Genetics England 100K Cancer Programme – Kay Lawson

100KGP
Cancer Programme
Genomics England : AIMS
• To establish structures to enable WGS as a routine test across the
NHS
• Create an ethical framework and valid consent process
• Capacity for high-throughput, cost-effective sequencing
• Architecture and pipelines for big data management
• Sample acquisition pathways and molecular pathology
• Reporting: expertise and standards for consistent, standardised
interpretation, reporting, validation, feedback and clinical
implementation/actionability
• Central repository of linked clinical and molecular data (for
clinical diagnostics/clinical research)
• Deliver benefit to individual patients
• Generate datasets informative to clinical research
• Catalyst for closer working with industry; kick start UK genomics
industry
The cancer programme is challenging….
• Complex patient and sample pathways
• Tumour typically a limited resource
• Tumour size  amount of tissue  DNA quantity
• Cellularity, % neoplastic cells
• Molecular Pathology
• Routine handling by FFPE  DNA quality
• Dynamic status of tumour and patient
• WGS utility sensitive to turnaround time
• Clinical utility of WGS in cancer patients less immediately
tractable
• Reduced patient/clinician incentive
• Variant calling is less robust; clonal heterogeneity, esp CNV/SV
(more important)
• Technical validation complex: heterogeneity, no DNA,
CNVs/SVs, commissioning
• Clinical field less evolved (TSBs, clinical actions)
Genomics England 100K Cancer program:
CURRENT STATUS: Overview
CURRENT
NEW
IMMINENT
Breast Cancer
Renal Cancer
Brain Tumours
Prostate Cancer
Sarcoma
Upper GI
Colorectal
Cancer
Germ Cell
Tumours
Ovarian Cancer
Endometrial
Lung Cancer
Melanoma
CUP
Childhood
• IIP: Tumour (FF AND optimised
FFPE) and constitutional
(blood) DNA collected
• CMP: Tumour (FF where
biologically possible OR
optimised FFPE) and
constitutional (blood) DNA
collected. No pre-treatment
• -omics: cfDNA, serum, plasma,
FF tissue/lysate, paxgene
• 75x median for tumour; 30x
median for germline
Sample acquisition,
Molecular Pathology
Validation,
Interpretation,
Feedback
Clinical Data capture
Which patients to
include: Eligibility,
Cohorts, Studies
Genomics England 100K –
The Principal Partners
NHSE
GMCs
Academics
(GeCIP)
Illumina
Genomics
England
Commercial
Partnerships
(GENE)
10th March 2016
@clare__turnbull @GenomicsEngland
Health
Education
England
#Genomes100K
Genetic Alliance meeting
Sample acquisition,
Molecular Pathology
Pilot Studies
• CRUK pilot: Manchester, Birmingham, Royal
Marsden, Leeds, Southampton
• FFPE+germline from <1500 patients
• Patterns in sample performance, WGS quality and
tumour purity by centre and tumour type
• BRC pilot: Oxford, UCLH, Imperial, Cambridge,
Kings, Royal Marsden
• FF+FFPE+germline from >400 patients
• Highly detailed individual-level sample metadata (34
variables: 16 for tissue processing, 18 for DNA
extraction)
• Multivariate analysis against pre-sequencing and WGS
metrics
CRUK pilot: attrition of FFPE samples
QC Requirements: >40% neoplastic cells (histology), 750ng DNA, delta
CQ<2.5, 260/280
Low-GC region
Fresh Frozen
FFPE: Centre 1
AT Dropout
FFPE: Centre 2
GC Dropout
GC-rich region
Can GMCs easily substitute FFPE with collection of fresh samples?
Number of Oxford patients recruited into Gel pilot per tumour site
Recruited FF collected FS>40%
% FF
Breast
58
39
32
55
CRC
88
59
41
46
Thoracic
45
11
8
18
Renal
Prostate
89
64
51
27
39
13
44
20
Ovary
33
21
8
24
Endometrial
Pancreas
22
23
19
12
15
7
68
30
Oesophagea
l
24
5
1
4
The Need to include Biopsies…
Indication
• Patients with primary disease undergoing neoadjuvant
chemotherapy
• Proven advanced or metastatic disease (biopsy primary or ?
metastatic lesion)
• Active surveillance eg low-grade prostate cancer
• Patient undergoing alternative radical therapy eg radiotherapy,
brachytherapy, HIFU
Challenges
• Consent for diagnostic biopsy (EXTRA tissue, ALTERNATIVE
HANDLING). Otherwise second procedure required.
• Pathways/DNA requirements: triangulation of:
•
•
•
•
DNA requirements >1200ng
Purity requirements >40-50% (seq at 75x): feasibility of macrodissection
#biopsies it is feasible to request/process from routine service
Requirement for histological examination if diagnostic sample fails
12
Literature review on lung biopsies
• Data from FFPE-biopsies in 2 centres:
• Bronchoscopic forceps biopsies (n=292)
median DNA yield 1.6µg, tumour content 30%
• EBUS-TBNA (n=155)
median DNA yield 1.4µg, tumour content 20%
• Percutaneous needle core biopsies (n=45)
median DNA yield 1.0µg, tumour content 50%
• GBC data - NDA
• SMP data based on DNA content in FFPE after all standard
diagnostic tests (H&E, levels, immunohistochemistry,
molecular tests) have diminished tissue
• Biopsy ‘pilot’ in a number of centres planned→Illumina R&D
pipeline ?facilitate ↓DNA requirements
Interpretation, Validation,
Reporting, Actioning
Validation, Interpretation and
Feedback Working Group
• Develop structures and standards for use across the NHS for
• sequence quality for calling presence/absence of variants
• annotations for clinical interpretation and actionability
• Linking to clinical trial availability
• Role of technical validation of findings by other platforms
• Platform for viewing, sharing, reporting on large genomic data .
Develop culture of TSBs
Gonzalez de Castro (ICR/RMH, SMP)
• Close working with UK NeQAS David
Shirley Henderson (Oxford)
Gary Middleton
(Birmingham,
Matrix)
• Close working with tumour-type experts
(Cancer
GeCIP
Rachel Butler (Cardiff, NeQAS)
leads)
Manuel Salto-Tellez (Belfast)
Gert Attard (ICR, DDU)
• Group of:
•
•
•
•
Phil Bennet (UCL)
Molecular Geneticists
Angela Hamblin (Oxford)
Molecular Pathologists
Andrew Wallace (Manchester)
Oncologists/Haematologists
Work in molecular diagnostics in NHS, SMP, trials
Clinical data capture
Primary clinical data capture
Identifiers
Outcomes/ Follow up
Tumour
Sample handling
Jim Davies (NHIC, Oxford)
Nancy Horseman (Cancer Registry)
Steve Harris (Oxford)
Amanda O-Neill (ehospital, Cambridge)
Adam Milward
Kay Lawson
Louise Jones
Clare Turnbull
Clinical episodes
Secondary data
• systemic anti-cancer therapy (SACT)
• radiotherapy dataset (RTDS)
• cancer outcomes and services (COSD)
•
•
•
•
•
•
•
Primary Care Data Set: CPRD GOLD (CPRD)
Patient Reported Outcome Measures (HSCIC)
Diagnostic Imaging Dataset (HSCIC)
Mental Health and Learning Disability (HSCIC)
Hospital Episode Statistics (HSCIC)
Secondary Uses Services (HSCIC)
ONS: Mortality dataset (HSCIC)
all from NCRS
(National Cancer
Registration Service)
Use resources to
create life course
data
•
18
Cancer Working Group
Meet 2 monthly
Develop strategies for the cancer
programme around:
• Tumour/patient cohort eligibility
• Individual patient benefit
• Tumour-type pathways
• Clinical research value
• Tumour sampling and sequencing (eg
multi-region biopsying, multiple
samples in space, longitudinally)
• Co-recruit to trials (eg: TracerX) and
develop new trials
• -omics
Dion Morton (pan cancer)
James Brenton (ovary)
Charles Swanton (lung)
Johann de Bono (prostate)
Nick Turner (breast)
Ian Tomlinson (colorectal)
Adrienne Flannagan (sarcoma)
Josef Vormoor (childhood)
James Larkin (renal)
Anna Schuh (haem-onc)
Crispin Hiley
Mark Linch
Samra Turajlic
Nischalan Pillay
David Gonzalez (Imperial GMC)
Frank McCaughan (SL GMC)
Paul Cane (SL GMC)
Tim Helliwell (NWcoast GMC)
John McGrath (Wessex GMC)
John Radford (Manchester GMC)
Sean Grimmond (ICGC)
David Cameron (clinical trials)
Ian Cree (RCPath)
Rowena Sharpe (CRUK)
GMC recruitment
Gear 1 


Broad recruitment of primary tissue.
Surgical resections or biopsies
No prior chemo, radio or hormonal therapy
Genomics England operational
requirements for initiation of this phase
•
•
•
[biopsy]
[FU data]
[DNA requirements reduced]

Real-time monitoring of patient
accrual AND sample performance
Robust infrastructure for collection of
FU data
Currently accepted: breast, ovarian, prostate, lung, CRC, renal,
sarcoma, Under development: childhood. Proposed: upper GI
(gastric, hepatobiliary, CUP, NET, pancreatic, HCC),
endometrial, bladder, brain, TGCT, melanoma
Gear 2 
Recruit specific cohorts of patients via established
pathways (e.g. co-recruitment to trials/studies)




Recruit specific cohorts of patients via new pathways
Biopsies likely key (diagnostic/recurrence)
Serial ctDNA in selected cohorts

Initiation of clinical trials in early stage
(adjuvant/consolidation) setting (?power)
Delivery of WGS in clinically meaningful time scale.
Gear 3 

Phase 1 trials/drugs off license/trials in advanced setting

Operationalisation of collection of
diagnostic biopsy (consent, processing
p/w).
 DNA requirements reduced
 Funding of additional ctDNA samples
agreed
TAT reduced to <3 months (robust)
TAT reduced to <(?)4 weeks (robust)
20
Building the future of genomic
medicine in cancer care the NHS
• Develop structures for collection in NHS of consistent, high-quality
consent, data and samples (for clinical AND research usage)
• Develop and deliver a legacy of infrastructure: sequencing centre,
sample pipeline, biorepository and large-scale data store, for
sustainable use by the NHS. Human capacity and capability
• Concentrating the UK Genomics Knowledgebase (clinical and
research) in a single location
• NHS, academics and industry partnerships working together at the
outset to drive Genomic Medicine into the NHS
Put genomic medicine right into clinical practice
in the National Health Service; make the NHS a
central hub for genomic research
Acknowledgements
PILOTS/EXPERIMENTS
Lab Leads:
Anna Schuh
Shirley Henderson
Gerry Thomas
Adrienne Flannagan
Andrew Wallace
David Gonzalez de C
James Brenton
Francesca Ciccarelli
Emily Shaw
Louise Jones
Clare Verrill
Pauline Robbe
Dimitris Vavoulis
James Hadfield
ILLUMINA R&D team:
Mark Ross
Jenn Becq
Zoya Kingsbury
Sean Humphray
David Bentley
CANCER WORKING GROUP
Dion Morton (pan cancer)
James Brenton (ovary)
Charles Swanton (lung)
Johann de Bono (prostate)
Nick Turner (breast)
Ian Tomlinson (colorectal)
Adrienne Flanagan (sarcoma)
Josef Vormoor (childhood)
James Larkin (renal)
Anna Schuh (haem-onc)
Crispin Hiley
Mark Linch
Samra Turajlic
Nischalan Pillay
David Gonzalez (Imperial GMC)
Frank McCaughan (SL GMC)
Paul Cane (SL GMC)
Tim Helliwell (NWcoast GMC)
John McGrath (Wessex GMC)
John Radford (Manchester
GMC)
Sean Grimmond (ICGC)
David Cameron (clinical trials)
Ian Cree (RCPath)
Rowena Sharpe (CRUK)
VALIDATION, INTERPRETATION AND
FEEDBACK WORKING GROUP
David Gonzalez de Castro (ICR/RMH)
Phil Bennet (UCL)
Angela Hamblin (Oxford)
Shirley Henderson (Oxford)
Manuel Salto-Tellez (Belfast)
Andrew Wallace (Manchester)
Gert Attard (Imperial)
Gary Middleton (Birmingham)
Rachel Butler (Cardiff)
GENOMICS ENGLAND CANCER TEAM
Louise Jones
Cristina Aguilera
Alice Tuff Lacey
Raj Judge
Jason Chattoo
Peter Scott
Joanne Mason
Nancy Horseman
Kay Lawson
Shirley Henderson
Nirupa Murugaesu
James Hadfield
Simon Thompson
James Peach
Matt Parker
Mark Caulfield
Augusto Rendon
Tom Fowler
www.genomicsengland.co.uk
E: [email protected]
T: 020 7882 3402