Biomedical Engineering Reference
In-Depth Information
from this trial suggests that cetuximab dose escalation is safe and
increases response rates in patients without a rash or those who
develop only a mild skin reaction within 3 weeks of starting therapy.
The response rate among patients with less than or equal to a grade
1 skin toxicity who were randomized to dose escalation was 30%
versus 13% in the control group who only continued standard dose
therapy [55]. This trend was not statistically significant and requires
more mature data from a larger sample population.
Using rash as an early clinical marker of benefit from anti-EGFR
moAbs does have some limitations. Rash has occurred in patients
without any apparent benefit from anti-EGFR moAbs, and conversely
clinical benefit has occurred in patients without rash. Some suspect
that rash may be a surrogate marker for a genetic profile that
predisposes individuals to rash and also modulate the response to
anti-EGFR moAbs. Also, rash could merely be a prognostic marker of
intact immunity or merely the result of treatment bias; as patients
who have intact immune systems or are treated long enough to
develop a rash may have prolonged survival [56]. Although, a clear
association between signaling inhibition in skin and antitumor
response has not been found, rash seems to correlate with drug
exposure, concentration, and likely reflects effectiveness.
7.4.2
Potential Predictive Genetic Alterations of the
EGFR Pathway in Patients with mCRC
7.4.2.1
KRAS mutations
Activating mutations in the
gene, which result in EGFR inde-
pendent activation of the MAPK pathway and possibly PI3K pathway
through direct KRAS activation of PI3K, are found in approximately
40% patients with CRC [57]. These mutations typically occur in co-
dons 12 (79%; exon 2), 13 (17.6%; exon 2) or 61 (exon 3) [57] and
do not seem to have any prognostic value in patients with mCRC.
However, in patients with mCRC mutations in
KRAS
are the strongest
negative predictive marker for benefit for anti-EGFR moAbs as single
agents and in combination with chemotherapy (see Section 7.4.2.3).
KRAS
7.4.2.2 KRAS mutation detection
The presence of KRAS mutations in colorectal tumor tissue can be
detected by several different molecular methods (see Table 7.3).
