Circulating tumour cells (CTC) have been in the spotlight during the last decade with many emerging technologies for CTC detection and isolation. However, despite their clearly demonstrated prognostic value, the complexity of their biology in relation to cancer progression and metastasis is still a challenge on the path to derive predictive information from CTCs. This year’s conference will gather many experts in the field to unravel the complexity of CTC biology including the heterogeneity, microenvironment, and interactions of CTC with other immune cells which can provide important insights for therapy selection. Advances in CTC technologies will also be discussed along with the significance of CTC detection in clinical context.
Final Agenda
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Recommended Short Course*
SC3: Liquid Biopsy for P4 Medicine: Predictive, Preventive, Personalized and Participatory [View Detailed Agenda]
Lorena Diéguez, PhD, Staff Researcher, Diagnostic Tools and Methods Research Group, Life Sciences, International Iberian Nanotechnology Laboratory, Portugal
Clotilde Costa Nogueira, PhD, Head, Liquid Biopsy Line, Roche-Chus Joint Unit, University Hospital of Santiago de Compostela, Spain
P4 Medicine is Predictive, Preventive, Personalized and Participatory. The P4 medicine concept is fully realised in the context of Liquid Biopsy, since the patient’s blood is used as a biomarker for the prognosis and diagnosis of the disease status. Therefore, Liquid Biopsy provides the ideal scheme to personalize the treatment in precision medicine. P4 medicine will permit to identify predictive and preventive biomarkers and genomic mapping, adapting treatments to each patient, and having the patients engaged for a successful outcome.
*Separate Registration required.
WEDNESDAY, 23 MAY
11:35 Plenary Introduction
John Carrano, CEO, Paratus Diagnostics, LLC, United States
11:45-12:15 The New EU IVD Regulation – What Will It Mean for Your Lab?
David E. Barton, PhD, Chief Molecular Geneticist, National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Ireland
In May 2017, Europe passed a new Regulation on in vitro Diagnostic Devices (IVDs). The regulation sets up a framework for controlling the market for diagnostic tests within the EU, setting out standards for the design and manufacture of in-vitro diagnostic devices (IVDs) and providing mechanisms for the oversight of these standards. This presentation will outline the content of the new regulations, with a particular focus on molecular diagnostics, and highlight the new requirements for clinical laboratories.
12:15-12:25 Introduction: Medicinal Product Regulators Point of View: Scientific-Regulatory Aspects of Companion Diagnostics and Challenges for Validation during Clinical Co-Development (Quality-Related Aspects)
Jörg Engelbergs, PhD, Scientific Expert and Assessor Biomedicines (Quality, Non-Clinic & Personalized Medicine), Section Mono- and Polyclonal Antibodies, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Germany
In Europe, the legislation for marketing of medicinal products (MP) and IVDs including predictive biomarker-based assays (Companion Diagnostics, CDx) are not directly linked which is challenging for co-development. The new IVDD involves MP regulators in the CDx review process for CE marking. This presentation will outline from the perspective of MP regulators the scientific-regulatory challenges for technical validation of CDx. Differences between exploratory assays and assays used for patient stratification, as well as aspects for complex assays will be addressed.
12:25-13:30 PANEL DISCUSSION: Changing Landscape for IVDs in the EU
Moderator:
Charlotte Ryckman, Covington & Burling LLP, Belgium
Panelists:
David E. Barton, PhD, Chief Molecular Geneticist, National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Ireland
Jörg Engelbergs, PhD, Section Mono- and Polyclonal Antibodies, Scientific Expert Biomedicines, Quality, Non-Clinic & Personalized Medicine (Biomarker/CDx), Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Germany
Maria Judite Neves, Health Products Director, Health Products Directorate, INFARMED – National Authority of Medicines and Health Products, Portugal
Sue Spencer, Global Service Director, Regulatory, UL, United Kingdom
Andreas F. Stange, PhD, Vice President, MHS Global IVD, TÜV SÜD, Germany
Doris-Ann Williams, MBE, Chief Executive, British In Vitro Diagnostics Association (BIVDA), United Kingdom
- Practical impact of the new IVD Regulation
- Regulatory aspects of companion diagnostics
- Challenges for validation
- Role of IVDs in the market
14:30 Chairperson’s Remarks
Jens K. Habermann, MD, PhD, Director, Interdisciplinary Center for Biobanking-Lübeck; Head, Section of Translational Surgical Oncology and Biobanking; Scientific Director, Surgical Center for Translational Oncology-Lübeck, Germany
14:35 Epigenetic Alterations in CTCs and Corresponding ctDNA
Evi Lianidou, PhD, Professor, Analytical Chemistry, Clinical Chemistry, Chemistry, University of Athens, Athens
Our group was the first to demonstrate epigenetic alterations in CTCs and corresponding ctDNA (Chimonidou et al., Clin Chem 2011, Clin Chem 2013). Epigenetic silencing of estrogen receptor gene (ESR1) could be of clinical relevance especially for its potential impact on endocrine treatment efficacy. In this study, we evaluated for the first time ESR1 methylation in CTCs, paired ctDNA and primary tumors of breast cancer patients.
15:05 Data-Driven Discovery of Extravasation Pathway and Integrated Regulatory Network for Epithelial-Mesenchymal Transition in Circulating Tumor Cells
Prashant Kumar, PhD, Faculty Scientist, Molecular Oncology, Institute of Bioinformatics, Bangalore, India
The talk will uncover promising CTC-driven signaling nodes in the extravasation pathway and identified the key contributors that may determine favorable clinical outcomes. These CTC-associated signaling profiles will provide a valuable resource to identify downstream events crucial to the functioning of CTCs in the metastatic cascade. These findings bring us further toward understanding the mechanisms of various biological processing pathways within the circulating cell.
15:35 Epithelial-to-Mesenchymal Transitions and Coagulation: Impact on the Metastatic Competence of Circulating Tumor Cells
Christine Gilles, PhD, Senior Research Associate FRS-FNRS, GIGA-Cancer, University of Liège, Belgium
Increasing data support the contribution of Epithelial-to-Mesenchymal Transitions (EMTs) in providing Circulating Tumor Cells (CTCs) with enhanced metastatic competence. Our most recent work shows that EMT endow tumor cells with coagulant properties, thereby facilitating early metastasis. Characterizing and targeting EMT-shifted subpopulations of coagulant CTCs constitute our future lines of research.
16:05 Refreshment Break in the Exhibit Hall with Poster Viewing
17:05 Tumor Heterogeneity Inferred from Single CTC Sequencing and CTC-Derived Explants (CDX)
Françoise Farace, PhD, Head, Rare Circulating Cells Translational Laboratory, Gustave Roussy, Université Paris-Saclay, France
Our results show that sequencing of individual CTCs can reveal undiagnosed mutations in matched-metastasis and provide a unique representation of metastasis mutational content that is otherwise inaccessible. We established and characterized four NSCLC and one prostate cancer CTC-derived explants (CDX). Genetic profiling of CDXs, CTCs and matched-tumor biopsies enabled the construction of phylogenic mutational trees and the identification clonal mutations and dominant clones with tumorigenic potential.
17:35 CTCs Characterization from a Triple Negative Breast Cancer Patient CDX
Clotilde Costa, PhD, Head, Liquid Biopsy Line, Roche-Chus Joint Unit, Clinical Hospital of Santiago de Compostela, Spain
The development of CTC-derived xenografts (CDX) is a powerful strategy for preclinical drug screening, biomarker identification, biologic studies, and personalized medicine strategies and is expected to provide crucial information on mechanisms involved in metastatic progression. We report the establishment and characterization of a triple negative breast cancer CDX using RNA-sequencing technology. We conclude that CDX technology is feasible in triple negative breast cancer, and this approach opens a promising way to reach a precision oncology in patients.
18:05 Breakout Discussions
Accelerating the Validation, Approval and Reimbursement of Blood Based Biomarker Assays.
Howard I. Scher, MD, D. Wayne Calloway Chair, Urologic Oncology; Co-Chair, Center for Mechanism Based Therapy; Head, Biomarker Development Initiative; Office of the Physician in Chief; Member and Attending Physician, Genitourinary Oncology Service, Medicine Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, United States
- Patient factors that may affect assay results.
- Determining when an assay is “fit for the purpose” of evaluation for a specific context of use.
- Clinical utility: a goal of biomarker development rarely demonstrated.
- Challenges in the design of dedicated biomarker trials.
Overarching Topic: Technical Challenges for CTC-Based Liquid Biopsies
Nikolas Hendrik Stoecklein, MD, Professor, Experimental Surgical Oncology, Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
- What is a sufficient definition of a CTC for clinical applications?
- What are the minimal requirements for SOPs from companies introducing a new CTC assay before testing it on clinical samples?
- What are the requirements for technical validation of CTC assays before clinical use?
- What is a realistic evidence requirement demonstrating clinical utility for a CTC-based liquid biopsy?
19:05 Close of Day
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THURSDAY, 24 May
08:30 Registration and Morning Coffee
09:00 Chairperson’s Remarks
Nikolas Hendrik Stoecklein, MD, Professor, Experimental Surgical Oncology, Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
09:05 Label-Free Isolation of Tumor Cells from Body Fluids and Multiplex Analysis on a Chip
Lorena Diéguez, PhD, Staff Researcher, Life Sciences, International Iberian Nanotechnology Laboratory, Portugal
Tumor cells from body fluids were isolated using a high-efficiency label-free microfluidic system, and their phenotype characterized by Surface Enhance Raman Scattering. Gold nanostars were synthesized and labelled with different Raman reporters and conjugated with different biomarkers against proteins in the cell wall. Each Raman reporter matched a cell receptor, and so the heterogeneity of each cell could be assessed on chip without the need of cell recovery and manipulation.
09:35 Detection of Viable Circulating Tumor Cells at the Single Cell Level Using Digital Microfluidics
Jean Baudry, PhD, Laboratoire Colloïdes et Matériaux Divisés (LCMD), ESPCI Paris, PSL Research University, CNRS UMR8231 Chimie Biologie Innovation, Paris, France
To enumerate CTCs and characterize their heterogeneity in peripheral blood, we have developed a massively-parallel-kinetic analysis of single CTCs. The method uses living cells, so real phenotypic properties of the CTCs are assayed, like secretion of protein of interest, as well as more classical surface markers quantification.
10:05 Multiplex Assays for Cancer Management Using πCode MicroDisc Technology
Stuart Palmer, PhD, COO, Administration, PlexBio Co., Ltd., Taiwan
PlexBio has developed a platform for high complexity mutation analysis. The IntelliPlexTM Lung Cancer Panel assesses the status of 57 somatic mutations and gene re-arrangements in liquid biopsy samples. The test offers a rapid, comprehensive and cost-effective way to interrogate patient samples with achievement of sensitivities of 0.01%-0.1%.
10:35 Coffee Break in the Exhibit Hall. Last Chance for Poster Viewing
11:20 The Molecular Second Look: A “Novel” Method for Identifying and Genetically Characterizing Residual Disease in Ovarian Cancer Patients following Surgery and Completion of Chemotherapy
John Martignetti, PhD, Professor, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, United States
With the ultimate complementary goals of earlier detection of residual disease, defining tumor heterogeneity, optimizing ovarian cancer treatment and improving survival, we propose a novel method of cancer surveillance. We have used ultra-deep, targeted gene sequencing of peritoneal washes following a patient’s surgery and completion of chemotherapy to provide a more sensitive means of detection of persistent disease as well as provide specific information about a tumor’s genetic features.
11:50 Circulating Tumor Cell (CTC) Analysis in Preclinical Models of Cancer Metastasis
Alison Allan, PhD, Senior Oncology Scientist, Associate Professor, Oncology and Anatomy & Cell Biology, Western University
The use of in vivo preclinical models that allow assessment of metastasis is critical for development of effective new cancer therapies. This presentation will discuss the use of circulating tumor cell (CTC) analysis as an effective means of tracking and characterizing metastatic disease progression in preclinical mouse models of breast and prostate cancer. In particular, the use of clinically-relevant CTC technologies such as the CellSearch and Parsortix platforms for pre-clinical CTC studies can serve to enhance the understanding and translation of cancer biology and new cancer therapies from animal to patient.
12:20 PANEL DISCUSSION
Moderator: Nikolas Hendrik Stoecklein, MD, Professor, Experimental Surgical Oncology, Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
What are the barriers for propagation and culture of CTC?What advances are needed to make the ease of CTC capture, analysis and interpretation easier, more reliable and more user-friendly?How can we address the challenge of clinical correlation with the detection of various tumor-associated circulating cells and other circulating targets?What strategies can we use to come to consensus on quality control and standardization for CTC characterization and analysis?12:50 Luncheon Presentation: Parsortix™ System Makes Unbiased Isolation and Identification of CTCs Possible
Anne-Sophie Pailhes-Jimenez, PhD, Senior Scientist, ANGLE plc, United Kingdom
The enumeration of circulating tumour cells (CTCs) in peripheral blood has shown prognostic relevance in several cancer types. The ParsortixTM system allows an epitope-independent enrichment of CTCs based on cell size and compressibility using a disposable cassette. We developed an in-cassette immunofluorescent staining to specifically identify CTCs from patient samples. This is a sensitive, flexible and semi-automated method for the capture, enumeration and characterisation of CTCs that has the potential to provide clinical value.
13:20 Session Break
13:50 Chairperson’s Remarks
Françoise Farace, PhD, Professor, University of Paris-Sud, Université Paris-Saclay, France
14:00 KEYNOTE PRESENTATION: Phenogenomic Subtyping of CTCs to Identify Biomarkers that Improve Prostate Cancer Patient Outcomes
Howard I. Scher, MD, D. Wayne Calloway Chair, Urologic Oncology; Co-Chair, Center for Mechanism Based Therapy; Head, Biomarker Development Initiative; Office of the Physician in Chief; Member and Attending Physician, Genitourinary Oncology Service, Medicine, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, United States
With the aim of rapidly identifying circulating tumor (CTC) populations that are sensitive to specific classes of drug to guide treatment selection, and building on the technology enabling clinical utility established in the area of the cytologic evaluation of Pap smears, we evaluated protein and morphologic features on individual CTC using the validated EPIC Sciences technology to define 15 unique cell populations. Sensitivity to specific drug classes was determined by the reduction in frequency of a particular cell type which was then sequenced to associate genotype to phenotype. The associations between cell type and response will be presented.
14:30 CTC Count in Breast Cancer: Clinical Validity Results & Utility Trials
Jean-Yves Pierga, MD, PhD, Institut Curie, Medical Oncology and Circulating Tumor Biomarkers Laboratory, SiRIC, Université Paris Descartes, Paris, France
Circulating tumour cell count has demonstrated a very significant clinical validity as a prognostic marker in both metastatic and early breast cancer patients. We will summarize the results obtained and present the ongoing attempt to demonstrate its clinical utility.
15:00 Workflows to Advance CTC-Based Liquid Biopsies
Nikolas Hendrik Stoecklein, MD, Professor, Experimental Surgical Oncology, Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
We developed workflows to profile individual CTCs for genetic and epigenetic alterations, e.g. to monitor genomic profiles of CTCs during therapy, which might help to identify genetic resistance mechanisms. However, a major challenge to use CTC-based liquid biopsies remains their extreme low concentration of CTCs and the minimal amount of investigated blood in standard CTC-tests. To tackle this problem, we introduced Diagnostic Leukapheresis (DLA), which resulted in an increase in CTC detection frequency and an escalation of the median CTC numbers. We hope that DLA, or similar approaches derived thereof, will advance the clinical utility of CTC-based liquid biopsies.
15:30 How Clinical Biobanks Can Support Precision Medicine: From Standardized Preprocessing to Treatment Guidance
Jens K. Habermann, MD, PhD, Director, Interdisciplinary Center for Biobanking-Lübeck; Head, Section of Translational Surgical Oncology and Biobanking; Scientific Director, Surgical Center for Translational Oncology-Lübeck, Germany
CTCs harbor an enormous potential for precision medicine. However, clinical implementation requires standardization. This is in contrast to e.g., CTC assessment in colorectal cancer, which is still hampered by major inter-study heterogeneity. This talk will address (i) current challenges and solutions for standardized CTC assessment and (ii) how clinical biobanks can support CTC research for precision medicine, the latter one being exemplarily demonstrated by CTC detection emphasizing distinct surgical procedures.
16:00 Refreshment Break in the Foyer
16:20 Biological Role and Clinical Significance of Experimentally-Derived CTC-Specific Genes in Breast Cancer
Emanuela Fina, PhD, Biomarkers Unit, Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Italy
Circulating tumor cells (CTCs) represent a unique source of information that might help to clarify numerous aspects of metastasis biology and identify new clinically useful biomarkers. CTC specific genes, including TFF3 and FADS3, derived from the MDA MB 231 xenograft model, were investigated i) to explore their role in metastasis by functional assays and ii) to assess their prognostic role when detected in CTC samples obtained from clinically non-metastatic and metastatic breast cancer patients.
16:50 Hypermetabolic Circulating Tumor Cells Predict Progression-Free Survival in Metastatic Breast Cancer Patients
Fabio Del Ben, MD, PhD, Research Collaborator, Cancer Research and Advanced Diagnostics, Immunopathology and Cancer Biomarkers Unit, CRO Aviano IRCCS National Cancer Institute; Clinical Pathology Resident, Medical Area, University of Udine, Italy.
Our group has developed a novel method to detect hypermetabolic CTC, by a single-cell, label-free measurement of their dysregulated pH (Del Ben, Turetta et al. Angew Chemie Int Ed 2016). Here, we present data on the prognostic value of hypermetabolic CTC in a small cohort of metastatic breast cancer patients, feasibility of sorting and harvesting of viable and label-free CTC, and results of genetic characterization of ESR1 and PI3KCA mutations in hypermetabolic CTC compared to cfDNA.
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