Biomedical Engineering Reference
In-Depth Information
of therapy. An ideal predictive marker is simple, reproducible,
correlates with a clinical endpoint, and is available prior to initiation
of treatment. Both clinical and cellular alterations have emerged
as potential predictive markers for anti-EGFR moAb therapies.
However, as with most predictive tests, none have been ideal at
predicting response or resistance to anti-EGFR moAbs. This is, in
part, due to the complexities in identifying appropriate markers for
testing and the scoring of these markers. EGFR inhibitor induced
skin rash is a clinical feature that has been evaluated as a potential
predictive marker. The cellular features that alter DNA, microRNA,
and/or protein in the EGFR pathway from colorectal cancers have
also been evaluated for predictive potential.
7.4.1
Clinical Features
7.4.1.1 EGFR inhibitor induced-skin rash
The toxicity profile of the anti-EGFR moAbs excludes several of the
severe side effects commonly associated with cytotoxic chemotherapy,
such as hematological suppression. However, the use of these agents
have been hampered by a constellation of dermatological toxicities
experienced by more than 90% of patients, notably, papulopustular
rash, xerosis, pruritis, and paronychia [51]. The patho-physiology
of the cetuximab-induced rash remains poorly understood, but
is likely due to the predicted downstream perturbations of EGFR
signaling that have been demonstrated in studies of skin biopsies,
such as phosphorylated EGFR, phosphorylated AKT, Ki67, and p27
in patients treated with anti-EGFR moAbs [52-54]. Though rarely
life threatening, these skin effects impact quality of life, increase
risk for infection, and may lead to dose modification or treatment
discontinuation, thus potentially affecting the overall clinical benefits
of therapy.
A significant positive correlation between cutaneous toxicity
and rates of response, PFS, and OS has been noted in all trials of
cetuximab [34], or panitumumab [35] in patients with advanced
colorectal cancer. Based on the association of cetuximab and rash,
the EVEREST trial was launched [55]. Patients with irinotecan-
refractory EGFR-expressing CRC were randomized to either a
standard dose of cetuximab or the dose escalation arm, which
increased the cetuximab dose up to 500 mg/m
2
if the patient did not
experience more than Grade 1 rash by week 3. Preliminary results
