Annals of Oncology Advance Access originally published online on March 19, 2008
Annals of Oncology 2008 19(5):1020-1021; doi:10.1093/annonc/mdn061
letters to the editor |
ErbB/HER receptor family in breast cancer—the more we search the more we learn
In their recent clinico-pathological study, Revillion et al. [1] nicely report the profile of ErbB protein receptor family ligands in a rather large number of breast cancer cases. These results combined with other recently published work highlight the importance of the multilevel complexity of ErbB receptor activation (e.g. different potential dimmers, multiple actively participating ligands, various downstream signaling pathways).Targeting of ErbB receptors with new biological agents is probably one of the major breakthroughs in cancer therapeutics during the last decade [2,3]. The limited efficacy of these agents in a group of patients, in particular trastuzumab in breast cancer, has, however, raised important questions. First, the mechanisms of intrinsic and/or acquired resistance in trastuzumab represent a major future problem due to its widespread application in the adjuvant clinical setting. The implication of the dimerization pattern of ErbB receptors, especially the role of epidermal growth factor receptor and HER-3 [4], and more recently the identification of the modulation of ErbB driven activation by their ligands [5] offer new perspectives. Secondly, the obvious need for early recognition of patients not responding or even developing resistance has not been clarified yet. In this vein, there are preliminary promising data evaluating some potential immunological markers [6] as well as the HER-2 extracellular domain [7] and HER-3 expression [8]. Thirdly, the current application of trastuzumab in breast cancer therapeutics is based on the dogma that HER-2 overexpression or amplification is a prerequisite for its efficacy. However, there are accumulating data challenging this as it is becoming increasingly recognized that there are indirect ways of activating HER-2 downstream signaling pathways [10]. For example, it seems that HER-3 and its ligands (heregulins) might act independently and therefore consist a potential target of trastuzumab even in low HER-2-expressing breast tumors [11,12].
In conclusion, future ErbB receptor-oriented research in breast cancer should combine both upstream and downstream morphological and functional studies since this might represent the only way for the identification of patient sub-cohorts who will benefit from tailored treatment decisions.
1 Department of Biological Chemistry, Medical School, University of Athens, Athens, Greece
2 Division of Hematology-Oncology University of Pittsburgh, Pittsburgh, PA
3 Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
* (E-mail: karam{at}otenet.gr)
References
1. Revillion F, Lhotellier V, Hornez L, et al. ERBb/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol (2008) 19:73–80.
2. Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med (2007) 357:39–51.
3. Karamouzis MV, Argiris A, Grandis JR. Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas. JAMA (2007) 298:90–182.
4. Karamouzis MV, Badra FA, Papavassiliou AG. Breast cancer: the upgraded role of HER-3 and HER-4. Int J Biochem Cell Biol (2007) 39:851–856.[CrossRef][Web of Science][Medline]
5. Ritter CA, Perez-Torres M, Rinehart C, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res (2007) 13:4657–4659.
6. Perez SA, Karamouzis MV, Skarlos DV, et al. CD4+CD25+ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clin Cancer Res (2007) 13:2714–2721.
7. Ali SM, Esteva FJ, Fornier M, et al. Serum HER-2/neu change predicts clinical outcome to trastuzumab-based therapy. J Clin Oncol (2006) 24(18S):500.
8. Smith BL, Chin D, Maltzman W, et al. The efficacy of herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins. Br J Cancer (2004) 91:1190–1194.[CrossRef][Web of Science][Medline]
9. Wollf AC, Hammond MEH, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol (2007) 25:118–145.
10. Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG. Trastuzumab—Mechanism of action and use. N Engl J Med (2007) 357:1664.
11. de Alava E, Ocana A, Abad M, et al. Neuregulin expression modulates clinical response to trastuzumab in patients with metastatic breast cancer. J Clin Oncol (2007) 25:2656–2663.
12. Menendez JA, Mehmi I, Lupu R. Trastuzumab in combination with heregulin-activated Her-2 (erbB-2) triggers a receptor-enhanced chemosensitivity effect in the absence of Her-2 overexpression. J Clin Oncol (2006) 24:3735–3746.
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