Prognostic value of the microtubule stability index (MTSI), defined by the quantitative ratio of MAP-tau to stathmin expression, for outcome in breast cancer.

Abstract

10523 Background: Microtubule associated proteins (MAPs) endogenously regulate microtubule stability, have been reported as prognostic markers, and may predict response to taxane therapy. Previous work in this laboratory has shown that high expression of MAP-tau, a microtubule stabilizer, is prognostic but not predictive for taxane response and that the microtubule destabilizing protein, stathmin, is prognostic with unknown predictive value. We hypothesize that assessing MAPs as ratios of stabilizers to destabilizers, which parallels endogenous cell division activity, may be more informative than single-marker studies. Here we create a microtubule stability index (MTSI) using the ratio of MAP-tau to stathmin expression and quantitatively assess prognostic value using a large retrospective breast cancer cohort. Methods: MAP-tau and stathmin expression was measured in a breast cancer cohort (n = 645) with 20 year follow-up using tissue microarray and quantitative immunofluorescence (AQUA) technology. MTSI, calculated as the ratio of MAP-tau to stathmin expression, was measured for each patient and correlated with clinical and pathological characteristics as well as disease free survival. Median MTSI score served as the pre-defined cutpoint differentiating high versus low patients. Results: MAP-tau and stathmin expression were not correlated (Spearman's Rho = -0.010; p = 0.8311). Prognostic evaluation using Cox univariate analysis indicated positive correlation between MTSI and disease-free survival (HR = 0.744; 95% CI = 0.591-0.856; p = 0.0002). Kaplan Meier analysis showed median 10-year survival of 65.6% for patients with high MTSI versus 59.1% survival rate for low MTSI (log rank, p < 0.001). Cox multivariate showed MTSI (continuous scale) was independent of age, tumor size, nuclear grade, nodal status, ER, PR, HER2, (HR = 0.756; 95% CI = 0.571-0.756; p = 0.004) and was synergistic when compared to either MAP-tau or stathmin. Conclusions: High MTSI shows synergistic and prognostic value for improved outcome in breast cancer. Future studies will determine if this index is valuable for selecting patients for anti-microtubule therapies. No significant financial relationships to disclose.