Francisco J. Esteva, MD, PhD

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Optimizing Outcomes in HER2-Positive Breast Cancer: The Molecular Rationale

November 1st 2005

The epidermal growth factor (EGF) receptor HER2 is a transmembranereceptor tyrosine kinase that plays a crucial role in the regulationof cell proliferation and survival. The overexpression of HER2correlates strongly with prognosis in breast cancer. The targeted blockadeof HER2 activity with monoclonal antibodies (eg, trastuzumab[Herceptin]) and small-molecule tyrosine kinase inhibitors (eg,lapatinib) results in the inhibition of tumor growth in HER2-positivecancers. Anti-HER2 therapies have also shown efficacy in combinationwith chemotherapy in clinical trials in patients with HER2-positive breast cancer. Their efficacy may, however, be limited bymolecular mechanisms that compensate for HER2 suppression (eg,activity of EGF receptor) or mechanisms of resistance (eg, loss ofPTEN). HER2 continues, however, to be overexpressed by the cancercells, and the continued suppression of HER2 may be required formaximum antitumor effect. It should be noted that in the absence ofdefinitive data from randomized trials showing an absence or presenceof benefit, the use of anti-HER2 agents such as trastuzumab in multiplesequential regimens has become the standard of care. CombiningHER2 blockers with agents that overcome the compensatory or resistancemechanisms may increase the efficacy of anti-HER2 therapies.In addition, anti-HER2 therapies can have synergy with common chemotherapyregimens and remain effective through multiple lines oftherapy. Optimizing the use of therapies that target HER2 signalingwill lead to further advances in the treatment of breast cancer.