Colon cancer is the fourth most common cancer in the US. Approximately 96,830 new cases of colon cancer and 40,000 cases of rectal cancer occur each year. While incidence rates have decreased, it remains the second leading cause of cancer deaths. Approximately 20% of colon cancer cases are associated with hereditary factors like Lynch syndrome and Familial Adenomatous Polyposis. Universal genetic testing of tumors is recommended to identify hereditary cases so that at-risk family members can be identified. First line treatments for metastatic colon cancer include FOLFOX, CapeOx, and FOLFIRI combinations, often with added targeted therapies like bevacizumab, cetuximab, or panitumumab

1. Colon Cancer Statistics in the US
Colorectal cancer is fourth most frequently diagnosed cancer in US
Second leading cause of cancer deaths
In 2013, estimated 96,830 new cases of colon cancer and approx. 40,000
cases of rectal cancer will occur.
Incidence of colon and rectal cancer has decreased from 60.5 per
100,000 people in 1976 to 46.4 in 2005.
Mortality decreased by 35% from 1990 to 2007.

2. Risk Assessment
• Approx 20% cases of colon cancer are associated with familial
clustering.
• Genetic susceptibility to colorectal cancer includes Lynch syndrome
(also known as HNPCC) and FAP (familial adomatous polyposis).
• Important to review family history.

3. Lynch Syndrome
• It is the most common form of genetically determined colon cancer
predisposition.
• Accounts for 2-4% of all cases.
• Results from germline mutations in DNA mismatch repair (MMR)
genes (MLH1, MSH2, MSH6 and PMS2).
• Patients to be sequenced have to undergo one of 2 tests:
1)immunohistochemical analysis for MMR protein expression, which
is diminished due to mutation or 2) analysis of MSI, which results
from MMR deficiency and is detected as changes in length of
repetitive DNA elements in tumor tissue caused by insertion or
deletion of repeated units.

4. Lynch Syndrome
• Testing BRAF gene for mutation is indiacted when IHC analysis shows
MLH1 protein expression to be absent in the tumor.
• Presence of BRAF mutation indicates that MLH1 gene expression is
downregulated through somatic hypermethykation of promoter
region of the gene and not through germline mutation.

5. • Cost effectiveness of Universal or reflex testing has been confirmed
• It is recommended that universal genetic testing should be done on tumors
of all patients with newly diagnosed CRC.
• Alternative approach is to test patients diagnosed before 70 years plus
patients diagnosed at older ages who meet Bethesda guidelines.
• This has a sensitivity of 95.1% and specificity of 95.5%.
• While this strategy failed to detect 4.9% of Lynch cases, it resulted in
approx. 35% fewer tumors undergoing MMR testing than a universal
approach.
• NCCN recommends the selective approach.
• MMR testing should be done in Stage II tumors.

6. Staging

7. Pathologic Review

8. Pathologic Review

9. Pathologic Review

10. Pathologic Review

26. FOLFOX
• The Phase III EORTC 40983 study, evaluated use of perioperative
FOLFOX (6 cycles before and 6 cycles after surgery) for patients with
resectable liver metastases.
• It showed absolute improvements in 3 year PFS of 8.1% (P=0.041) and
9.2% (P=0.025) for all eligible and resected patients when chemo
with surgery was compared with surgery alone.
• No difference in OS was seen.
• Oxaliplatin is associated with increased risk of peripheral sensory
neuropathy.

27. FOLFOX
• Results of OPTIMOX1 study showed that a “stop-and-go” approach
using oxaliplatin free intervals resulted in decreased neurotoxicity and
did not affect OS in patients receiving FOLFOX as initial therapy for
metastatic disease.
• Discontinuation of oxaliplatin from FOLFOX or CapeOx should be
considered after 3 months of therapy, while maintaining the other
drugs in the regimen for 6 months or till tumor progression.
• Patients with oxaliplatin induced neurotoxicity should not receive it
again until near complete resolution.
• No role of calcium/magnesium infusions in preventing oxaliplatin
induced neurotoxicity.

28. CapeOx
• It is an active first line therapy for patients with metastatic CRC.
• CapeOx and FOLFOX have similar median PFS.
• Toxicities associated with Capecitabine include the following:
• 1)Patients with diminished creatinine clearance may accumulate levels of
the drug requiring dose modification.
• 2) The incidence of hand-foot syndrome was increased in patients receiving
Capecitabine based regimens as compared to 5FU/LV based regimens.
• 3) North American patients may have increased risk of adverse events at
doses tolerated by their European counterparts.
• Recent studies have shown that capecitabine induced hand-foot skin
reactions are associated with an improved OS.
• Bevacizumab may be added to Capecitabine as first line therapy.

29. FOLFIRI
• FOLFOX and FOLFIRI have comparable efficacy in terms of response
rate, PFS and OS.
• Toxicities associated with irinotecan include both early and late forms
of diarrhea, dehydration and severe neutropenia.
• Irinotecan is inactivated by the enzyme uridine diphosphate
glucuronyltransferase 1A1, which is also involved in converting
bilirubin into more soluble forms through conjugation.
• Deficiencies in UGT1A1 can be caused by genetic polymorphism and
can result in conditions associated with unconjugated
hyperbilirubinemias such as types I and II Crigler-Najjar and Gilbert
syndromes.

30. FOLFIRI
• Irinotecan should be used with caution and at a decreased rate in patients
with Gilbert syndrome or elevated serum bilirubin.
• Certain polymorphism can decrease level of glucuronidation of the active
metabolite of irinotecan and result in toxic levels of the drug.
• Dosing of irinotecan should be individualized based on UGT1A1 genotype.
• Commercial tests for detecting UGT1A1 allele which is associated with
decreased gene expression and reduced levels of UIGT1A1 expression.
• No role of testing for UGT1A1 allele in patients who develop irinotecan
related toxicity since these patients require a dose reduction regardless.
• Avastin as well as Cetuximab/Panitumumab may be added to FOLFIRI.