The influence of treatment sequence in the prognostic value of TMPRSS2‐ERG as biomarker of taxane resistance in castration‐resistant prostate cancer.

TMPRSS2‐ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration‐resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane‐resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2‐ERG was tested by quantitative reverse‐transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2‐ERG expression was correlated with prostate‐specific antigen (PSA)‐progression‐free survival (PFS), radiological‐PFS (RX‐PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2–2.8) and blood TMPRSS2‐ERG detection (HR 2, 95% CI 1.1–3.7) were independently associated to lower PSA‐PFS. In patients without prior A/E, blood and tumor TMPRSS2‐ERG independently predicted lower PSA‐PFS (HR 3.3, 95% CI 1.4–7.9 and HR 1.8, 95% CI 1.02–3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2‐ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2‐ERG and prior A/E related to PSA‐PFS (p = 0.032) and RX‐PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E‐cadherin. We conclude that prior hormone‐therapy may influence taxanes response and TMPRSS2‐ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow‐up evaluation. What's new? Despite known resistance mechanisms, no molecular biomarkers to predict taxane resistance are clinically available. TMPRSS2‐ERG rearrangement is a prostate cancerspecific genetic alteration known to impair taxane sensitivity in preclinical models. This study shows that blood and tumour TMPRSS2‐ERG expression independently predicted lower prostate‐specific antigen progression‐free survival in metastatic castration‐resistant prostate cancer (mCRPC) patients following taxanes. When prior abiraterone/ enzalutamide therapy was administered, TMPRSS2‐ERG was not associated with outcome. Prior hormone‐therapy may influence taxane response and TMPRSS2‐ERG prognostic value, suggesting the need for multiple and sequential biomarkers in mCRPC follow‐up evaluation. [ABSTRACT FROM AUTHOR]