A117 (About (EGFr and CRC))
Comparison of Epidermal Growth Factor Receptor Levels in Neoplastic and in Normal Colonic Mucosa of Patients with Colorectal Cancer.
Giulia Piazzi,1Paola Paterini,1 Claudio Ceccarelli,2 Maria A. Pantaleo,3 Guido Biasco.3 Centre of Applied Biomedical Research (CRBA), S.Orsola-Malpighi Hospital,1 Bologna, Italy, Centre of Applied Biomedical Research (CRBA) and Surgical Pathology Unit, S.Orsola-Malpighi Hospital, University of Bologna,2 Bologna, Italy, Institute of Haematology and Medical Oncology, S.Orsola-Hospital, University of Bologna,3 Bologna, Italy.
Background:
Aberrant regulation of epidermal growth factor receptor (EGFr) signaling seems to be involved in the development and progression of many solid tumors, including colorectal cancer (CRC).
EGFr immunohistochemical content shows a very wide
variability in CRC, however most recent literature agree that EGFr is overexpressed.
In this study we evaluated EGFr content in colorectal neoplasia and in normal colonic mucosa of patients who underwent colonic surgery for CRC.
Patients and methods:
Samples of neoplasia and normal mucosa (approximately 15 cm distant from the lesion) were taken from 38 CRC patients (21 males; 17 females; age range:46-84 yr). Samples were analyzed for EGFr content using ELISA (Human Full Length EGFR Immunoassay Kit, Biosource International,USA) and Taqman Realtime PCR (iCycler, Bio-Rad Laboratories,
USA).
Paired t-test was used to detect differences in EGFr protein and mRNA levels between normal and cancerous tissue. Associations between these variables were assessed by the Spearman rank test. Correlation with clinico-pathologic parameters was done by unpaired t-test.
All calculations were performed using StatView
5.0 statistical software (SAS Institute Inc., Cary NC, USA).
Results:
EGFr protein mean content was 4.41 ng EGFr/mg total proteins (range 0.61-8.58) in normal mucosa and 2.06 ng EGFr/mg total proteins (range 0.26-5.96) in colorectal carcinoma.
EGFr mRNA mean content, normalized to the internal reference b-actin, was 10.93 10-3 (range 1.05-41.74 10-3) in normal mucosa and 7.98 10-3 (range 0.25-25.06 10-3) in colorectal
carcinoma.
Both EGFr protein and mRNA mean content were significantly higher in normal mucosa than in cancer tissue (p=0.001 and p=0.03, respectively).
According to Spearman rank test, EGFr content showed a relationship between CRC and normal mucosa both in ELISA (R=0.49; p=0.03) and Realtime PCR (R=0.64; p=0.001).
Neither EGFr protein nor mRNA content were associated with histological grading, tumour location or staging.
Conclusions:
Our data showed a linear relationship between paired
normal and neoplastic EGFr content, suggesting that impaired EGFr expression may not be restricted to CRC tissue but also may occur in morphologically normal mucosa.
These results seem to weigh against a true EGFr overexpression in CRC shedding new light on its biological significance and the related clinical implications.
End of Abstract ......
I cannot really read the above but does it say:
(1) EGFr content is in BOTH the good and bad tissue
(2) there is NO EGFr expression in CRC
(3) The August Article cited below (I thought) indicated that we have NOT yet developed a true *test* to determine over-expression of EGFR
In other words I think this KIT is broke ...
ELISA (Human Full Length EGFR Immunoassay Kit, Biosource International,USA)
SEVERE EDIT
<<<<<<<<<<<<<<<<<<<<<<<<<<
Immunohistochemical Testing
Is immunohistochemical (IHC)
testing of EGFR necessary or appropriate
for the use of cetuximab? No.
From a medical and scientific perspective,
it is neither reasonable nor
appropriate. The currently available
tests for “determining” the EGFR status
of a tumor have no clinical usefulness
whatsoever.
There is absolutely no prospective
clinical evidence that supports the use
of these tests in this setting. In the
original report on cetuximab plus
irinotecan,[16] the response rates for
1+, 2+, and 3+ positive patients, as
determined by an independent response
assessment committee, were
virtually identical. The same was
found to be true in a larger confirmatory
trial.[14] In all of these studies,
patients felt to be “negative” for the
EGFR were excluded from treatment.
Only two reports thus far have specifically
explored the use of cetuximab-
based therapy in EGFR-negative
patients. Lenz et al reported a small
series of nine EGFR-negative patients
who were treated with single-agent
cetuximab; two patients responded.[
15] Independent radiology review
of the nine patients confirmed one
partial response and classified four
patients as having achieved stable disease.
(Recall that up to a 49% regression
regression
is classified as stable disease from
a regulatory perspective.)
A somewhat larger set of patients
was recently reported by Chung et
al,[20] who reviewed the experience
with cetuximab at Memorial Sloan-
Kettering Cancer Center for patients
who initiated treatment with cetuximab
during the first 3 months of its
commercial availability. The computerized
pharmacy records were used to
eliminate recall bias in identifying all
patients who received this drug.
Records were then reviewed to identify
patients who were negative for
EGFR by IHC staining. Of 16 EGFRnegative
patients, 14 had received
cetuximab plus irinotecan and 2 had
received single-agent irinotecan alone.
(As would be expected, both patients
who received cetuximab alone had
indications of significant comorbidities
and poor performance status, and
one received only two doses of cetuximab.)
A review of scans by a reference
radiologist first confirmed that
all 16 patients had demonstrated tumor
growth on a prior irinotecanbased
regimen. Further review then
identified four confirmed partial responses
to cetuximab-based therapy,
all of which were durable at a 6-week
(or later) follow-up scan. All four responders,
as well as two additional
minor responders, had received cetuximab
plus irinotecan.
Clearly, the idea that patients who
lack IHC expression of EGFR are incapable
of responding to cetuximab
is overtly false (Table 2). This does
not mean that EGFR is not the target
for cetuximab. Rather, it means that the
currently available IHC techniques are
seriously flawed and are essentially useless
from a clinical perspective. In truth,
since it has been demonstrated that IHC
expression of EGFR can vary over storage
time and be influenced by the type
of fixative used,[21] as well as vary
from primary to metastasis, it is not
reasonable to believe that these stains
will be sufficiently sensitive and specific
to allow for definitive selection
or exclusion of patients.
The implications of these findings
are clear: Currently available IHC
stains for EGFR have failed to show
any predictive value in terms of the
efficacy of cetuximab-based therapy;
thus, no clinical decision should be
made on the basis of these stains, and
they should not be performed in routine
practice. No patient who is felt to
be otherwise appropriate for cetuximab-
based therapy should be excluded
from such therapy solely on the
basis of a negative EGFR IHC stain.
Similarly, a high degree of EGFR expression
is meaningless in terms of
predicting for cetuximab activity, in
colorectal cancer or otherwise, and
this should not be used as justification
for use of the drug.
<<<<<<<<<<<<<<<<<<<<<<<<<<
Title:
Metastatic Colorectal
Cancer: Is There One
Standard Approach?
By:
LEONARD B. SALTZ, MD
Attending Physician and Member
Gastrointestinal Oncology Service
Memorial Sloan-Kettering
Cancer Center
Professor of Medicine
Weill Medical College of
Cornell University
New York, New York
August 2005
Journal of Oncology (?)
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