Transcript Advancements in the Workup of Colorectal Cancer

Emerging Concepts in the
Workup of Colorectal Cancer
APMG Pathologist, MD FCAP
Mismatch Repair System
(MMR)
• During replication of each cell’s 3 billion DNA
bases, mistakes are introduced
• The mismatch repair system (MMR) corrects
errors during replication
– Functional protein complex composed of four
subunits – MLH1, MSH2, MSH6 & PMS2
• Proteins can be detected using IHC
• Normal cells express the proteins
Defects in the Mismatch Repair
System (dMMR)
• Sporadic (2/3rd of cases)
– Usually the result of methylation (DNA inactivation)
of MLH1 gene
– Biologic behavior of tumor similar to tumors in
patients with inherited mutation
• Inherited (1/3rd of cases)
– Born with one defective copy of MMR gene
– During life, second copy is mutated by chance
during DNA replication
– Most often MLH1 or MSH2
• Both result in microsatellite instability (MSI)
Microsatellite Instability (MSI)
• Develops as a result of defects in the mismatch
repair system (MMR)
• Cells that cannot repair their DNA acquire
compounding defects with every cell division
• Microsatellites are areas of highly repetitive
DNA
– Especially prone to errors during DNA replication
Colorectal Cancer
From: de la Chapelle A. Microsatellite Instability. N Engl J Med. 2003 Jul 17;349(3):209-10.
dMMR and MSI
• Same underlying biology of the tumor
• Test for protein expression (IHC) or genetic
abnormalities (MSI)
• Significantly better prognosis identified in
multiple studies
– For stage II – III disease, help decision making for
which patients should receive adjuvant
chemotherapy
EGFR inhibitors
(e.g. cetuximab, panitumimab)
• Monoclonal antibodies targeted at epidermal
growth factor receptors (EGFR)
• First line therapy for unresectable,
inoperable or metastatic colorectal cancer
– Second line therapy after failure of 1st line
• No benefit in the presence of a mutation in
the KRAS gene!
– The targeted pathway is already activated
downstream
Antibodies approved for colorectal cancer therapy
From: Gazdar FA. Cancer
Metastasis Rev (2010) 29:37–48
KRAS
• Mutations in codons 12-13 associated with
resistance to EGFR inhibitors
– A codon is a set of 3 nucleic acids in a row that
code for the amino acid to be inserted when
building the protein
– Mutations in codons 12-13 cause KRAS to
continually signal downstream in the absence of
upstream signal, i.e. “switch is stuck in the on
position”
• Test either the biopsy, primary resection, or
metastasis
– Mutation occurs early during oncogenesis and
persists
BRAF
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BRAF, like KRAS, is in the EGFR pathway
One dominant mutation… V600E
Worse prognosis
Mixed data whether BRAF mutations confer
resistance to EGFR inhibitors, but most believe
it does
– … the mutation appears to cause downstream
signaling in the absence of ligand binding =
resistance to anti-EGFR therapy
When to test?
• Select patients by request or at the time of metastasis?
– Testing can take up to 2 weeks
– Sequential testing takes longer
• Select patients at the time of initial diagnosis or primary
resection?
– Clinical information and pathologic stage are often incomplete
– Does not allow all prognostic values to be incorporated in decision making
• All patients at the time of initial diagnosis or primary resection?
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More comprehensive diagnostic classification
Determination of (in)eligibility for therapy in advance
Ideal if not for costs
But… there is growing recognition among payers of the need for testing
and support for up-front algorithms
– and… cost is relatively small in total cost of cancer care
Consider Testing
• All colorectal adenocarcinomas greater than
stage I for:
– KRAS Codon 12-13 Mutations
– BRAF V600E Mutation
– Microsatellite Instability (MSI)
Added benefit… detection of inherited cases of
colorectal cancer offers opportunity to screen
family members.
Questions
• Contact pathologist with questions or to sort
out appropriate testing on a patient:
APMG Pathologist, MD FCAP
[email protected]
(888) 555-1212
About these slides
• Provided by the CAP as an aid to pathologists
• Intended as a “starting point” from which
customization / modifications can be made for
personal use
• CAP requests to be notified when the presentation
has been used via email to [email protected]
• Content has been reviewed by experts at the CAP,
but does not necessarily reflect the official opinion
of the College of American Pathologists.
• Version 1.0.1, rev. 4/27/2012
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