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
4370 - Continental differences in pathologic response with neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO) in patients with macroscopic stage III melanoma in the phase 2 OpACIN-neo trial.
Presenter: Irene Reijers
Session: Poster Display session 3
Resources:
Abstract
3230 - Comparable responses of melanoma at primary site and synchronous lymph node metastases upon neoadjuvant ipilimumab (IPI) and nivolumab (NIVO)
Presenter: Judith Versluis
Session: Poster Display session 3
Resources:
Abstract
3171 - Adjuvant Therapies for Stage III Melanoma: Benchmarks for Bringing Clinical Trials to Clinical Practice
Presenter: Tina HIEKEN
Session: Poster Display session 3
Resources:
Abstract
3493 - Mixture-cure modeling for resected stage III/IV melanoma in the phase 3 CheckMate 238 trial
Presenter: Jeffrey Weber
Session: Poster Display session 3
Resources:
Abstract
3036 - An open-label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib for patients with unresectable advanced BRAFV600-mutant melanoma: a subgroup analysis of patients with brain metastasis
Presenter: Caroline Dutriaux
Session: Poster Display session 3
Resources:
Abstract
2233 - Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
Presenter: Jean Jacques Grob
Session: Poster Display session 3
Resources:
Abstract
2435 - A Single Arm, Open Label, Phase II, Multicenter Study to Assess the Detection of the BRAF V600 Mutation on cfDNA from Plasma in Patients with Advanced Melanoma
Presenter: Piotr Rutkowski
Session: Poster Display session 3
Resources:
Abstract
1766 - Efficacy and Safety of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600 Mutation-positive Melanoma in the Real-World Setting – Interim results of the non-interventional COMBI-r study
Presenter: Carola Berking
Session: Poster Display session 3
Resources:
Abstract
2131 - Trial update: A randomized Phase Ib/II study of the selective small molecule Axl inhibitor Bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma
Presenter: Oddbjørn Straume
Session: Poster Display session 3
Resources:
Abstract
4074 - Analysis of pyrexia in patients (pts) treated with dabrafenib (D) and/or trametinib (T) across clinical trials
Presenter: Caroline Robert
Session: Poster Display session 3
Resources:
Abstract