Taxane sensitivity markers in prostate cancer.

Abstract

285 Background: The results from the CHAARTED and STAMPEDE trials that docetaxel plus androgen-deprivation therapy (ADT) significantly improves survival over ADT alone among men with metastatic, hormone-sensitive and hormone-naïve prostate cancers, represents a potential practice-changing movement. Clinical data exist to support the role of various predictive markers for taxane response, including low or negative class III beta tubulin (TUBB3), positive transducin-like enhancer of split 3 (TLE3) and low or negative p-glycoprotein (PGP/ABCB1). We examined a database of molecularly-profiled prostate cancer patients for taxane sensitivity markers for insight into the mechanism behind the clinical effect of docetaxel. Methods: 348 patients with prostate cancer were included in the study and tested centrally at a CLIA laboratory (Caris Life Sciences, Phoenix, AZ). Tests included one or more of the following: gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (C/FISH). Results: In all prostate cases tested, protein levels for taxane markers are: TLE3+ 58.6% (174/297), TUBB3 - 76.8% (228/297) and PGP – 89.9% (267/297). Combined rate of expression (TLE3+/TUBB3-/PGP-) is 41% (121/297), representing a subgroup of patients that may have best responses to taxane therapy. Taxane sensitivity markers by stage and AR status are shown in the table below. Conclusions: Taxane sensitivity markers are observed at a statistically significant higher frequency in AR-positive prostate cancer patients, providing a potential molecular hypothesis for the increased effectiveness of chemo-hormonal therapy observed in hormone-sensitive prostate cancers. A substantial number of both AR positive and negative patients have sub-optimal biomarker profile for taxane responsiveness highlighting an unmet need for on-going drug development in this disease. [Table: see text]