction of the gastrointestinal (GI) tract suggests a larger
tumor and a poorer prognosis. If the tumor has invaded the muscularis propria and adjacent tissue, pain
and site-specific symptoms may be present. This may include tenesmus from rectal invasion,
pneumaturia from bladder penetration, or perineal or sacral pain from pelvic invasion. Cachexia is also
common in patients with advanced GI malignancies.

Anatomical Site of CRC

Clinical data have shown disparities in incidence, outcomes, genetic alterations, and pathogenesis
depending on the anatomical site of the tumor in CRC. Right-sided colon cancer (RCC) occurs in the
proximal colon, which consists of cancers of the cecum and ascending and transverse colon. Left-sided
colorectal cancer (LCRC) occurs in the distal colorectum and consists of cancers of the descending and
sigmoid colon and the rectum.

Tumors of the proximal colon tend to be larger, have a higher TNM-stage, and have increased frequency
of vascular invasion than LCRC. Mucinous adenocarcinoma, which is characterized by abundant
extracellular mucin, is more frequently found in the proximal colon and is associated with microsatellite
instability (MSI). MSI-positive CRCs have a better overall outcome compared with microsatellite-stable
tumors. KRAS and p53 mutations are more commonly found in LCRC than RCC.

Although RCCs are more likely to be MSI positive, when adjusted for tumor stage, survival is significantly
worse for RCC compared with LCRC. The higher mortality of RCCs is likely due to more aggressive
microsatellite-stable RCC, which tend to have mutations in the BRAF gene. LCRC may have a lower
mortality rate because it is more easily diagnosed due to screening of the distal colon and more
apparent symptoms. RCC often presents with subtle signs and symptoms, such as microcytic anemia,
weight loss, and occult bleeding. LCRC is more likely to lead to rectal bleeding and alterations in bowel
habits.

A retrospective analysis of the CALGB/SWOG 80405 study suggested that patients with left-sided tumors
had significantly longer median overall survival (OS) versus those with right-sided tumors retrospective
analysis of tumor sidedness in patients with RAS wild-type CRC in the CRYSTAL and FIRE-3 trials
concurred with these findings, showing that OS is significantly longer in patients with left-sided versus
right-sided mCRC. The addition of cetuximab to chemotherapy improved OS in left-sided tumors and
had limited or no effect in right-sided tumors. 
Summary of differences between right-sided colon cancer and left-sided colorectal cancer

 
Biomarkers

VEGF

Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis, the formation of
new blood vessels from the endothelium of preexisting vasculature. Angiogenesis is an early event in
tumorigenesis and plays an important role in promoting tumor growth by supplying nutrients, oxygen,
and growth factors needed for tumor proliferation. VEGF expression is significantly associated with
advanced stage and poor prognosis in patients with CRC. In a study of VEGF concentrations, 56% of CRC
tumors expressed VEGF compared with 17% of normal mucosa cells, with significantly higher levels of
expression in tumor cells. Lymph node and liver metastases were also significantly associated with
elevated VEGF expression. The 5-year overall survival of patients with negative and positive expression
of VEGF was 84% and 40%, respectively. 7,8 Bevacizumab, ramucirumab, and aflibercept are anti-VEGF
agents that have been shown to improve OS and clinical outcomes in patients with mCRC.

KRAS/NRAS

Epidermal growth factor receptor (EGFR) is overexpressed in many types of cancer, especially CRC, and it
is associated with a more aggressive disease. Activating mutations in KRAS, a small G-protein
downstream of EGFR, correlates with poor response to anti-EGFR antibodies in mCRC. 9 It is estimated
that up to 80% of all sporadic CRC is due to chromosomal instability, characterized by mutational
activation of oncogenes (KRAS) and the loss of tumor suppressor gene activity This pattern of activity is
characteristic of LCRC, particularly rectal cancer

Since the discovery that patients whose CRC tumors have KRAS mutations will not benefit from EGFR-
antibody therapy, resistance to EGFR blockade in mCRC has been extensively studied. About 80% of all
the KRAS mutations occur in exon 2 (codon 12 and 13). Multiple studies demonstrated that mutations
in KRAS exons 3 and 4 or NRAS exons 2 to 4 can also predict lack of response to EGFR-targeted
antibodies given in combination with first-line chemotherapy. In a study assessing the efficacy of
panitumumab in mCRC, 43% of tumors were found to have KRAS mutations. The treatment effect on
progression-free survival (PFS) in the wild-type KRAS group (HR = 0.45; 95% confidence interval [CI],
0.34–0.59) was significantly greater (P<0.0001) than in the mutant group (HR = 0.99; 95% CI, 0.73–1.36).
Response rates were 17% for the wild-type group and 0% for the mutant group.  After an initial response
to EGFR-targeted antibodies, wild-type tumors invariably acquire KRAS point mutations leading to
secondary resistance to therapy.10 CRC tumors should be tested for RAS mutations (KRAS or NRAS)
before initiating treatment. Cetuximab and panitumumab are anti-EGFR antibodies that improve OS only
in CRC patients with wild-type RAS genes.

BRAF V600E

Mutations in the BRAF gene may be found in up to 18% of CRC patients and are associated with shorter
PFS and OS. Mutation of BRAF, the gene encoding the serine/threonine-specific protein kinase B-Raf, is a
predominant event in cancers with poor prognosis such as melanoma and CRC.  The BRAF mutation leads
to a constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, which is essential
for cell proliferation and tumor progression. Up to 80% of all BRAF mutations are V600E mutations.

Several studies have confirmed the association of BRAF mutations with poor outcomes in CRC. A
systematic review and meta-analysis investigating the correlation between the BRAF mutation and OS
survival in patients with mCRC and melanoma has shown that the BRAF mutation more than doubles the
risk of mortality in CRC patients. Approximately 60% of melanoma patients have BRAF mutations, and
BRAF inhibitors have shown a response rate of 50–80% in these patients. However, in CRC patients, the
response rate to BRAF inhibitors is approximately 5%. BRAF-mutated tumors are often right-sided and of
higher grade and are associated with MSI and older age. Clinical trial data have demonstrated that EGFR
inhibitors such as cetuximab and panitumumab are not effective in treating CRC unless given with a
BRAF inhibitor such as vemurafenib.

dMMR/MSI-H

Microsatellites (MS) are tandem repeats of short DNA sequences that are abundant throughout the
human genome. In individuals with MSI, mutations in DNA mismatch-repair (MMR) proteins that
normally identify and repair mismatched bases during DNA replication, lead to an accumulation of
microsatellites. Microsatellites found within protein coding sequences cause frameshift mutations,
producing highly altered and immunogenic proteins. 16 Microsatellite instability-high (MSI-H) status is
found in 10–15% of sporadic CRC and is a strong prognostic factor of favorable outcomes, such as lower
stage at diagnosis.17,18 However, its prognostic value varies, depending on tumor stage, tumor location,
and BRAF mutation status.

Assessing for somatic mutations in BRAF in conjunction with MSI status may be prognostically valuable.
The V600E mutation renders BRAF constitutively active, resulting in a worse prognosis. 12 One study
stratified CRC patients based on MSI and BRAF status into three prognostic groups: MSI/BRAF-wild type
or mutant (best prognosis), microsatellite stable (MSS)/BRAF-wild type (intermediate prognosis), and
MSS/BRAF mutant (worst prognosis). Other studies have reached conflicting results, and no consensus
exists to date on the best prognostic subgroupings. 21

Clinical studies have shown that MMR status is associated with responsiveness to PD-1 blockade, with
reported PFS rates up to 78% in MMR-deficient (dMMR) CRC patients, compared with 11% in MMR-
proficient (pMMR) patients. It is believed that the dMMR CRC tumors are responsive to checkpoint
inhibitors because MSI status is usually associated with increased neoantigen burden. Anti-PD-1
antibodies that are effective in metastatic CRC include pembrolizumab, nivolumab, and ipilimumab.