Reply to F. Bellati et al

Abstract

The antitumor activity of trastuzumab in human epidermal growth factor receptor 2 (HER2) –positive breast cancer has been ascribed to both immunologic and nonimmunologic mechanisms. It is unlikely that any one of these mechanisms alone is responsible for the antitumor activity of trastuzumab. We thank Bellati et al for pointing out the importance of the adaptive immune response as another mechanism involved in mediating trastuzumab antitumor activity. We agree with Bellati et al that HER2-based vaccines represent a promising therapeutic approach in the treatment of breast cancer. Our group is conducting an ongoing study combining lapatinib with a HER2-directed vaccine to further understand the role of the immune system in HER2-directed therapy antitumor activity (ClinicalTrials .gov Identifier: NCT00952692). As we have previously shown in preclinical models, total HER2 blockade using anti-HER2 antibodies generated in response to various HER2 vaccines in combination with lapatinib results in enhanced antitumor activity compared with either treatment alone. These experiments were conducted in cell culture without the addition of immune effector cells, which further implicates the role of nonimmunologic mechanisms in the antitumor activity. The clinical validation of these studies was recently demonstrated in a randomized phase III clinical trial in women with advanced stage HER2-positive breast cancer who had progressed on trastuzumab-containing therapy, where we showed the clinical benefit of combining trastuzumab with lapatinib compared with lapatinib treatment alone. This should dispel some of the concern about possible antagonistic effects of combining trastuzumab with small molecule inhibitors of ErbB2 tyrosine kinase activity. In addition, the article referenced in the correspondence of Bellati et al described the binding of lapatinib to epidermal growth factor receptor by x-ray crystallography, not HER2. To our knowledge, similar x-ray crystallographic studies of lapatinib interaction with HER2 have not been reported. Finally, we completely agree with Bellati et al and Winer and Burstein in their Editorial that greater insight into predictors of response to targeted therapies, such as trastuzumab, is needed. Quantitative HER2 status alone has clearly not been sufficient to predict for clinical response to trastuzumab. To more effectively treat individuals with HER2-positive breast cancer, a greater understanding of the tumor profile and patient immunological status that predict for clinical response to trastuzumab and potentially other HER2-targeted therapies is needed.