2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

BIOMARKERS AND COLORECTAL CANCER
Fig. 1. Signalling pathways that are activated upon
ligation of epidermal growth factor with its receptor
(EGFR).
Abbreviations: CRC, colorectal cancer; EGFR, epidermal
growth factor receptor; PI3K, phosphoinositide 3-kinase;
PTEN, phosphatase and tensin homolog.
prognosis have various weak links. A few examples of this
are discussed in the following sections.
EGFR Antibodies and Mutations in KRAS and BRAF
Dr. Bendell accurately points out that the majority of
retrospective clinical trials support the notion that patients
whose tumors harbor mutations in codon 12 of KRAS show
very little or no response to EGFR MoAby, whereas tumors
with mutations in codon 13 seem to respond as well as Ras
wild-type tumors. 27 But Dr. Bendell has omitted the observation
from the COIN, NORDIC, PACCE, and CAIRO-2
suggest that there is a detrimental effect of adding cetuximab
to chemotherapy in patients with tumors containing
mutant KRAS compared with chemotherapy alone. 28-31 The
Fig. 2. Prevalence of epidermal growth factor (EGFR)
pathway deregulations and response to monoclonal antibodies
targeting EGFR in chemotherapy-refractory advanced
colorectal cancer.
Abbreviations: PI3K, phosphoinositide 3-kinase; PTEN,
phosphatase and tensin homolog.
assumption that approximately 40% of colorectal cancers harbor
ras mutation is misleading. The focus most likely should
be on the estimated 75% to 80% KRAS codon 12 mutations.
Further, the story of Braf is more complicated. Dr. Bendell’s
point is well taken that tumors with BRAF mutations
(10% of colon cancer) have a poorer prognosis than wild-type
tumors, but they may respond equally well to EGFR inhibition
as do wild-type tumors. But, there are other abnormalities
that can mimic (phenocopy) KRAS mutation vis à vis
EGFR inhibition that merit more emphasis than discussed
by Dr. Bendell. PTEN blocks signaling downstream of
growth factor receptors; PTEN especially manifests this
effect by impairing signaling emanating from PI3K step 27
(Fig. 1). Although the assay methodology for PTEN has not
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