Docetaxel, carboplatin, trastuzumab, and bevacizumab (TCH+B) for early-stage HER2/neu(+) breast cancer and bone marrow micrometastases.

Abstract

TPS655 Background: Bone marrow (BM) micrometastases confer a poor prognosis to early-stage breast cancer (BC) and HER-2/neu(+) BC is a high-risk phenotype. We have shown that BM-associated stromal cells support the survival of metastatic BC in microenvironmental niches and this activity is dependent on VEGF and CXCL-12. Therefore, the growth of nascent tumor cell clusters in BM might be impeded by disrupting stromal cells or their activating ligands, such as VEGF. There is also a positive association between HER-2/neu and VEGF expression in BC, thereby implicating VEGF in the aggressive phenotype of HER-2/neu overexpression. These observations support the use of combination therapies directed against both HER-2/neu and VEGF for the treatment of HER-2/neu(+) BC. We therefore hypothesize that an anti-VEGF agent (bevacizumab) given with docetaxel, carboplatin and trastuzumab (TCH) will eradicate the BM of HER-2/neu(+) BC micrometastases by disrupting stromal cell support within the micrometastatic BM niche. Methods: Subjects with AJCC Stage I-III HER2/neu(+) BC will undergo a single iliac-crest BM aspirate and biopsy. If the BM is positive for CK+ micrometastases, up to 17 patients will receive TCH+B therapy (docetaxel at 75 mg/m2 IV and carboplatin at AUC 6 IV given every 3 weeks for 6 cycles; trastuzumab at 4 mg/kg IV loading dose, then 2mg/kg IV every week; bevacizumab at 15 mg/kg IV every 3 weeks). Four weeks after the 6th cycle of therapy, a repeat BM aspiration and biopsy will be performed to score for response of BC micrometastases to therapy. Patients with a complete clinical response in BM will continue with trastuzumab every 3 weeks at 6 mg/kg to a total of 1 year. Patients with persistent micrometastases will receive both trastuzumab and bevacizumab every 3 weeks to a total of 1 year of therapy. These patients will then have a repeat BM aspirate and biopsy at the end of the 1 year to score for final response. The primary objective of this clinical trial is to determine clinical response against BC micrometastases in BM. The second objective is to investigate the specific contribution of VEGF and CXCL-12 signaling to BM support of micrometastatic BC cells.