Microtubule-Associated Protein Expression and Predicting Taxane Response PRINCIPAL INVESTIGATOR:

The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 14. ABSTRACT Taxanes are microtubule targeting agents (MTAs) and potent cytotoxic molecules recognized as highly effective chemotherapeutic agents. In large randomized clinical trials, taxane-based chemotherapies provided benefits in overall and disease-free survival, but they are accompanied by significant adverse effects. Thus the clinical utility of taxane therapy would be enhanced if there were companion diagnostic tests so that only the taxane-sensitive patients (about half of breast cancers) could be treated with this drug. Accumulating evidence indicates that microtubule associated proteins (MAPs) may be responsible for tumor cell resistance to taxanes. Our results indicate that MAP-tau functions as a prognostic factor in both the Yale cohort and the TAX 307 cohort with high MAP-tau expression associated with longer overall survival and TTP. Tau does NOT behave as a predictor of response to taxane-based chemotherapy since differences between low and high MAP-tau groups by treatment arm and response rate were not observed in the TAX 307 clinical trial cohort. Our data supports the use of MAP-tau as a prognostic marker, but does not support its use as a singular predictive factor for response to docetaxel. We have also evaluated the microtubule destabilizer, stathmin, and found high expression is associated with worse outcome. Since stathmin expression is useful in predicting survival, it may serve as marker to accurately select patients for current taxane-based or other anti-microtubule therapies in combination with a microtubule stabilizer such as MAP-tau.