HER-2 Overexpression

Published immunohistochemical studies of overexpression of HER-2 report a wide range of overexpression rates, ranging from 9 to 60%. The likely reason for this variation is the use of different antibodies, tissue types, and fixation and staining protocols. In addition, different scoring systems result in interpretation differences. To minimize these variations the use of a uniform immunohistochemical method, such as the HercepTest, is recommended. The HercepTest kit provides standardized procedure and evaluation criteria. 

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Trastuzumab specifically binds the extracellular domain of HER-2 that is found overexpressed on the membrane of cancer cells in 15-20% of patients with breast cancer. It has been approved in HER-2 overexpressing (HER-2 +++ or FISH +) breast cancers. 

Trastuzumab (Herceptin ) Roche mAb HER-2 HER-2 overexpressing breast cancer in the adjuvant and metastatic settings... 

Modi S, Stopeck AT, Gordon MS, Mendelson D, SoUt DB, BagateU R, Ma W, Wheler J, Rosen N, Norton L, Cropp GF, Johnson RG Hannah AL, Hudis CA. (2007) Combination of trastuzumab and tanespimycin (17-AAG KOS-953) is safe and active in trastuzumab-refractory HER-2 overexpressing breast cancer A phase I dose-escalation study. J Clin Oncol 25 5410-5417. 

Gy. This benefit is specific to cells with HER-2 overexpression (69). 

Initial phase I and II trials with trastuzumab were done in patients with metastatic breast cancer with documented HER-2 overexpression as measured by immunohis-tochemistry. The first phase Ell study reported by Baselga et al. (22) enrolled patients heavily pretreated with chemotherapy and demonstrated an objective response rate of 11%. Side effects were minimal and consisted of occasional fever and chills acutely... 

Wood et al. (1991) have used the Southern hybridization method for detecting DNA amplification and a possible structural rearrangement of the HER-2/nen oncogene in 1 of 12 bladder tumors. Amplification of this oncogene in the tumor was sixfold that of oncogene found in placental DNA. Approximately 36% of the tumors studied overexpressed HER-2 mRNA, which was 3- to 38-fold that of normal urothelium. HER-2 overexpression occurred in superficial and invasive tumors. Deoxyribonucleic acid amplification occurs infrequently in bladder carcinoma, in contrast to its occurrence in some other carcinomas. Immunohistochemical analysis has shown that pi85 HER-2 polyclonal antibody is specific for HER-2 protein overexpression in bladder carcinoma. This study was carried out prior to the use of Herceptin. 

TABLE 12.3. Scores for HER-2 Overexpression in Breast Tumor using the Dako Hercep Test... 

TABLE 12.4. Incidence of HER-2 Overexpression in Human Solid Tumors ... 

The incidence of HER-2 overexpression varies considerably in different tumors. Table 12.4 shows an average score of HER-2 overexpression in representative human solid tumors commonly evaluated in clinical practice. The specimens in this study consisted of resections of primary tumors. Locally advanced and metastatic lesions of the same tumor types may show significantly different incidences of HER-2 overexpression. Infiltrating ductal carcinoma is one of the few tumor categories for which the incidence of HER-2 overexpression is consistent in most studies. These data were obtained using a single, standardized immunohistochemical method (Herceptin). 

Bussolati G, Montemurro F, Righi L, et al. A modified Trastuzumab antibody for the immunohistochemical detection of HER-2 overexpression in breast cancer. Br. J. Cancer. 2005 92 1261-1267. 

Vogel, C. L., Cobleigh, M. A., Tripathy, D., Harris, L., Fehrenbacher, L., Slamon, D., Ash, M., Novotny, W., and Shak, S. (1998). Efficacy and safety of Herceptin (Trastuzumab, humanized anti-HER-2 antibody) as a single agent in first-line treatment of HER-2 overexpressing metastatic breast cancer (HER-2+/MBC). Breast Cancer Res. Treat. 50, 232a. 

Tsuda H, AkiyamaF, Terasaki H, et al. Detection of HER-2/neu (c-erb B-2) DNA amplification in primary breast carcinoma. Interobserver reproducibility and correlation with immunohistochemical HER-2 overexpression. Cancer. 2001 92 2965-2974. 

About 30% of unselected breast carcinomas are associated with HER-2 overexpression most of them are invasive ductal carcinoma, infiammatory breast cancer, Paget s disease as well as breast cancer arising in pregnant women, whereas invasive lobular carcinoma, mucinous carcinoma and medullary carcinoma of the breast are rarely accompanied by HER-2 overexpression. HER-2 overexpression is also found in a significant percentage of male breast carcinomas (about 30%). 

Another considerable observation is the relationship between the expression of HER-2 oncoprotein and the expression of steroid hormone receptors. Tumors vfith HER-2 overexpression show usually a low expression level of estrogen and progesterone receptors, while tumors with a high expression level of estrogen and progesterone receptors often lack overexpression of the HER-2 oncoprotein. Moreover, there is an inverse relationship between the expression of the bd-2 oncoprotein and the expression of both HER-2 and EGER. It is also interesting to mention that BRCA-1- and BRCA-2-related breast carcinomas are rarely associated with HER-2 overexpression. 

Breast cancers with HER-2 overexpression have a poor prognosis with a median survival rate of 3 years compared with tumors lacking the HER-2 overexpression having a median survival rate of 6-7 years. 

Tumors with HER-2 overexpression are frequently poorly differentiated and a high percentage of the tumor cells is in the S phase. 

A high percentage of tumors with HER-2 overexpression is associated with P53 mutations and the tumor cells are usually bcl-2-negative. 

Tumors with HER-2 overexpression are usually resistant to anti-estrogen therapy and CME (cyclophosphamide/methotrexate/5-fluorouracil) chemotherapy. 

The extracellular domain of the HER-2 neu molecule is the therapeutic target for the specific IgGlx humanized chimeric monoclonal antibody Trastuzumab (Herceptin ), approved 1998 and found to be effective in malignancies with HER-2 overexpression. An important aspect of this specific immunotherapy includes the efficiency against non-proliferating disseminated tumor cells (dormant cells), which are usually in the GO phase of the cell cycle, where conventional chemotherapy is less effective. The HER-2 neu molecule is also the target for specific tyrosine kinase inhibitors such as Tykerb (lapatinib ditosylate), which block the kinase-substrate interaction and the extracellular tyrosine kinase receptors on tumor cells. 

Tumors with scores of 0 or 1+ have no gene amplification and no HER-2 overexpression and consequently show a poor sensitivity to the specific immunotherapy. Tumors with a score of 3+are associated with HER-2 overexpression and show a good... 

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