Human epidermal growth factor receptor-2 (HER2/erbB-2) is a member of a family of four transmembrane receptor tyrosine kinases that regulate cell growth, survival and differentiation via multiple signal transduction pathways. Amplification of the HER2 gene occurs in 20-25% of human breast cancers. This amplification event is an independent adverse prognostic factor as well as a predictive factor for increased response to doxorubicin-based combination chemotherapy, response to trastuzumab and decreased response to hormonal therapy. Methods for detecting protein overexpression or gene amplification in clinical tumor specimens include immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques, with the latter considered by some to be more accurate. Trastuzumab (Herceptin) is a recombinant humanized monoclonal antibody which targets an epitope in the extracellular domain of the HER2 protein. Preclinical models demonstrated that this antibody has significant anti-tumor activity as a single agent and has synergy with certain chemotherapeutic drugs. Phase II and III clinical trials performed in women with metastatic breast cancer that overexpress HER2 have shown that trastuzumab has clinical activity when used as first-, second- or third-line monotherapy, and improves survival when used as first-line therapy in combination with chemotherapy. Newer combinations with numerous chemotherapeutic drugs have also shown significant clinical activity in phase II studies. In all of these trials, trastuzumab was generally well-tolerated, but cardiac toxicity (particularly when the antibody was combined with anthracyclines) was an unexpected adverse effect. Although trastuzumab is currently usually administered on a weekly intravenous schedule, evidence suggests that a triple dose of the drug given once every three weeks has a pharmacokinetic profile expected to be equally efficacious. Neither the optimal schedule nor the optimal duration of trastuzumab therapy has yet been clearly defined in controlled clinical trials. Current clinical investigations of trastuzumab include its use in both the adjuvant and neoadjuvant settings as well as in combination with other chemotherapy drugs or new biologic targeted agents.
"Trastuzumab (Herceptin®) is a humanized IgG1 mAb directed against the extracellular domain of Her2 (Agus et al., 2005; Garnock-Jones et al., 2010). Trastuzumab is approved for the treatment of HER2 overexpressing breast and gastric tumours (4–8 mg·kg -1 then 2–6 mg·kg -1 every 1 to 3 weeks) (Scholl et al., 2001; Yeon and Pegram, 2005; Herceptin USPI, 2010). "
[Show abstract][Hide abstract] ABSTRACT: Monoclonal antibodies (mAbs) and fusion proteins directed towards cell surface targets make an important contribution to the treatment of disease. The purpose of this review was to correlate the clinical and preclinical data on the 15 currently approved mAbs and fusion proteins targeted to the cell surface. The principal sources used to gather data were: the peer reviewed Literature; European Medicines Agency 'Scientific Discussions'; and the US Food and Drug Administration 'Pharmacology/Toxicology Reviews' and package inserts (United States Prescribing Information). Data on the 15 approved biopharmaceuticals were included: abatacept; abciximab; alefacept; alemtuzumab; basiliximab; cetuximab; daclizumab; efalizumab; ipilimumab; muromonab; natalizumab; panitumumab; rituximab; tocilizumab; and trastuzumab. For statistical analysis of concordance, data from these 15 were combined with data on the approved mAbs and fusion proteins directed towards soluble targets. Good concordance with human pharmacodynamics was found for mice receiving surrogates or non-human primates (NHPs) receiving the human pharmaceutical. In contrast, there was poor concordance for human pharmacodynamics in genetically deficient mice and for human adverse effects in all three test systems. No evidence that NHPs have superior predictive value was found.
British Journal of Pharmacology 12/2011; 166(3):823-46. DOI:10.1111/j.1476-5381.2011.01811.x · 4.84 Impact Factor
"As such, signaling through key molecules located “downstream” of the receptor, such as phosphatidylinositol 3 kinase (PI3K) and mitogen-activated protein kinase (MAPK), is disrupted.40 Furthermore, since ErbB receptors can be recycled to the cell membrane in a functional state, it is believed that trastuzumab enhances lysosomal breakdown of HER2 by recruiting a protein known as c-Cbl.41 This theory, however, has been challenged on the basis that surface downregulation is not an important mechanism of drug action.42 "
[Show abstract][Hide abstract] ABSTRACT: The ability to probe diseases at the genomic level has improved our understanding and enhanced the treatment of breast cancer. One important finding relates to the HER2 oncogene which encodes a novel transmembrane receptor that, when overexpressed, appears to confer growth and survival advantages to breast tumor cells. This fortuitous discovery enabled researchers to develop agents which could inhibit receptor-mediated tumor cell signaling. Numerous clinical trials of such agents have demonstrated improved outcomes in patients with HER2-positive breast cancer. Nonetheless, not all tumors respond to therapy targeting the receptor, while relapses occur after an initial response to treatment. This paper provides a historical and current perspective of the treatment of patients with HER2-positive breast cancer.
International Journal of Women's Health 08/2010; 1(1):155-71.
"Total HER2 expression is an independent predictor of poor prognosis [2,7] and is also a clinical target for treatment . In this study, 8% of the patients had HER2-positive tumors in accordance with this being a hormone receptor-positive population, and HER2 positivity was associated with shorter disease-free survival. "
[Show abstract][Hide abstract] ABSTRACT: High expression of total HER2 protein confers poor prognosis for breast cancer patients. HER2 is a member of the HER family consisting of four receptors, HER1 to HER4. HER receptor activity is regulated by a variety of mechanisms, and phosphorylation of the C-terminal part of the HER receptors is a marker for active signaling. The importance of phosphorylation and thereby activation of the HER1 to HER4 receptors, however, has not been investigated concomitantly in breast tumors. In the present study we examined the importance of active HER signaling in breast tumor biopsies and paired metastases, by evaluating the expression of phosphorylated HER1, HER2, HER3, Erk, Akt and the total level of HER4 and HER2.
Immunohistochemical analysis was performed on 268 primary breast tumors and 30 paired metastatic lesions from postmenopausal women with hormone receptor-positive breast tumors, who had received adjuvant tamoxifen therapy. The observed protein expression levels were analyzed for co-expression, for correlation to clinicopathological parameters and for prognostic value in relation to disease-free survival and overall survival. Lastly, the difference between protein levels in primary tumors versus metastasis was evaluated.
In the primary tumors, 8%, 18%, 14% and 15% of cases were scored positive for total HER2, pHER1, pHER2 and pHER3 expression, respectively. HER4 was expressed with strong intensity in 68% and at moderate intensity in 29% of cases. The activated forms of Akt and Erk were quite uniformly expressed in the categories; negative, moderate or strong. In univariate analysis, expression of total HER2, pHER1, pHER2 and pHER3 was significantly associated with poor disease-free survival. Strong HER4 expression was associated with prolonged disease-free as well as with overall survival. Expression of pAkt and pErk was not correlated with survival. In multivariate analysis, pHER2 expression was clearly an independent marker for poor disease-free survival and overall survival when tested against tumor size, tumor grade, nodal status and HER2. Lastly, comparison of HER receptor expression in metastatic versus primary tumors showed a significant increase in expression of pHER1 and pHER3 in the metastases.
In hormone receptor-positive breast cancer, determination of pHER2 yields additional prognostic information about poor prognosis compared with the current clinical standard for measuring HER2.
Breast cancer research: BCR 03/2009; 11(1):R11. DOI:10.1186/bcr2230 · 5.49 Impact Factor
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