Abstract 5198
Background
Taxanes are the most active chemotherapeutic agents in metastatic castration-resistant prostate cancer (mCRPC), with demonstrated survival benefit. However, patients eventually develop resistance and no predictive molecular biomarkers are clinically available. This study analysed molecular changes associated with cell plasticity in CRPC-cell models resistant to docetaxel (D) and cabazitaxel (CZ), as well as in circulating tumour cells (CTCs) and tumour biopsies from patients with mCRPC treated with taxanes.
Methods
cDNA microarrays were performed in D and CZ-resistant (DR and CZR) DU-145 and PC-3 cell lines. Differential gene expression of a gene subset was validated by qRT-PCR and Western Blot analyses. Gene expression was evaluated in CTCs enriched samples and tumour samples from 22 and 118 patients, respectively.
Results
Microarrays analysis revealed a pronounced and intermediate epithelial-mesenchymal transition phenotype in DR and CZR cells, respectively. The penetrance of stem-cell-like and neuroendocrine phenotypes generated by D and CZ-resistance differed in the DR and CZR models. Gene expression changes also occurred in CTCs after taxane treatment. Low expression of ESRP1 in tumour samples predicted lower PSA-progression-free survival (PFS) in D-treated (HR 0.4, 95%CI 0.2-0.7, P < 0.001) than in CZ-treated patients (HR 2.3, 95%CI 1.1-4.8, P = 0.034). Moreover, tumour EMT phenotype (defined by ESRP1 downregulation and ZEB1 and AXL overexpression) was also associated with a lower PSA-PFS to D (HR 2.2, 95%CI 1.3-3.8, P = 0.005), contrary to CZ (HR 0.3, 0.1-0.7, P = 0.006). NE-markers EZH2 and SYP correlated with lower OS in D (HR 1.6, 95%CI 1.1-2.5, P = 0.023) and CZ (HR 3.6, 95%CI 1.6-8.1, P = 0.002), respectively.
Conclusions
Molecular changes associated with cell plasticity are different in D or CZ resistance. The EMT profile expression in primary tumour was differentially associated to D or CZ benefit. ESRP1 expression in tumour may be a potential predictive biomarker of different sensitivity to D and CZ.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Hospital Clínic de Barcelona.
Funding
Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación; European Regional Development Fund (ERDF); CERCA Programme/Generalitat de Catalunya; Astellas Pharma S.A; Sanofi.
Disclosure
N. Jimenez: Travel / Accommodation / Expenses: Sanofi. O. Reig: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Janssen-Cilag; Speaker Bureau / Expert testimony: Bayer. A. Font: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Janssen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astra-Zeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Pierre Fabre. A. Rodriguez-Vida: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer ; Research grant / Funding (institution): Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Astra-Zeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Sanofi-Aventis; Advisory / Consultancy: Clovis. J. Carles: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson&Johnson; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD ; Advisory / Consultancy: Roche; Advisory / Consultancy: Astra-Zeneca; Speaker Bureau / Expert testimony: Asofarma. C. Suárez: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: Astellas ; Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony: Roche/Genentech; Speaker Bureau / Expert testimony: Astra-Zeneca; Travel / Accommodation / Expenses: Roche. M. Domenech: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Janssen. N. Sala-González: Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen. A. Prat: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Nanostring; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly. M. Marín-Aguilera: Travel / Accommodation / Expenses: Bristol-Myers Squibb. B. Mellado: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Ipsen; Research grant / Funding (institution): Bayer. All other authors have declared no conflicts of interest.
Resources from the same session
3630 - Results of phase 1 clinical trial of high doses of Seleno-L-methionine (SLM) in sequential combination with Axitinib in previously treated and relapsed clear cell renal carcinoma (ccRCC) patients
Presenter: Yousef Zakharia
Session: Poster Display session 3
Resources:
Abstract
2356 - Safety and Efficacy of CDX-014 , an Antibody-Drug Conjugate against T Cell immunoglobulin mucin-1 (TIM-1), in advanced Renal Cell Carcinoma
Presenter: Bradley McGregor
Session: Poster Display session 3
Resources:
Abstract
1028 - SPAZO2 (SOGUG): Outcomes and prognostic significance of IMDC intermediate prognosis subclassification in metastatic renal cell carcinoma (mRCC) in patients treated with 1st-line pazopanib (1stPz).
Presenter: Begona P. Valderrama
Session: Poster Display session 3
Resources:
Abstract
2293 - Effect of Antacid Intake on the Therapeutic Efficacy of Sunitinib (SUN) in Metastatic Renal Cell Carcinoma (mRCC) Patients (pts): a Sub-Analysis of the STAR-TOR Registry
Presenter: Katrin Schlack
Session: Poster Display session 3
Resources:
Abstract
1451 - Randomized phase 3 trial of avelumab + axitinib vs sunitinib as first-line treatment for advanced renal cell carcinoma: JAVELIN Renal 101 Japanese subgroup analysis
Presenter: Motohide Uemura
Session: Poster Display session 3
Resources:
Abstract
4399 - Overall and progression-free survival according to MSKCC scores in 1st line sunitinib treatment of metastatic renal cell carcinoma (mRCC)
Presenter: Jindrich Finek
Session: Poster Display session 3
Resources:
Abstract
1344 - Combination therapy with checkpoint inhibitors for first-line treatment of advanced renal cell carcinoma: A systematic review and meta-analysis of randomized controlled trials
Presenter: Kyaw Thein
Session: Poster Display session 3
Resources:
Abstract
3462 - A phase II trial of TKI induction followed by a randomized comparison between nivolumab or TKI continuation in renal cell carcinoma (NIVOSWITCH)
Presenter: Viktor Grünwald
Session: Poster Display session 3
Resources:
Abstract
5268 - Nivolumab (N) treatment beyond progression in a real-world cohort of patients (pts) with metastatic renal cell carcinoma (mRCC)
Presenter: Sophie Hans
Session: Poster Display session 3
Resources:
Abstract
4235 - First results of safety profile of nivolumab (NIVO) in combination with stereotactic body radiotherapy (SBRT) in II and III line of patients (pts) with metastatic renal cell carcinoma (mRCC) in NIVES Study
Presenter: Cristina Masini
Session: Poster Display session 3
Resources:
Abstract