Global monitoring of the WHO ‘25 by 25’ target

Global monitoring of the
WHO ‘25 by 25’ target
- proposal from the
Section of Cancer Information
Freddie Bray
WHO target - IARC proposal
• Global target to reduce premature
mortality from all NCDs by 25% by 2025
(4 key NCDs, ages 30-69)
• Proposal:
– Evaluate national cancer mortality trends
against the ‘25 by 25’ target
• Quantify whether the reduction is attainable
based on recent trends via prediction models
• Deliver a report card on cancer control progress
at the national and global level
Data sources and availability
• Mortality extracted from the WHO mortality
database by country, cancer site, year, sex, age
• Data available for ≥15 years:
– 78 countries
(35 Europe, 25 Americas, 15 Asia, 2 Oceania, 1 Africa)
• Data available for <15 years:
– 8 countries
(4 Asia, 2 Europe, 2 Africa)
• Quality (coverage, completeness, timeliness)
National mortality series: availability
Methods
• Standard prediction models fitted to recent trends
(e.g. 1991-2010) to predict mortality 2011-2025
• National data available for ≥15 years:
– Age-period-cohort models based on a 15- or
20-year prediction base: NORDPRED (Moller et al, 2003)
• National data available for <15 years:
– Time-linear models based on a 10-year prediction
base (e.g. Dyba & Hakulinen, 1997)
• Future ‘all sites’ burden derived from site-specific
analyses (top ten cancers + residual sites by sex)
Key output & dissemination
For ‘all sites’ + leading 10 cancers,
ages 30–69 & all ages, by country and sex:
• Number of recorded deaths and age-standardised
rates (up to 2010) and predicted (up to 2025)
• Cumulative risk of death (up to age 70)
• % change in cancer deaths (2008 v. 2025)
Dissemination
• Global Status Report
Online user-friendly toolkit
Deaths
2008
Deaths
2025
% change
% due
to pop
% due
to risk
Males
33462
42904
28
51
-23
Females
29085
35939
24
31
-7
62457
78843
26
41
-15
Total
Questions for the Scientific Council
• What could be done in monitoring the
target in LMIC?
• Should we incorporate other indicators
(incidence, survival)?
• Is the analytic strategy adequate?
• Extensions
– Revision of target for remaining major NCD groups?
– Incorporate scenarios for specific cancer interventions?
Future perspectives of quantitative risk
assessment for the IARC Monographs
Kurt Straif, IMO
IARC Scientific Council, January 2013
IARC Monographs
on the Evaluation of
Carcinogenic Risks to
Humans
“A cancer ‘hazard’ is an agent that is capable of causing
cancer under some circumstances, while a cancer ‘risk’ is an
estimate of the carcinogenic effects expected from exposure to
a cancer hazard. The Monographs are an exercise in
evaluating cancer hazards, despite the historical presence of
the word ‘risks’ in the title.” (Preamble, 2006)
Problems encountered with hazard identification
• "International cancer experts have moved tanning beds
and other sources of ultraviolet radiation into the top
cancer risk category, deeming them as deadly as arsenic
and mustard gas.“ (Associated Press, 2009)
• “Evaluations in the IARC Monographs provide
a qualitative assessment of carcinogenicity. The HPV
types that have been classified as carcinogenic to humans
can differ by an order of magnitude in risk for cervical
cancer. The Working Group cautions that the design of
HPV screening tests must also consider other factors
that are discussed in the General Remarks.“ (Vol. 90)
Consideration of risk assessment in IARC Monographs
• IARC workshop: Quantitative Estimation and Prediction
of Risk (IARC Sci Pub 131, 1999).
- no recommendations regarding risk assessment
for the IARC Monographs
• Advisory Group on Future Priorities for the
IARC Monographs, 2003
- many different approaches to risk assessment,
- inclusion of critical reviews of published risk assessments?
- approach based on epidemiological data?
- Working Groups themselves would not embark on risk
assessment.
Consideration of risk assessment in IARC Monographs
Advisory Groups on amendment of the Preamble to the IARC
Monographs, 2005.
• inclusion of a new section in future Monographs that would
summarize data on carcinogenic risks (focus on results that
involve minimal or no unverifiable assumptions, summary
relative risks from meta-analyses),
• systematic incorporation of quantitative analysis of carcinogenic
risk that do not involve extrapolation outside the range of the
available data,
• use of a separate group of experts to develop a supplement to
a specific Monograph focusing on quantitative risk assessment.
• a programme in QRA will require specialized expertise and a
significant commitment of resources.
Consideration of risk assessment in Monographs
The amended Preamble (IARC, 2006) includes the
following guidance on quantitative data:
• Objective and Scope: “A Monograph may undertake to
estimate dose–response relationships within the range of
the available epidemiological data, or it may compare the
dose–response information from experimental and
epidemiological studies. In some cases, a subsequent
publication may be prepared by a separate Working Group
with expertise in quantitative dose–response assessment.”
• Cancer in humans: “Dose–response and other quantitative
data may be summarized when available.“
• Cancer in experimental animals: “…dose–response and
other quantitative data are also summarized.”
Advisory Group meeting planned for November 2013 on
“Perspectives of quantitative risk assessment for the IARC Monographs“
Specific questions to be addressed by the SC
1. Pros and Cons of a move towards risk assessment
(including issues such as other key players and potential users);
2. Potential approaches for the IARC Monographs:
- integration into regular Monographs versus separate meetings
on selected agents;
- restriction to observed exposure–response relationships on
cancer in humans versus low dose-extrapolation, between
species extrapolation and/or use of mechanistic data to inform
such extrapolations;
3. Strategic approach for funding: if move towards risk assessment is
recommended by the AG should this be integrated into the next
5-year grant proposal to US NCI due in summer 2014 and/or which
other funding sources would be suggested?
Current Scientific Initiatives
Mechanisms of Carcinogenesis Section
(MCA)
Zdenko Herceg, PhD
Carcinogenesis in aristolochic acid nephropathy
(MMB Group)
Aim:
Elucidate molecular basis and develop biomarkers
for Upper Urinary Tract (UUT) carcinogenesis
associated with aristolochic acid nephropathy
(AAN)
AAN is a public health problem of global
proportions caused by dietary exposures to
aristolochic acid
Aristolochic acid is a highly potent carcinogen
(Group I) present in plant species used on a worldwide scale in herbal remedies (India, Asia, Africa,
N.& Central America, Europe)
As the source of the exposure is known and its
effects can be detected at the molecular level, this
is a potentially preventable cancer
UUT tumor sites
AAN = global public health problem
prospectively preventable malignancy, with largely unknown and underestimated incidence
128
47+
4
4
1
2
6
16
116
33
?
158
?
Debelle F.D. et al, Kidney Int, 2008
Heinrich M. et al, J Ethnopharm, 2009
Moriya M. et al, Int J Cancer 2011
Jelakovic B. et al, Kidney Int, 2012
Chen C.H. et al, PNAS USA, 2012
Country/Region
Established cases
(published)
Population at risk
Belgium
128
1,800
The Balkans
47+
100,000
Taiwan
126+
8,000,000
China
116+
100,000,000
India
33
?
Approach to study molecular mechanisms and identify
biomarkers
Clinical course
Molecular mechanisms/epidemiology
• Exposure to AA
• Mol. mechanisms (identify early
« driver » events)
• Nephrotoxicity, renal failure
• Prophylactic renal surgery
• UUT carcinoma
<30 yrs • Tumor resection
+2-10
yrs
• 2o tumour formation
• Contralateral kidney UUC
• Bladder
• Identify biomarkers of AA
exposures and carcinogenesis
(mutations, miRNAs)
• Assess biomarkers in new and
unmapped populations at risk
Identification of “driver” mutations in AAN-linked UUT cancers
Mutation type distribution in tumours
(whole-exome sequencing, n=3)
Genome-wide A>T distribution
A>T
40
30
20
10
0
60
30
0
- AA-induced tumors exhibit stochastic
accumulation of genome-wide A>T transversions
- 65% of missense deleterious SNV alterations
are A>T
- A>T is a candidate « driver » event in AAN
tumorigenesis (to be tested in animal/cell models)
300
150
0
J. Zavadil, unpublished
Questions
• Can we exploit animal/cellular models of AAinduced cancer to study early (“driver”) and
genetic/epigenetic events
• How should we best utilize results of these studies
to build relevant and efficient preventive measures
in populations at risk
Epigenetic biomarkers associated with cancer risk
(EGE Group)
Question: Can epigenome changes in peripheral blood be used as
biomarkers of exposure or intermediate biomarkers for cancer risk
Most studies investigated epigenetic changes in cancer tissues
Advances in epigenomics have opened opportunities for identifying
epigenetic biomarkers in genome-wide and high throughput settings
Aims:
Analyse the epigenome (methylome) of WBC of cancer cases and controls
using large samples from the EPIC prospective cohort and epigenome-wide
technology
Identify epigenome changes associated with cancer risk and diet/lifestyle
(alcohol, obesity/physical activity) and endogenous factors (1-carbon
metabolites, hormones)
Focus on breast cancer (collaboration with NME Section); other cancer types
(lung cancer, collaboration with GEN Section) are considered
Study design
EPIC Cohort
Selection of breast
cancer cases (n=500)
Selection of matched
controls (n=500)
DNA methylome profiling
(Illumina 450K Arrays)
Bioinformatics analysis
Analysis of onecarbon metabolites
Validation of top hits in 1500
cases and 1500 controls
(pyrosequencing)
Biostatistics/bioinformatics
analysis
Epigenetic predictors
of cancer risk
Epigenetic signatures
of exposures
Database on risk
factors/exposures/
hormones
Expected outcome
•Discover whether significant epigenome variations in WBC
among cancer cases and controls exist prior to diagnosis
•Discover whether epigenetic variations are caused by
endogenous (hormones, 1-carbon metabolites) and/or environ.
factors
•Prospective design will rule out the possibility that changes are
not influenced by the disease process (“reverse causality”)
Questions
•Issues relevant to epigenomic profiling of prospectively collected
blood samples in studying exposures/cancer risk
•Criteria in selecting exposures associated with breast cancer
(low- vs high-resource settings)
Section of Molecular Pathology
Head: Dr Hiroko Ohgaki
Objectives
- To elucidate the molecular bases and genetic pathways to
human tumours, and to identify clues as to their etiology
- To correlate histologically recognized phenotypes with genotypes
- To establish a molecular classification of tumours
Achievements
- Identification of genetic pathways to gliomas
- Definition of primary and secondary glioblastomas
- Population-based genetic analyses in gliomas in Zurich, Switzerland
- Contributions to the WHO Classification of Tumours of Nervous System
Plan of exome sequencing analysis in glioblastomas
diagnosed in a population
Objectives:
- To assess genetic profiles of glioblastomas at a population level
- To identify molecular markers that predict sensitivity to radio-chemotherapy
in particular in elderly patients
Research plan:
Cancer registries, neurosurgeons, neuropathologists, University Hospitals
Zurich (population, approx. 1 300 000)
Basel (population: Basel Stadt, 185 000; Basel Land, 269 000)
Ticino (population, 328 000)
Diagnosed in 2014 - 2016 (estimated no. of cases, approx. 320)
To collect frozen tumour tissues and blood samples from all patients for
exome sequencing
Challenges
In contrast to retrospective population-based studies, patients will be
initially identified in surgical centres, but not by cancer registries. Thus,
identifying all cases at a population level may be challenging, and
we may lose a significant fraction of elderly patients if they are not treated
in surgical centres.
Questions to Scientific Council:
Does the Scientific Council recommend that IARC carries out populationbased exome sequencing study on brain tumours?
What are the questions that cannot be answered using samples collected
in clinical trials?
WHO Classification of Tumours Series
(WHO Blue Books)
Objectives:
To establish a histopathological and molecular classification of
human tumours that is accepted and used worldwide.
Without clearly defined clinical and histopathological diagnostic
criteria, and more recently genetic and expression profiles,
epidemiological studies and clinical trials are difficult to conduct.
WHO Classification of Tumours (WHO Blue Books) 4th edition
Central Nervous
System
July 2007
Print run 20,000
Haematopoietic
and Lymphoid
Tissues
Sept 2008
45,000
Digestive
System
Oct 2010
20,000
Breast
Soft Tissue
and Bone
June 2012
Initial 10,000
Jan 2013
Initial 10,000
616 contributors (pathologists, clinicians, scientists) from 39 countries participated
>64,000 copies were distributed in >105 countries by WHO Press
Accepted as the international standard of histological and genetic criteria of diagnosis
of human tumours
Challenges
In order to deal with rapid progress in genetics in human neoplasms,
it is necessary to revise the WHO Classification more frequently
than previously.
Increasing demand of online version.
Meeting on the Strategic Directions on Future of
the WHO Classification of Tumours (January 11, 2013)
- New procedures to speed up completion of the 4th edition
- To move to the online option in the near future
- PubCan as online version of WHO Classification of Tumours
PubCan (Public database of human cancers)
Developed by Dr Paul Kleihues, former IARC Director
Officially transferred to IARC in 2011
Contains
all disease entities in the latest WHO Classification tables
and
all terminologies in the ICD-O3 (International Classification of Diseases for Oncology)
Two volumes of WHO Blue Books were transferred to PubCan
Tumours of the Digestive System 4th edition
Tumours of Haematopoietic and Lymphoid Tissues 4th edition
Questions for the SC
Does the Scientific Council support our intention to move to the online
option in the near future?
What should be the timeline?
What additional considerations should the Agency consider in moving
forward?
Cervical cancer prevention in Bhutan and
Rwanda
and synergies between oncogenic viruses
with environmental factors
Infections Section and Cancer Infections and Cancer Biology
Group. Head: Dr Massimo Tommasino
Infections and Cancer Epidemiology Group. Silvia Franceschi
Monitoring HPV vaccination and HPV screening
programs to promote sustained implementation
in low-income countries (PI: Dr Gary Clifford, ICE)
• Bhutan and Rwanda have been the first low-resource countries
(LRCs) to implement a successful nation-wide HPV vaccination
program;
• They will be important to determine if the full anticipated decrease
in disease can be realized in LRCs;
• Monitoring HPV vaccine impact on cervical cancer onset will take
more than 20 years;
• In the near-term, the most feasible and informative outcome to
measure is the variation in type-specific HPV infection in
sentinel populations of young sexually active women and
adolescents.
Monitoring HPV vaccination and HPV screening
programs to promote sustained implementation
in low-income countries
Bhutan
Rwanda
Population
~700,000
~15 M
Cervical cancer incidence
≥ 20.4/100,000
≥ 34.5/100,000
First HPV vaccination year
2010
2011
Age target (yrs)
12-18
6th grade (~10-15)
Vaccine delivery
Mainly schools
Mainly schools
Campaign
92%
93%
Routine (mainly health
centers)
60-80%
Not yet,
Catch up on-going
Current cervical screening
Pap test, ~25%
None
Cervical screening plans
Rapid HPV testing
Rapid HPV testing/VIA
HPV vaccine coverage
Objectives of HPV monitoring
1.
Age- and type-specific prevalence of HPV in exfoliated
cervical cells in women aged 18-69 years (n=2,500), and
cervical cancer and CIN2/3 (2012-13);
2.
Double HPV testing in IARC (ultra-sensitive) and Amsterdam
(clinically set sensitivity);
3.
Early impact of HPV vaccination by repeat cervical cell
surveys (2016; 2021) of young women <29 years
(n=1,500);
4.
Type-specific prevalence in urine in girls aged 18-19-year
(n=1,000) (2013; 2015; 2017).
5.
Shifting from cytology (Bhutan) to or introduction (Rwanda) of
cervical screening using Rapid HPV testing in women aged
30+ (from 2013). This investment would improve cervical
cancer prevention in older women and could ultimately serve as
the basis for long-term vaccination monitoring.
IARC HPV Surveys, sexually active women, 15-59 yrs (1995-2013)
HPV Prevalence (%)
N
Guinea
Mongolia
Vanuatu
Nigeria
Bhutan
Poland
China, Shenzhen
Argentina
India
China, Shenyang
China, Shanxi
Chile
Colombia
Georgia
Korea
Mexico
Vietnam, Ho Chi Minh
Italy, Turin
Thailand, Lampang
Nepal
Iran
Netherlands
Algeria
Thailand, Songkla
Spain
Pakistan
Vietnam, Hanoi
833
969
987
932
2066
834
1027
978
1891
685
662
955
1834
1309
863
1340
922
1013
1035
932
825
3304
759
706
911
899
994
0
5
10
15
20
25
30
35
40
45
50
hpv 16 or 18
other high-risk type
low-risk type only
55
When vaccines are not available, intervention on
environmental co-factors is especially promising
Inhibition of apoptosis
Infection
Induction of proliferation
Facilitators of
viral life cycle
Oncoproteins
Evasion of the
immune system
Persistent infection
immunosuppressants
Inflammation
DNA damaging agents
Chromosomal
instability
Well known association:
Aflatoxin B1 and HBV in
sub-Saharan Africa, work
from C Wild et al
Cancer
Aflatoxin B1 stimulates Epstein-Barr Virus replication
in in vitro experimental models: a role for EBV,
in addition to malaria, in Burkitt Lymphoma in subSaharan Africa?
EBV
+
in presence or absence of
Aflatoxin B1
0.12
viral copy number/infected cell
Primary B cells
0.08
0.04
0.00
Control
Aflatoxin 1
UV, beta HPV types and squamous-cell skin cancer
• UV irradiation is a key risk factor for squamous-cell carcinoma
(SCC) in HPV38 E6/E7 transgenic mice (183 and 187 lines)
1.0
• UV and impairment of the immune system (HIV+; organrecipients) also strongly increases the risk of SCC in humans
1.0
0.6
0.4
Tg-1
183
Tg-2
187
0.2
120
0.4
450
0.6
0.8
SCC incidence
UVB doses (mJ/cm2)
183
187
FVB/N
0.8
Chronic UV irradiation of WT or
HPV38 E6/E7 transgenic mice
0.2
1
2
3
15
16 17
18
(Weeks)
19
20
29
30
WT
0.0
0
0.0
00 55
20
20
25
25
Weeks of UV irradiation
30
30
Discussion topics
• Monitoring HPV vaccination
from 2018 until the
predictable decline of
cervical cancer in Cancer
Registry can be seen (~2040)
• Further studies aiming to
identify novel unknown
synergies between
oncogenic viruses with
environmental factors
1. Adding genotyping to HPV-based
cervical screening;
2. Improving information on HPV
vaccination status, eg,
computerization of initial
vaccination records (~130,000 in
Rwanda and 50,000 in Bhutan);
3. Other (immunogenicity; vaccine
failures, etc.)
1. New hypothesis?
2. Strategies and procedures to
evaluate synergies/interactions?
Environment and Radiation Section
Dr Joachim Schüz
Pesticides and cancer (AGRICOH)
AGRICOH – consortium of agricultural cohort studies
• Participating studies are 27 cohort studies from 11 countries
• Objective of AGRICOH: promote collaboration and pooling of data to
study the association between a wide range of agricultural
exposures and health outcomes.
• Farmers and agricultural workers form large proportion of work
force worldwide
• Lower morbidity for some diseases but increased risk of several
cancer types, respiratory diseases, or neurotoxic outcomes
Leon et al. 2011, Int J Environ Res Public Health
AGRICOH
• A consortium of agricultural cohort studies can address
research gaps in health outcomes associated with
agricultural exposures by pooling data from studies
collaborating in research projects
• Pooling data can increase statistical power to study rare
diseases (e.g. ovarian, testicular, thyroid cancers) or
uncommon exposures (infrequently applied chemicals)
• Opportunity to replicate findings from individual studies
• IARC-ENV: - Study coordinator
- Member of Steering Group
- Data Management Center
Cohort studies included in AGRICOH
Norway (3)
Canada (3)
UK (1)
USA (7)
Denmark (1)
France (3)
Korea (1)
Costa Rica (2)
South Africa (2)
Australia (2)
New Zealand (2)
Ongoing projects lead by IARC/ENV
• Exposure to pesticides and risk of lymphoma,
myeloma and leukaemia in the AGRICOH
consortium: a pooled analysis
– Cohorts from France (187,471 adult farmers), Norway
(248,000) and USA (52,394)
– Funded by ONEMA (France)
• Cancer incidence and mortality in agricultural
cohort studies in the AGRICOH consortium
– Cohorts from Australia (n=2), South Korea (1), France
(1), Norway (3), USA (2)
– Co-Funded by NCI
Questions to the SC
• STRATEGIC: Less than half of cohorts can provide
cancer data. IARC coordinates and contributes
heavily to infrastructure. Should this continue or
should we advocate a coordination more
subdivided by outcome?
• EXPANSION: Majority of cohorts are from highincome countries. To include more cohorts from
low-medium income countries, general population
cohorts including farmers might need to be
considered. Balance being open for LMIC while
staying restrictive for HIC?
Research on Chernobyl Health available infrastructures
Cohorts of:
•
exposed to Chernobyl fallout in childhood and adolescence in
Belarus and Ukraine with detailed thyroid dose measurements
(BelAm, UkrAm cohorts ~30,000)
•
Chernobyl clean up workers (liquidators) from Baltic countries,
Belarus, Russia and Ukraine (~600,000)
•
Evacuees (including exposed in utero) (~100,000) and offspring of
exposed parents (~43,000)
Registries:
•
Cancer registries (Baltic countries, Belarus, Ukraine)
•
Chernobyl registries (Belarus, Ukraine), National Medical and
Dosimetric Registry (Russia)
ARCH – what is proposed?
•
ARCH assembled a group of experts who developed a
strategic research agenda (SRA) and recommended:
–
–
setting up an international mechanism to coordinate and fund
studies to enable assessment of the overall long-term health
effects - Chernobyl Health Effects Research Foundation
creation, maintenance and follow-up of Chernobyl Life Span
cohort
New IARC/ENV initiative on
international cooperation
• Building partnerships with Belarus, Russian
federation, Ukraine, Japan, US and EU to take
the Strategic Research Agenda forward:
– bring together key scientific players and funding
partners
– seek sustainable funding for Chernobyl research
priority areas
– identify the nature and structure of an
international coordinating mechanism
Questions to the SC
• How much should IARC support the training and
education of researchers in Belarus, Russian
federation and Ukraine e.g. for monitoring and
analysing cancer trends in the contaminated
regions?
• The question whether there was an increase in
infant leukaemia in Europe after Chernobyl is still
open; how much effort should be made to collect
additional data?
Section of Genetics
James McKay
Genetic Cancer Susceptibility Group
Genetics Section
• Two opportunities that take advantage of the large
GEN bio-repositories and NGS:
1. Mutation profiling of tumours
• Focus on rare histologies/subtypes
• Targeted sequencing of known cancer genes (identified from TCGA)
2. Genomic biomarkers
• Early detection and outcome
1. Mutation profiling in tumour subgroups
• Early stage lung cancer cases from CRC Moscow
- All with blood and tumour tissue, some adjacent normal tissue
- Comprehensive baseline and follow-up details
- 450 collected, expand to 900 by 2014
• Initial focus on bronchioloalveolar carcinoma (BC)
- Relatively rare subtype, particular clinical characteristics
 41 cases identified
23 NEVER SMOKERS (56%)
22 WOMEN (54%)
30 ALIVE AFTER ONE YEAR (73%)
• Exome sequencing finalised on 12 pairs of normal and
tumour material and underway for remaining 29
Effect of smoking on mutations
results from initial 12 tumours
Genes observed mutated TP53, KRAS (poster)
Questions to be investigated
Compare BC-LC with adenocarcinoma LC and squamous LC
(data from The Cancer Genome Consortium (TCGA))
Overlap with Adeno &
Squamous
What somatic variants
are unique to BC?
Relation to Outcome
Lung Adeno.
(n=334 TCGA)
BC n=52
(IARC 41 &
11 TCGA)
Lung Squam.
(n=243
TCGA)
Both questions are of clinical
relevance for treatment and
subsequent outcomes
Mutation profiling in tumour subgroups
within GEN
• Other potential priority cancer sites:
– Head and neck cancer with a focus on HPV
status (IARC-INCA Brazil collaborative project)
– EBV status in Hodgkin’s lymphoma
Genes mutated within head and neck
tumours
• Within 100 (TCGA) head and neck tumours, 95% mutations
reported within 10 genes.
• It becomes possible to design targeted sequencing assays to cover
most mutations, and at low cost.
Stransky N et al (2011). Science
Rapid and cheap comprehensive sequencing of
many tumours is only now becoming feasible
Exome/Genome Sequencing
Many genes/Few samples
Targeted Resequencing
Few genes/Many samples
Targeted Resequencing Ion Torrent Experiment Cost (35 amplicons, 150X coverage)
72.8 €/sample
 X 6 cost through GCS optimization
12.2 €/sample
Plan to sequence 450 lung cancer tumours for top (TCGA) mutated genes
2. Genomic biomarkers for early detection
Circulating tumour DNA (ctDNA)
in the blood
• Tumour ctDNA comprises ~ 0.2% of total plasma DNAs,
excess of wild-type DNA makes ctDNA identification
challenging.
• NGS to screen many genes at a very high sensitivity
(sequencing at > 5000X coverage to be able to detect
0.2% ctDNA).
• Ion Torrent sequencing pilot data (MMB group): expected
EGFR mutations detected within patient plasma material
(totalling 1 to 3% of sequence reads).
Circulating tumor DNA (ctDNA) as
a non-invasive biomarker
• To what extent are tumour mutations (or mutation
combinations) also identifiable in ctDNAs from blood?
• 450 early stage LC define mutation profile by sequencing
10 commonly mutated genes (TCGA: TP53, CDNK2A….)
• Can we detect DNA mutations in the plasma from same
patients?
• If so, can we detect mutations in samples collected 1-3
years prior to diagnosis (EPIC study)?
Questions for the Scientific Council
• What types of sequencing studies should we try
to initiate, taking into account our access to large
bio-repositories but our limited sequencing
capabilities?
• Should we take advantage of other biomarker
opportunities that arise with NGS, including studies
that aim to detect circulating tumour DNA in plasma
or serum samples?