"Liquid Biopsies and the Future of Cancer Detection" - Nicola Aceto SNSF Professor of Oncology Cancer Metastasis Lab - University of Basel - Swiss Re
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“Liquid Biopsies and the Future of Cancer Detection”
Swiss Re – Insurance Medicine Summit 2017 – 15-17 November 2017
Nicola Aceto
SNSF Professor of Oncology
Cancer Metastasis Lab – University of Basel
Presentation Outline 1. A snapshot on Liquid Biopsy: CTCs and ctDNA 2. CTC success story: ex vivo culture for individualized testing of drug susceptibility 3. Investigating the vulnerabilities of metastasis through the analysis of CTCs 4. ctDNA success story: sequencing cancer patients at the University Hospital Basel
Diaz and Bardelli, JCO, 2014
10 mL Whole Blood
50 billion RBCs
50 million WBCs
0-100 CTCs
0-1 ctDNA in 100-10’000 cnDNA
What can we learn from a liquid biopsy?
www.cancerworld.org
CTC success story: ex vivo culture for individualized testing of drug susceptibility
Typical Metastatic Breast Cancer Patient History
Yu, Bardia, Aceto et al., Science, 2014
Ex vivo Culture of CTCs
Yu, Bardia, Aceto et al., Science, 2014
Mutation Analysis – 1000 hotspots panel
Yu, Bardia, Aceto et al., Science, 2014Mutation-based Screening to Identify Drug Susceptibility
Yu, Bardia, Aceto et al., Science, 2014Validation in Mouse Cancer Models Yu, Bardia, Aceto et al. Science, 2014
Investigating the Vulnerabilities of Metastasis Through the Analysis of CTCs
DAPI: DNA
FITC: PSMA
TxRed: CD45
Stott et al., Science Transl Med, 2010CTC-clusters and Poor Prognosis in Cancer Patients
BREAST CANCER
PROSTATE CANCER
Aceto et al., Cell, 2014CTC-clusters are Oligoclonal and
CTC-clusters are 50x More Metastatic than Single CTCs
50x more metastatic than single CTCs
Aceto et al., Cell, 2014
Aceto et al., Trends in Cancer, 2015Cell-cellJunctions
Cell-cell Junctionsare
areRequired
Requiredfor
forCTC-clustering
CTC-clustering
Plakoglobin is increased Plakoglobin is required for
~215-fold in clusters vs CTC-clustering and metastasis
single CTCs
Aceto et al., Cell, 2014CTC-clusters
CTC-clusters
1. CTC-clusters originate from individual tumor deposits and
are not the result of intravascular tumor cell aggregation
2. CTC-clusters are rare but highly metastasis-competent,
accounting for half of metastatic lesions in mouse model
3. Plakoglobin helps tether CTCs within clusters, thereby
enhancing metastatic spreadctDNA Success Story: Sequencing Cancer Patients at the University Hospital Basel
Molecular Pathology Services in Basel
Building a competence Centre, step by step
Full
accreditation for 1st Cynvenio platform installed in
Installation of 1st Continental Europe for CTC
the use of NGS S5XL sequencer (Under evaluation for
in routine in Switzerland Diagnostics )
diagnostic
April 2016 December
April 2015 2016
February September
2015 2015 October 2016
Introduction of fully Introduction of Liquid Fusion with the
automatized solutions to Biopsy (cfDNA) as a Medical Genetics and
expand throughput diagnostic test establishment of the
capacity Molecular Diagnostics
Unit
Dr Luca Quagliata - Property of the University Hospital of Basel -
Confidential not to distributeMolecular Pathology is Facing a Substantial Growth
Trend of analyzed samples (Basel)
“Investments made (e.g. NGS instrumentations) n = 1,700
within the Molecular Unit turned into a constant n = 1’501 2017
1,500 and substantial growth over the past years Prediction
with a overall CAGR of 10.42%” About
n=100 LB
n = 1’255
External (60%)
n = 1’156
n = 980
1,000
n = 887 n = 907
Samples
n = 750
Internal - USB (40%)
500
0
2010 2011 2012 2013 2014 2015 2016
Dr Luca Quagliata - Property of the University Hospital of Basel - CAGR: compound annual growth rate
Confidential not to distributeExamples of Analyzed Sample Types: What is Happening?
Heterogeneous source of starting material – Is Liquid Biopsy a game changer?
The Past
Laser
Resected Biopsy Biopsy Cytology microdissection Liquid Biopsy
The Future
Due to technical limitations in the past, resected samples were mostly use for molecular testing.
Nowadays, very limited tissue collected through a biopsy is typically used as routine starting material for
tumor profiling, especially in the metastatic setting. Cytology and laser microdissected specimens are more
commonly used for this purpose. Limited FFPE tissue amount, resulting in low quality DNA/RNA, represents
a challenging issue for current molecular diagnostics laboratories and requires high level of expertise and an
appropriate laboratory setting. Liquid Biopsy is likely to represent the future of Molecular Pathology.
Dr Luca Quagliata - Property of the University Hospital of Basel -
Confidential not to distributeMolecular Diagnostics: No Sample is Left Behind
Make the best out of the limited resources, mastering FFPE and Liquid Biopsy specimens
Sample DNA/RNA Data
Sequencing Report
Reception extraction generation
L858R
DEL18
EGFR INS9
G719A
G719S
L861Q
ERBB2 INS12
BRAF V600E
G12V
KRAS G12A
G12D
PIK3CAC E545K
90% 10%
Loading 33,811,833 Empty wells DAT processing
100% 33,811,202 0%
Enrichment No template
Classification
62% 21,115,607 38%
Clonal Polyclonal
Signal processing
Base caller
Read filter
Alignment QC
From the initial sample to the final report within 5-7 working days
Dr Luca Quagliata - Property of the University Hospital of Basel -
Confidential not to distributeLiquid Biopsy: new generation of solutions
Mostly used panels in cancer diagnostics, collaboration with Thermo Fisher Scientific
Lung Cancer Breast Cancer Colorectal Cancer
ALK KRAS PIK3CA AKT1 ESR1 SF3B1 AKT1 FBXW7 PIK3CA
BRAF MAP2K1 ROS1 EGFR FBXW7 TP53 BRAF GNAS SMAD4
EGFR MET TP53 ERBB2 KRAS CTNNB1 KRAS TP53
ERBB2 NRAS ERBB3 PIK3CA EGFR MAP2K1 APC
ERBB2 NRAS
• Amplicons: 58 • Amplicons: 76 • Amplicons: 48
• Key hotspot mutations in 11 genes • Key hotspot mutations in 10 genes • Covering key hotspot
• Increase in hotspot SNVs & indels • Increase in hotspot SNVs & indels mutations in 14 genes
• Fusions (49) – ALK, RET, ROS1 • CNVs – CCND1, ERBB2, FGFR1 • 244 Hotspot SNVs & indels
• CNV – MET • More complete coverage of TP53
• MET exon 14 skipping (3) • Single library to detect SNVs and
• Single library from both DNA & CNVs
RNA
A comprehensive Pan-Cancer cfDNA panel will be available in Q2 2018
Dr Luca Quagliata - Property of the University Hospital of Basel -
Confidential not to distributeLB in Clinical Practice: Patient Case -56-year old female never-smoker
Histology: NSCLC,
Adenocarcinoma
Markers: CK9(+), TTF-1 (+)
Stage: IV, cT2, cN1, M1a
Mutation Status: EGFR Ex19 Stage IV PR Oligo - PD
Mut. at diagnosis
Dr Luca Quagliata - Property of
TKI-3
the University Hospital of Basel -
Confidential not to distribute
Tissue Biopsy Pleural effusion Liquid Biopsy
EGFR Exon 19 (20%) EGFR Exon 19 (20%)
Bronchoalveolar lavage KRAS p.G13D (55%) EGFR Exon 19 (29%) EGFR T790M (2%)
MET p.N375S (40%) P53 p.G245V (10%) P53 p.G245V (3%)
EGFR Exon 19 MET p.T1010I (20%) MET p.N375S (59%) MET p.N375S (55%)Take home
(1) Liquid biopsy is rapidly evolving as an accepted
method for cancer diagnosis and patient stratification
(2) CTCs and ctDNA are complementary, and can be used
in parallel to enable “Precision Medicine”
(3) CTCs enable ex vivo testing of drug susceptibility, as
well as “discovery” approaches, protein and RNA
expression studies
(4) ctDNA testing is already available, and preliminary
data showed its robustness and capability to identify
cancer-associated mutations in patientsOpen questions and Future Perspectives related to Liquid Biopsy
CTCs:
- Generation and survival of CTCs
- Implementing drug susceptibility testing
- Vulnerabilties of metastasis
ctDNA:
- Raise awareness regarding tumor genotyping via
liquid biopsy in cancer patients
- Implementing ctDNA testing as a standard procedure
in clinical practice
- To assess the potential of ctDNA testing for early
cancer detectionAcknowledgements
Acknowledgements
Aceto Lab DBM University Hospital Basel Pathology Basel
Sofia Gkountela Christoph Rochlitz Luca Quagliata
Francesc Castro Giner Walter Weber Lukas Bubendorf
Barbara Szczerba Viola Heinzelmann Christian Ruiz
Manuel Scheidmann Alfred Zippelius Serenella Eppenberger
Cinzia Donato Marcus Vetter
Anatomy Basel
Ramona Scherrer Julia Landin
Magdalena Müller-Gerbl
Ilona Krol Catherina Balmelli
D-BSSE ETH Zürich Heike Pueschel DBM Bioinformatics
Niko Beerenwinkel Andrea Banfi Robert Ivanek
Timm Schroeder Nunzia Di Maggio
Christian Beisel Biozentrum Imaging Facility
Leo Kunz NEXUS Platform ETH Oliver Biehlmaier
Jochen Singer Zürich Wolf Heusermann
Katharina Jahn Christian Stirnmann
Jack Kuipers Daniel Stekhoven Harvard/MIT Boston
Daniel Haber
Funding Shyamala Maheswaran
Mehmet TonerBasic Copyright Notice & Disclaimer ©2017 This presentation is copyright protected. All rights reserved. You may download or print out a hard copy for your private or internal use. You are not permitted to create any modifications or derivatives of this presentation without the prior written permission of the copyright owner. This presentation is for information purposes only and contains non-binding indications. Any opinions or views expressed are of the author and do not necessarily represent those of Swiss Re. Swiss Re makes no warranties or representations as to the accuracy, comprehensiveness, timeliness or suitability of this presentation for a particular purpose. Anyone shall at its own risk interpret and employ this presentation without relying on it in isolation. In no event will Swiss Re be liable for any loss or damages of any kind, including any direct, indirect or consequential damages, arising out of or in connection with the use of this presentation.
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