Preclinical study of prolonged administration of trastuzumab as combination therapy after disease progression during trastuzumab monotherapy

The clinical relevance of prolonged trastuzumab administration in combination therapy beyond progressive disease (PD) has been suggested. Here, we examined whether trastuzumab treatment is effective in combination after failing to show antitumor activity as monotherapy in HER2-positive human breast cancer xenograft models. We established trastuzumab PD models with HER2-positive breast cancer xenograft models and compared the antitumor activity of trastuzumab in combination with a taxane versus monotherapy with a taxane in the models subsequent to tumor progression under trastuzumab monotherapy. We established trastuzumab PD model using the HER2-positive human breast cancer line MDA-MB-361 and KPL-4 in in vivo. In these models, trastuzumab at the same dose as the initial treatment showed no significant antitumor activity at 3 weeks after start of treatment. Re-inoculated tumor tissues showing PD regained sensitivity to trastuzumab. In the trastuzumab PD models, the HER2 status of the tumor tissues did not decrease. Also, the pAKT level continued to decrease, as with the initial treatment, and IGF-1R was not found to be up-regulated. Instead, differences were observed in the gene-expression profiles of the tumor tissues showing PD. Trastuzumab in combination with G-CSF, which is expected to enhance antibody-dependent cellular cytotoxicity (ADCC), showed significant antitumor activity, even though the single agents alone showed no antitumor activity in the PD model. In the MDA-MB-361 trastuzumab PD model, the combination of trastuzumab with paclitaxel showed significantly more potent antitumor activity compared with paclitaxel or docetaxel monotherapy. In the KPL-4 trastuzumab PD model as well, trastuzumab showed significant antitumor activity in combination with taxanes or capecitabine after PD had developed in response to trastuzumab monotherapy. We established in vivo trastuzumab PD models, in which trastuzumab monotherapy ceases to have antitumor activity during the treatment. The mechanisms of PD with trastuzumab are considered to involve both reversible changes in the gene expression profiles in tumor tissues and a decrease of ADCC activity in the host. Our present results demonstrated that trastuzumab showed antitumor activity in combination with taxanes or capecitabine even though it showed no antitumor activity as a monotherapy, suggesting a clinical relevance of treatment with trastuzumab as a combination therapy beyond PD.