Emerging Concepts in the Workup
of Colorectal Cancer
Short Presentation in Emerging Concepts
(SPEC)
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)
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
•
•
•
•
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?
–
–
–
–
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.
Selected Resources
Ross JS. Clinical implementation of KRAS testing in metastatic colorectal carcinoma:
the pathologist’s perspective. Arch Pathol Lab Med. 2012;136:1–10.
Hutchins G, Southward K, Handley K et al. Value of Mismatch Repair, KRAS,
BRAF mutations in predicting recurrence and benefits from chemotherapy In
colorectal cancer. J Clin Oncol. 2011;29:1261-1270.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in
Oncology: Colon Cancer v.3.2012.
http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf . Accessed
August 28, 2013
Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit
from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:17571765.
Additional Free Resource for CAP Members
NOTE: please remove this page before
presenting.
CAP Member Exclusive: CAP Pathology Resource Guides
Focused on a specific hot-topic technology, these
comprehensive guides highlights current resources, select
journal articles, as well as CAP and non-CAP educational
opportunities. And don’t miss the “Insights From Early
Adopters” section in each guide to gain perspective from
pioneering colleagues.
AVAILABLE NOW:
• Molecular Pathology (single gene test, small panel)
• Genomic Analysis (large panel, exome, genome)
Learn more: go to cap.org and type Pathology Resource Guides in the
“search” field located at the top of your screen.
“An outstanding overview
of basic materials,
including the technology
and links to a number of
individuals and centers
that can assist.”
“Extremely well done,
of high practical and
educational value.”