Biomedical Engineering Reference
In-Depth Information
associated with disease control in patients treated with cetuximab
[78]. Moreover, patients with high AREG and EREG expression, as
detected by ELISA, had a longer PFS compared with those with a low
expression (EREG: median of 103.5 vs. 57 days; and AREG: median
of 115.5 vs. 57 days). This study was soon corroborated in an
independent cohort of patients with mCRC testing for ligand mRNA
in primary tumor samples [127]. A chemotherapy refractory cohort
was accrued, but this time treated with irinotecan and cetuximab as
opposed to monotherapy. Again, increased expression of AREG and
EREG in
WT tumors predicted for response, PFS and OS.
Although promising as an additional test to predict for benefit
from anti-EGFR moAbs in patients with mCRC and
KRAS
WT tumors,
further validation of the above ligand data is required in prospective
controlled trials, as well as in trials involving anti-EGFR moAbs in
earlier lines of treatment and in combination with chemotherapy.
Moreover, the techniques to detect and score the levels of
amphiregulin and epiregulin expression must be standardized
before this can be applied to clinical practice.
KRAS
7.4.4.3
PTEN loss of expression
PTEN
(phosphatase and tensin homologue gene) encodes an
enzyme that when functioning properly, signals cells to stop dividing
and induces apoptosis when necessary. PTEN
inactivation leads
to uncontrolled signaling via PIP3 accumulation and subsequent
AKT
hyperphosphorylation, resulting in loss of responsiveness to
apoptotic stimuli of cancer cells [128].
PTEN loss has been observed
in different sporadic tumors, including colorectal cancers [129].
Preclinical data has demonstrated the importance of a functioning
PTEN/PI3K/AKT pathway in determining the sensitivity of
CRC cell
lines to cetuximab [118].
7.4.4.4 Measuring PTEN expression
PTEN expression is most often measured with immunohistochemistry
(IHC). Although, several antibodies exist for the detection of PTEN
with IHC, none have been determined to be superior over another
(see Table 7.6). Similar to EGFR, the IHC for PTEN is subject to some
of the same criticisms. To date, there has been no standardization
in the IHC assay in regards to tissue handling, optimized storage
duration, and semi-subjective scoring algorithms.
