Author(s): Valentina Rossi 1 , Stefania Redana 1 , Andrea Milani 1 , Elena Geuna 1 , Giorgio Valabrega 1 , Massimo Aglietta 1 , Filippo Montemurro [[dagger]â ] 2
adjuvant chemotherapy; breast cancer; chemotherapy; HER2; trastuzumab
Breast cancer is the most frequent cancer among women worldwide  . Owing to screening programs and increased awareness of the importance of early diagnosis, breast cancer is operable at presentation in most patients. Owing to the risk of microscopic systemic involvement, surgery of nonmetastatic disease is usually followed by adjuvant medical treatments. Chemotherapy and endocrine therapy effectively reduce the risk of disease recurrence and death after surgery by controlling the growth of micrometastases  . More recently, the monoclonal antibody trastuzumab, which targets the product of the HER2 oncogene, has been confirmed as an important component of adjuvant regimens in patients whose tumors carry this abnormality  .
The HER2 oncogene, which is located on chromosome 17, encodes a transmembrane tyrosine kinase protein belonging to the EGF receptor family, together with HER1 (EGF receptor 1), -3 and -4  . Since no specific ligand has been identified for HER2, this receptor is believed to act by forming homo- or hetero-dimers with other members of the EGF receptor family, activating a cascade of cell signaling involved in cell cycle progression and regulation, and proliferation and apoptosis.
HER2 is amplified, with consequent overexpression of its product (HER2 positivity), in approximately 20% of human breast cancers  . Tumors bearing this alteration display an aggressive clinical behavior characterized by early relapse, visceral metastatic spread and resistance to endocrine manipulation [5,6] . By contrast, HER2 positivity predicts a benefit from anthracycline-based chemotherapy  . Owing to these features, HER2 was identified as a potential pharmacological target. Trastuzumab is the first humanized monoclonal antibody specifically directed against this oncogene product that was made available for clinical use [8-â10] . In women with HER2-positive advanced breast cancer, the addition of trastuzumab to chemotherapy resulted in a significant improvement in response rate, progression-free survival and overall survival (OS) compared with chemotherapy alone [11,12] . The results obtained in the metastatic setting and the favorable toxicity profile of trastuzumab prompted its testing in the management of operable disease. Four large international and two smaller single-country randomized trials comparing chemotherapy with or without trastuzumab have been published or presented at international meetings (Figure 1) [13-â20] . A recent meta-analysis of five of these trials demonstrated that the addition of trastuzumab to adjuvant chemotherapy reduces the risk of relapse by 38% and the risk of death by 34%  . One striking feature of all the adjuvant trials with trastuzumab except one is the consistency of results despite some major differences in trial design.
In fact, when establishing trastuzumab-containing adjuvant combinations, investigators had to consider lessons learned from studies with trastuzumab in the metastatic setting. For example, as a single agent, trastuzumab is active when administered to a subset of appropriately selected HER2-positive patients [8-â10] . However, it is the combination with chemotherapy, as previously demonstrated in preclinical models, that allows the full exploitation of its clinical potential  . Cardiac dysfunction has been associated...