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HER2-targeted therapy: an ongoing challenge

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One of the most notable discoveries in cancer translational research has been the identification of the HER2-positive tumors and the subsequent successful development of HER2-targeted therapies. HER2 overexpression has been described in a variety of human malignancies, while HER2 gene amplification is rare ...

One of the most notable discoveries in cancer translational research has been the identification of the HER2-positive tumors and the subsequent successful development of HER2-targeted therapies. HER2 overexpression has been described in a variety of human malignancies, while HER2 gene amplification is rare except in breast cancer, in which both amplification of the gene and HER2 overexpression occur in approximately the same proportion of cases (20-30%). HER2 amplification/overexpression has been historically associated with poor prognosis. Indeed, perturbation of HER2 signaling causes the formation of activated homo or heterodimers with other members of the HER family receptors, mediating a downstream cascade of altered cellular signals through complex, interconnected, and still incompletely understood signal transduction pathways. The negative prognostic impact of HER2 gene amplification and/or oncoprotein overexpression has been greatly ameliorated by the development of HER2-targeted therapies, although many patients with HER2-positive tumors do not benefit from these treatments. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from HER2 inhibition. Different mechanisms of intrinsic and/or acquired resistance to HER2-targeted therapies have been identified in preclinical and clinical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through other receptor or intracellular signaling pathways, defects in mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. However, to date, none of these markers have proven sufficiently reliable in vivo for use in identifying patients likely to be resistant to HER2-targeted therapy. Only with the advances achieved in molecular medicine and molecular oncology it has been and will continue to be possible to optimize prognosis, prediction and therapy of HER2-positive breast carcinomas and to evaluate gene expression in tumors on a genome-wide basis rather than the single-gene level. To fulfill the promise of tailored tumor care, an improved understanding of the biological and functional behavior of individual tumors is prerequisite for "improved stratification" of patients who require additional treatment.


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