Biomedical Engineering Reference
In-Depth Information
mutated CRC was
not overcome by the combination with chemotherapy in the
setting of first- and second-line treatment (see Table 7.4). Phase 3
trials of second or third line chemotherapy and moAbs have also
demonstrated benefit with the addition of and EGFR inhibitor is
limited to patients who harbor
Resistance to anti-EGFR moAbs in
KRAS
wild-type tumors. Based on
the above findings, panitumumab and cetuximab are approved in
Europe and North America, only for patients with mCRC and
KRAS
KRAS
WT tumors, in the first or second-line second as monotherapy or in
combination with standard chemotherapy.
mutations
are resistant to the effects of cetuximab. Among patients with
chemotherapy refractory CRC, a particular
Interestingly, a recent study suggests that not all
KRAS
mutation in codon
13, namely p.G13D, was associated with longer overall and PFS when
compared with other
KRAS
mutated tumors [82]. This was only an
observational study and evaluation of cetuximab therapy in these
patients with tumors harboring the p.G13D mutation in prospective
randomized trials is warranted.
Finally, predicting response to an anti-EGFR moAbs based on
KRAS
KRAS
mutation status is not perfect. Although a positive mutation
status is a highly specific test for non-response (almost 95% of
KRAS
mutant tumors do not respond), it is only moderately sensitive For
instance, only 40-60% of patients with WT
colorectal cancers
respond to an anti-EGFR moAb. This suggests that there may be other
components in the EGFR pathway that may determine resistance
and predict for response to treatment.
KRAS
7.4.2.6
BRAF mutations in patients with mCRC
The
gene encodes a serine threonine protein kinase that acts
as a downstream effector of KRAS signaling [83]. The
BRAF
gene is
composed of 18 exons, and the most common activating mutation
occurs in exon 15, a thymine to adenine transversion, leading to a
valine to glutamate substitution at codon 600, denoted V600E [84].
The encoded mutant protein has more than a 10-fold increase in
kinase activity [85]. The V600E
BRAF
BRAF
activating mutation, which
occur mutually exclusive with
KRAS
mutations, are found in about
10% of mCRCs [86, 87].
