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
3140 - Phase 2 study of olaparib in previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) or homologous recombination repair deficiency (HRD): LYNK-002
Presenter: David Hyman
Session: Poster Display session 3
Resources:
Abstract
2655 - The K-BASKET trial: A prospective phase II biomarker-driven multiple basket trial in Korean solid cancer patients.
Presenter: Seul Kim
Session: Poster Display session 3
Resources:
Abstract
5938 - Cambridge Liquid biopsy “CALIBRATION” study: Can changes in circulating tumour DNA (ctDNA) predict durable tumour responses in patients with advanced oesophageal cancer receiving MEDI4736?
Presenter: Constanza Linossi
Session: Poster Display session 3
Resources:
Abstract
3799 - Validation of a tumour mutational burden workflow on routine histological samples of colorectal cancer and assessment of a cohort with synchronous hepatic metastases
Presenter: Andrea Mafficini
Session: Poster Display session 3
Resources:
Abstract
4647 - Microsatellite Instability Testing and Lynch Syndrome Screening For Colorectal Cancer Patients Through Tumor Sequencing
Presenter: Li Liu
Session: Poster Display session 3
Resources:
Abstract
3231 - "Liquid Withdarw" technique in CT-guided cutting needle lung biopsy: decreased incidence of complications and increased tissue amount for lung cancer molecular testing.
Presenter: Xue Wang
Session: Poster Display session 3
Resources:
Abstract
3282 - WGS Implementation in standard cancer Diagnostics for Every cancer patient (WIDE)
Presenter: Paul Roepman
Session: Poster Display session 3
Resources:
Abstract
5905 - Known and unknown gene fusion detection capabilities of solid tumor laboratories conducting next generation sequencing in 6 countries
Presenter: Steph Finucane
Session: Poster Display session 3
Resources:
Abstract
4238 - Clinical and Analytical Accuracy of a 523 Gene Panel Next-Generation Sequencing (NGS) Assay on Formalin-Fixed Paraffin-Embedded (FFPE) Solid Tumor Samples
Presenter: Ina Deras
Session: Poster Display session 3
Resources:
Abstract
2493 - Methylation analysis of MLH1 using droplet digital PCR and methylation sensitive restriction enzyme.
Presenter: Celine De Rop
Session: Poster Display session 3
Resources:
Abstract