Issue No. 51QUARTERLY NEWSLETTERJune, 2000

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Administrative Office

St. Joseph's Hospital Site, L301
-
10

50 Charlton Avenue East

HAMILTON, Ontario, CANADA L8N 4A6

PHONE: (905) 521
-
6141

FAX: (905) 521
-
6142

http:
//www.fhs.mcmaster.ca/hrlmp/


Issue No. 51

QUARTERLY NEWSLETTER

June,


2000


HER
-
2/neu (C
-
erbB
-
2) TEST IN BREAST CANCER



BACKGROUND:

HER
-
2/neu is a proto
-
oncogene localized to chromosome 17 that encodes a
transmembrane tyrosine kin
ase human epidermal growth factor receptor protein. Overexpression of
HER
-
2/neu protein or HER
-
2/neu gene amplification is seen in 10
-
33% of breast cancers
1,2
and at a lower
frequency in a number of other solid tumor types. In common with other members of
epidermal growth
factor family, the HER
-
2/neu protein has three domains: an extracellular receptor binding site, a lipophilic
transmembrane segment, and an intracellular area with tyrosine kinase activity. Ligand binding to the
receptor complex on the cell

surface leads to activation of intrinsic protein tyrosine kinase activity. This
triggers a cascade of events leading to gene activation resulting in mitogenic stimulation. The HER
-
2/neu
receptor, therefore, plays a key role in cellular growth.

HER
-
2/neu

AS A PROGNOSTIC AND PREDICTIVE FACTOR IN CANCER
: It is generally accepted that
there is a significant correlation between a positive HER
-
2/neu status and an adverse clinical outcome in
node positive tumours.
3,4

There is still controversy concerning its pro
gnostic significance in node negative
patients.
5,6

The clinical studies have shown an apparent resistance of tumours with a positive HER
-
2/neu
status to hormone therapy alone
7,8
and a strong interaction between HER
-
2/neu overexpression and
chemosensitivity

to some chemotherapy regimes.
9,10

CANCER THERAPY:

HERCEPTIN (Trastuzumab) is a recombinant DNA
-
derived humanized
monoclonal antibody that selectively targets the extracellular domain of HER
-
2/neu protein. This anti
-
HER
-
2/neu monoclonal antibody therapy re
sults in alterations of signaling and therefore reduced tumour
growth. Apart from this action, Herceptin is also known to potentiate the activity of chemotherapy agent
such as paclitaxel. In Ontario, Herceptin is approved for the treatment of patients with

metastatic breast
cancer whose tumours overexpress HER
-
2/neu. Herceptin therapy should only be initiated under the
supervision of a physician experienced in the treatment of cancer patients.


TESTING HER
-
2/neu

STATUS:

Immunohistochemistry (IHC), fluoresce
nt in situ hybridization (FISH),
and quantitative PCR are powerful assays that are useful for detection of HER
-
2/neu overexpression and
amplification respectively in formalin fixed paraffin embedded tissue samples from primary breast
cancers, lymph nodes,
or metastases. The following figures show negative and positive HER
-
2/neu using
IHC (DAKO A0485). As per Cancer Care Ontario guidelines, HER
-
2/neu testing should be undertaken in
laboratories supporting regional cancer centers or institutions providing med
ical oncology practice. These
laboratories must have an established immunohistochemistry department with sufficient volume to
maintain technical/professional knowledge and skill. The laboratories must confirm indeterminate results
using either FISH or quan
titative PCR.





NEGATIVE

POSITIVE


REFERENCES:

1.

Ali IU, Campbell G, Lidereau R, Callahan R. Lack of evidence for the prognostic significance of c
-
erbB
-
2 amplification in human breast carcinoma. Oncogene Res 1988;3:139
-
46.

2.

Berger MS, Locker GW, Saurer S
, Gullick WJ, Waterfield MD, Groner B, et al. Correlation of c
-
erbB
-
2 gene amplification and protein expression in human breast carcinoma with nodal status
and nuclear grading. Cancer Res 1988;48:1238
-
43.

3.

Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A,

McGuire WL. Human breast cancer:
correlation of relapse and survival with amplification of the HER
-
2/neu oncogene. Science
1987;235:177
-
82.

4.

Ross JS, Fletcher JA. The HER
-
2/neu oncogene in breast cancer: prognostic factor, predictive
factor, and target fo
r therapy. Stem Cells 1998;16:413
-
28.

5.

Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsy S, et al. Neu/erbB
-
2
amplification identifies a poor prognosis group of women with node
-
negative breast cancer. J Clin
Oncol 1998;16:1340
-
9.

6.

Clark G.

Should selection of adjuvant chemotherapy for patients with breast cancer be based on
erb
-
2 status? N Natl Cancer Inst 1998;90:1320
-
21.

7.

Bianco AR, DeLaurentis M, Carlomagno C, et al. 20 year update of the Naples gun trial of
adjuvant breast cancer therap
y: evidence of interaction between c
-
erbB2 expression and
tamoxifen efficacy. Proc Am Soc Clin Oncol 1998;17:97a.

8.

Newby JC, Johnston SR, Smith IE, Dowsett M. Expression of epidermal growth factor receptor
and c
-
erbB2. Clin Cancer Res 1997;3:1643
-
51.

9.

Paik

S, Bryant J, Park C, Fisher B, Tan
-
Chiu E, Hyams D, Fisher ER, Lippman ME, Wickerham
DL, Wolmark N. erbB
-
2 and response to doxorubicin in patients with axillary lymph node
-
positive,
hormone receptor
-
negative breast cancer. J Natl Cancer Inst 1998;90:1361
-
70.

10.

Ravdin PM, Green S, Albain KS, et al. Initial report of the SWOG biological correlation study of c
-
erb2 expression as a predictor of outcome in a trial comparing adjuvant CAFT with tamoxifen (T)
alone [abstract]. Proc Am Soc Clin Oncol 1998;17:97a.

D
r. L. Elavathil, Pathologist

Dr. B. Carter, Pathologist

Hamilton Regional Laboratory Medicine Program Henderson General Site,


Hamilton Health Sciences Corporation