From the trastuzumab era to new target therapies: beyond revolution.

In the October 2005 edition of The New England Journal of Medicine, Gabriel Hortobagy claimed that ‘‘the results of trastuzumab adjuvant trials are not evolutionary but revolutionary’’ [1]. In effect, from the early results of the first target therapy, tamoxifene, this is the first time that such enthusiastic and dramatic results, in terms of outcome of an adjuvant therapy, have been realized. Interim analysis of four randomized phase III trials, in patients with HER2-positive early-stage breast cancer, indicated significant improvement in disease-free survival (DFS) compared with chemotherapy alone [hazard ratio (HR) 0.48–0.64] and an overall survival (OS) benefit in three of the four trials (NCCTG N9831/NSABP B-31: HR 0.67, P = 0.015; HERA: HR 0.66; P = 0.0115) when trastuzumab was added to standard therapy. It is obvious that there are certain limitations in the use of this extraordinary drug. The first is that trastuzumab can only be used in a small number of patients; the majority (HER-2 negative) cannot benefit from its use. The second problem is the potential cardiotoxicity of this treatment. In clinical practice, treatment with trastuzumab can be resumed when the patients are no longer symptomatic and cardiac function is normalized. The third dilemma is whether the duration of therapy should be short or prolonged. The fourth problem concerns the high cost of trastuzumab treatment to the National Health Service, which is not to be disregarded. Finally, the fifth dilemma is to decide which patients should be treated with trastuzumab. It is obvious that all node-positive patients should receive treatment, but probably not all node-negative patients. Other potential strategies for evaluating response to trastuzumab therapy might include the assessment of surrogate markers of critical HER2-mediated signaling pathways, including the PI3K/Akt pathway, and circulating HER2 extracellular domain levels. In addition, the NSABP B-31 trial identified c-Myc amplification as a predictive factor for responsiveness to trastuzumab. Acquired and de novo resistance to trastuzumab is a significant clinical challenge. bevacizumab