Oral Vinorelbine and Capecitabine Plus Bevacizumab in Recurrent Inflammatory Breast Cancer: Gene Profiling and Response to Treatment

Background: Therapies that target vasculolymphatic processes - angiogenesis, lymphangiogenesis, and vasculogenesis — have shown potential in the treatment of inflammatory breast cancer. Methods: We randomly assigned 46 patients to receive oral vinorelbine 55 mg per square meter of body surface on days 1 and 3 and capecitabine 2000 mg per square meter on days 1 to 14 every 3 weeks either concurrent or sequential to bevacizumab 15 mg per kilogram of body weight on days 1 and 21 (BEVIX). The primary end point was progression-free survival; the response rate and overall survival were a secondary end point. For correlative studies we collected baseline tissue and blood samples of all patients. Gene expression profiling was performed using Affymetrix HG-U133 Plus 2.0 arrays. Data were analyzed using Partek Genomic Suite 6.4 and GeneSpring 7.0. Tissue from normal breast was used as control. Results: From July 2007 through January 2010, a total of 46 patients were enrolled. Concurrent oral vinorelbine and capecitabine plus bevacizumab significantly increased the objective response rate as compared to the sequential treatment (11.1% vs. 46.4%, p=0.025). No difference in progression-free survival was observed between the two arms (median time to progression 4.3 vs. 4.7 months, p=0.69; Hazard Ratio: 0.86, 95% CI: 0.41-1.80). The median overall survival was 9.1 months in concurrent arm and 15.8 months in sequential arm, (p=0.43). Global gene expression was analyzed in tumor samples from 18 pts bearing a triple negative phenotype. This cohort displayed a specific gene expression profile, including high expression levels of several cytokeratins, Aurora kinase A, Cyclin E and others, similar to the basal-like subtype. This profile did not include genes previously reported as differentially expressed in inflammatory breast cancers. We identified a set of 75 genes whose expression correlates with response to bevacizumab base therapy. Conclusions: BEVIX is an active treatment for patients with recurrent inflammatory breast cancer. These tumors showed a gene expression pattern similar to that of basal-like type. We identified a set of 75 genes whose expression levels predict the response to BEVIX. The validity of this expression signature is currently being assessed. Supported by Roche and Associazione Italiana per la Ricerca sul Cancro (AIRC) grants. Data partially submitted to 2010 ASCO Meeting.