Biomedical Engineering Reference
In-Depth Information
Based on the high specificity of cetuximab for EGFR, it was
originally assumed that expression of EGFR, as detected by IHC,
would be a predictor of benefit to the agent. As a result, the early
clinical trials testing cetuximab (and panitumumab) were limited to
those patients whose tumors expressed EGFR as detected by IHC.
Contrary to this assumption, subsequent studies demonstrated that
objective responses could be observed in patients who had EGFR
negative tumors as determined by IHC and treated with cetuximab
or panitumumab [125]. Moreover, most studies have failed to
demonstrate any relationship between level of EGFR expression and
the clinical activity of anti-EGFR drugs. There are several hypotheses
as to the reasons behind the benefit observed in patients with
EGFR negative tumors, as detected by IHC, from anti-EGFR moAbs.
First, there have been several technical reasons proposed causing
the inconsistent results. This includes, variability in EGFR staining
based on processing and handling of tumor tissue samples, such as
fixation methods and prolonged storage time. Also, the variability
may arise from the use of different antibodies, targeting different
epitopes as compared with those targeted by the anti-EGFR moAbs.
Finally, false-negative results may be encountered due to the partially
subjective scoring of IHC. Based on these inconsistencies, IHC testing
for EGFR is inadequate at identifying patients who would and would
not benefit from anti-EGFR moAbs.
7.4.4.2 EGFR ligands: amphiregulin and epiregulin
Both amphiregulin (AREG) and epiregulin (EREG) are alternative
ligands for EGFR. Epiregulin is known to bind more weakly to EGFR
than EGF but is more potent than EGF and results in prolonged
receptor activation [126]. It was hypothesized that elevated
expression of these ligands may stimulate an autocrine loop through
the EGFR. As a result, this may identify those cancer cells that are
dependent on EGFR signaling and therefore indicate sensitivity to
anti-EGFR agents that block receptor to ligand binding.
demonstrated that
in chemotherapy refractory patients treated with cetuximab
monotherapy, tumors that had high gene expression levels of the
EGFR ligands, AREG and EREG, and WT
A recent study by Khambata-Ford
et al.
were more likely to
have disease control on anti-EGFR treatment. This study employed
a global genomic approach, using microarray analyses of 95
colorectal cancer liver metastases, to identify markers that were
K-RAS
