Biomedical Engineering Reference
In-Depth Information
is measured. Normally, the GCN is two per nucleus, representing the
diploid nature of cells and the alleles inherited from either parent.
Variations of GCN, either gains or losses, can be detected via these
methods.
gene in
normal cells and anything above two would be considered abnormal
on a cellular basis. Although abnormal, this may not be the threshold
level for which gene copy number (a continuous variable) would
predict for benefit to anti-EGFR moAbs, in fact, predictive thresholds
for GCN have varied from 2.47 and above, to greater than and equal to
6 (see Table 7.5) [8, 76, 105, 106, 108, 112]. This varied threshold is
due to the variable ratios of disomy versus polysomy or amplification
within nuclei from the same tumor specimen, representing the
inhomogeneous
As mentioned above, there are two copies of the
EGFR
FISH pattern of mCRC [106, 113]. Moreover,
gene amplification representing high levels of genomic gains is more
readily identifiable by FISH and CISH, compared with subtle degrees
of chromosomal gains (as with polysomy). Both of these reasons
make it difficult to score and evaluate GCN with FISH and CISH.
EGFR
7.4.3.4 Specimen selection for EGFR gene copy number
Statistically significant concordance between primary colorectal
tumors and their metastases with regard to
gene copy number
has been demonstrated by FISH analyses [105, 108]. Capuzzo
EGFR
et al
.,
reported that in only one out of 21 patients was a different
EGFR
gene score encountered from primary lesion and distant metastatic
site, as measured by FISH [105]. Although not conclusive, it suggests
that FISH analyses for
EGFR
GCN can be performed on either primary
or metastatic tissue.
7.4.3.5
Prognostic value of EGFR gene copy number
It was initially thought that increased
GCN might affect
patient prognosis, possibly relating to CRC biology, as opposed to
being a predictor of the therapeutic benefits with cetuximab. This
is based on an earlier phase II study that evaluated the antitumor
activity of cetuximab, in patients with mCRC refractory to standard
chemotherapy [111]. No relationships between
EGFR
GCN, response
and PFS were observed in this study, but OS did appear to be related
to GCN. However, in this study the
EGFR
GCN was measured with a
quantitative PCR assay and may have been prone to false negative
EGFR
