Molecular pathways and gene ontology categories in association with response to combination chemotherapy plus bevacizumab in inflammatory and locally advanced breast cancer

Abstract

509 Background: Inflammatory breast cancer (IBC) is an extremely aggressive subtype of locally advanced breast cancer (LABC) accounting for 1% to 6% of all breast cancers. The overall response rate to a combined modality therapy is 61.4%-83.5% and 15-year overall survival is 20%. Identification of Gene Ontology (GO) category or molecular pathway signature to distinguish subsets of patients with distinct clinical outcomes is imperative. Methods: 20 patients with IBC and 1 with LABC received one cycle of bevacizumab at 15mg/kg followed by six cycles of doxorubicin at 50mg/m2 and docetaxel at 75mg/m2 plus bevacizumab before surgery. Response to combination chemotherapy plus bevacizumab was measured with radiologic imaging modalities. Gene expression profiles from 20 tumor biopsies at baseline (1 with PD had inadequate biopsy) were measured with Agilent Whole Human Genome arrays and utilized to correlate with clinical response. Results: 14 (67%) of 21 patients (95% CI, 43%-85.4%) had a clinical partial response (PR), 5 had stable disease (SD) and 2 had progressive disease (PD). Of 103 molecular pathways, those of the stathmin and breast cancer resistance to antimicrotubule agents, and BTG family proteins and cell cycle regulation were significantly associated with response (PR versus SD+PD; P = .002 and .003). Members of the stathmin pathway are cyclin B1, cell division cycle 2, stathmin 1 (kinase interacting with leukemia-associated gene), and mitogen-activated protein kinase 13; BTG family members are retinoblastoma 1, CCR4-NOT transcription complex, subunit 7, and B-cell translocation gene 1. Sixteen of 965 GO classes were differentially expressed between patients with PR and PD plus SD (P < .005). Those include GO categories of transcription factor complex (14 genes; P = .00009), extracellular matrix (69 genes; P = .0006), and protein kinase activity (90 genes; P = .002). Tumor differentiation, ER, HER2/neu, and p53 were not associated with clinical response. Conclusions: Two pathways that regulate microtubule stability and cell cycle, and 16 GO categories are significantly associated with the response to the combination chemotherapy of docetaxel-doxorubicin plus bevacizumab. No significant financial relationships to disclose.