High β-III tubulin expression in triple-negative (TN) breast cancer (BC) subtype and correlation to ixabepilone response: A retrospective analysis

Abstract

3587 Background: High βIII-tubulin (βIII) expression confers resistance to many anti-microtubule agents (Sève, Lancet 2008; 9: 168). The anti-microtubule agent ixabepilone (Ixa) demonstrates efficacy in βIII over-expressing tumor models resistant to taxanes and has clinical activity in patients with TN BC. The incidence and expression of βIII by BC subtype have not been delineated. Methods: Retrospective analyses of βIII mRNA expression were conducted in two microarray datasets of BC cohorts. Using intrinsic gene clustering, BC tumors from the Ixa neoadjuvant study CA163–080 (080) and the International Genome Consortium (IGC) were defined as basal-like (BL), luminal-like, Her2-overexpressing (Her2+) or normal-like subtypes. For study 080, IHC status subtyping defined TN, Her2+ and Her2-ER+PR+ patients. Mean expression of TUBB3, the gene encoding for βIII, was determined for each subtype. Clinical responses for 080 patients were compared to βIII expression levels. Results: For both cohorts, mean expression of TUBB3 was higher in BL and Her2+ tumors (one-way ANOVA and Tukey's HSD test; both p < 0.001). TUBB3 expression was rank-ordered: low, medium and high. In 080 and IGC cohorts, high expressors represent >50% of patients in BL and Her2+ subtypes and ∼20% of other BC subtypes. Subtyping 080 patients by receptor expression status demonstrated mean TUBB3 expression was higher for TN compared to Her2+ and Her2-ER+PR+ patients (t-test; p = 0.009). TN patients (n = 11/46) in study 080 had a trend to higher pCR rate than the overall population (n = 29/161), 26 vs. 18%. Receiver operating characteristics (ROC) analysis with AUC=0.66 demonstrates that high TUBB3 expression may predict for Ixa response in the overall 080 population. Conclusions: BC patients with TN, BL and Her2+ tumors have higher βIII expression. For the 080 study, responses to Ixa were higher for TN BC patients, and ROC analysis correlated response to βIII levels in the overall population. These data suggest high βIII in BL and TN BC may contribute to the aggressiveness of these subtypes and predict for Ixa clinical response. Additional studies are needed to address the activity of taxanes relative to βIII expression in TN BC. [Table: see text]