Abstract 2777: TMPRSS2-ERG predictive value for taxanes resistance according to prior second-line hormonal manipulations in metastatic castration resistant prostate cancer
Authors: Marín-Aguilera Mercedes , Reig Òscar , Jiménez Natalia , Victoria Iván , Gaba Lydia , López Sandra , Prato Javier , Pereira Maria Verónica , Vilella Teresa , Domenech Montserrat , Badal Josep , Font Albert , García-Mosquera Juan José , Etxaniz Olatz , Carrato Cristina , Suárez Cristina , Carles Joan , Racc Fabriccio , Fernández Pedro Luis , Prat Aleix , Mellado Begoña 
Published: July 2017

Abstract
Background: TMPRSS2-ERG is a genetic alteration specific of prostate cancer, present in primary tumors and maintained under castration resistant prostate cancer (CRPC) progression. It results in androgen-driven overexpression of ERG, which is involved in resistance to taxanes in preclinical models. In prior work, we found that TMPRSS2-ERG expression in blood correlated with docetaxel resistance in metastatic CPRC. Here, we investigated if TMPRSS2-ERG expression in primary tumors predicts taxanes resistance in CPRC and the potential impact of prior second-line hormonal manipulations with abiraterone (A) or enzalutamide (E).
Methods: Patients with metastatic CRPC treated with taxanes were included. Formalin-fixed paraffin-embedded (FFPE) tumors and peripheral blood mononuclear cells (PBMCs) fraction were tested for TMPRSS2-ERG by RT-qPCR. FFPE from hormone-sensitive disease (primary diagnosis) were retrospectively obtained. PBMCs were prospectively collected prior taxane initiation. TMPRSS2-ERG expression was tested by RT-qPCR. TMPRSS2-ERG detection was correlated with taxane response and clinical outcome.
Results: A total of 84 tumor samples from 74 patients were included: 65 (87.3%) treated with docetaxel, 19 (25.7%) with cabazitaxel and 10 (13.5%) with both. Forty-six tumor samples (54.7%) were TMPRSS2-ERG+ and 38 (45.2%) TMPRSS2-ERG-. Overall, no correlation between tumor TMPRSS2-ERG expression and taxanes response or clinical outcome was observed. In 42 (50%) samples matched tumor and PBMC samples were available at the time of this analysis: 23 (54.7%) had detectable TMPRSS2-ERG on tissue and 11 (26.2%) on PBMCs fraction. In 27 patients, taxanes were administered as a first-line therapy and in 15 after A or E progression. TMPRSS2-ERG was detected in PBMC from 8 (29.6%) and 3 (20%) patients without or with prior A or E. In patients without prior A or E, TMPRSS2-ERG expression in primary tumors predicted a lower median PSA-PFS (5.5 vs 10.1 months for TMPRSS2-ERG+ vs -, respectively; p&lt;0.05). Similarly, when analyzing PBMCs samples from patients without prior A or E, PSA response was observed in 0% of TMPRSS2-ERG+ vs 55.6% of TMPRSS2-ERG- patients (p = 0.009). Median PSA-PFS, Rx-PFS were 2.9 vs 8.1 months (p &lt; 0.01) and 3.2 vs 7.3 (p &lt; 0.05), for TMPRSS2-ERG+ and TMPRSS2-ERG- patients. However, no significant differences were found either in PBMCs or FFPE samples in patients that received A or E prior to taxanes, regarding to PSA response, PSA-PFS, Rx-PFS and OS parameters between TMPRSS2-ERG+ and TMPRSS2-ERG- samples.
Conclusions: The role of TMPRSS2-ERG in taxane resistance may be different according to prior exposure to second-line hormone-therapy in CRPC. Prior androgen receptor inhibition may result in TMPRSS2-ERG downregulation and/or activation of alternative mechanisms of resistance. Further data according to this hypothesis will be presented.
Citation Format: Mercedes Marín-Aguilera, Òscar Reig, Natalia Jiménez, Iván Victoria, Lydia Gaba, Sandra López, Javier Prato, Maria Verónica Pereira, Teresa Vilella, Montserrat Domenech, Josep Badal, Albert Font, Juan José García-Mosquera, Olatz Etxaniz, Cristina Carrato, Cristina Suárez, Joan Carles, Fabriccio Racc, Pedro Luis Fernández, Aleix Prat, Begoña Mellado. TMPRSS2-ERG predictive value for taxanes resistance according to prior second-line hormonal manipulations in metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2777. doi:10.1158/1538-7445.AM2017-2777