Vandetanib, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (HER1), Potentiates Anti-Tumor Effects of Combined Endocrine and Trastuzumab Treatment in Estrogen Receptor-Positive (ER+)/HER2-Overexpressing Xenografts.
Authors: Malorni L. , Hilsenbeck S. , Soliz R. , Ward R. , Ryan A. , Osborne K. , Schiff R. 
Published: December 2010

Background: Compelling evidence suggests that cross-talk between the pathways of ER and HER1/HER2 contributes to endocrine resistance. Using a xenograft model of human ER+ breast cancer cells engineered to overexpress HER2 (MCF-7/HER2-18), we have shown that tamoxifen (Tam) stimulates tumor growth resulting in de novo resistance. Anti HER1/HER2 targeted treatment overcomes this Tam resistant phenotype, though these effects are transient using single agents like the anti-HER2 antibody trastuzumab (T), thus suggesting that a more potent anti-HER therapy or simultaneous inhibition of alternative pathways is required to reverse resistance. Both ER and HER2 are known to promote angiogenesis. Vandetanib (V) (ZD6474, ZACTIMA) is an orally active, VEGFR/HER1 tyrosine kinase inhibitor that has shown both anti-angiogenic and anti tumor cell activities in different models. We thus hypothesize that in ER+/HER2+ tumors, the addition of V to the combination regimen of Tam+T would increase antitumor effect and delay onset of resistance due to inhibition of tumor angiogenesis and delivery of a more complete blockade of the HER network.Methods: Mice bearing MCF-7/HER2-18 tumors were randomized and treated with Tam given alone or in combination with T (10 mg/Kg, bi-weekly), V (50 mg/Kg, 5 d/week), or T+V. Tumor volumes were followed weekly. Mean tumor regression (M-TR) ± SD and median time to tumor progression (M-TTP, defined by tumor doubling from its size at randomization) and 95% CIs were analyzed by Wilcoxon Rank Sum and survival analysis methods (Kaplan-Meier estimates and generalized Wilcoxon test), respectively. All statistical tests were two-sided and adjusted (Holm) for multiple comparisons.Results: Tam monotherapy had minimal effect on tumor growth (M-TR 22%±15 SD) after which all tumors progressed rapidly [M-TTP 42 (35-56) days, 95% CI]. The addition of either T or V to Tam significantly improved tumor regression compared to Tam monotherapy (M-TR 66%±27, P=0.0012, and 67%±25, P=0.001, respectively) and significantly delayed time to tumor progression [M-TTP 91 (70-119) days, P=0.012, and 77 (63-98) days, P=0.02, respectively]. However, the combined regimen of T+V with Tam was significantly more effective than either T or V added separately to Tam, resulting in further significant tumor regression (M-TR 81%±29, P=0.0086 vs. T and 0.0012 vs. V) and a prolonged M-TTP (&gt;154 d, P=0.02 vs. T and 0.01 vs. V).Conclusions: This study supports the concept that the dual VEGFR/HER1 inhibitor vandetanib can improve efficacy of combined endocrine and anti-HER trastuzumab therapy in ER+/HER2+ tumors, probably due to angiogenesis inhibition and to a more potent blockade of HER family signaling and its cross-talk with ER. Clinical studies to examine this approach are warranted.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5128.