The use of adjuvant chemotherapy and endocrine therapy has had a significant impact on breast cancer survival. However, not all patients will benefit from each of these therapies. Increasing data suggests that patients with hormone receptor-positive breast cancer derive marginal benefit from the addition of adjuvant chemotherapy. Identification and characterization of cellular signaling pathways active in the pathogenesis of breast cancer has lead to the development of multiple targeted therapies that hold enormous promise for patients with less toxicity than conventional chemotherapy. Treatment strategies employing neoadjuvant therapy have found that pCR is predictive for ultimate outcome. Due to this, the use of neoadjuvant therapy has become an intense area of investigation in operable breast cancer. In the IMPACT trial, the aromatase inhibitor anastrozole was found to improve eligibility for breast conservation and was associated with a favorable clinical objective response after 12 weeks of therapy.~In this proposed study, we plan to study the combination of ZD6474, a dual inhibitor of EGFR and VEGFR-2, with anastrozole in the neoadjuvant setting for patients with Stage I-III breast cancer. The aim is to overcome mechanisms of resistance and simultaneously block multiple critical signaling pathways known to stimulate breast cancer. The two agents have non-overlapping toxicities and are both administered orally, allowing for a more tolerable treatment regimen. By using this combination in the neoadjuvant setting, we will target the critical signaling pathways early and follow tumor responses during therapy, allowing for prompt evaluation of the effectiveness of this treatment strategy. Pathologic tumor specimens obtained at the time of definitive surgery will be evaluated for pathologic complete response thus adding to the body of literature. By examining molecular markers such as ER, PR, EGFR, and Ki-67 pre- and post-treatment, we hope to correlate modulations in these biomarkers to response. Finally, using a novel second generation functional breast MRI we will investigate the ability of MRI to predict response to antiangiogenic therapy.
In this study we plan to study the combination of ZD6474, a dual inhibitor of EGFR and VEGFR-2 with anastrozole in the neoadjuvant setting for patients with Stage I-III breast cancer. The aim is to overcome mechanisms of resistance and simultaneously block multiple critical signaling pathways known to stimulate breast cancer.