1. Martin Wiseman
Medical and Scientific Adviser
WCRF International
London
UK
Visiting Professor of Human Nutrition
University of Southampton
UK
Continuous Update Project -
Systematic Review of Mechanistic Evidence

3. Journal citations - WCRF/AICR Reports
0
50
100
150
200
250
300
350
400
450
500
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
Numberofcitations
Doll & Peto 1981
1997 EXPERT REPORT
2007 EXPERT REPORT

4. Breast
Global variation in cancer incidence
Colorectum

5. Migration data Trends in incidence
(Japan)
CancerIncidence
Per 100,000, world population standard

6. Systematic reviews
• Expert international Task Force for method
• Nine centres - USA, UK, NL, Italy
• SLR centre coordinator
• Test of reproducibility
• Standardised search, analysis and display
• Epidemiology and mechanisms
• Quality assessment
• Peer review - protocol, report
• Defined expertise required
– Nutrition, epidemiology, systematic review, cancer biology, statistics

7. Inferring causality
• Strength
• Consistency
• Specificity
• Timing
• Dose Response
• Plausibility
• Coherence
• Experiment
• Analogy
Bradford Hill

8. GRADING CRITERIA
Predefined requirements for:
–Number and types of studies
–Quality of exposure and outcome assessment
–Heterogeneity within and between study types
–Exclusion of chance, bias or confounding
–Biological gradient
–Evidence of mechanisms
–Size of effect

9. Basis for
recommendations
• Convincing
• Probable
• Limited Evidence – Suggestive
• Limited Evidence – No Conclusion
• Substantial Effect on Risk Unlikely
GRADING THE EVIDENCE

12. OBITUARYWylieVale
andan elusivestress
hormonep.542
HISTORYOFSCIENCEDescartes’
lost letter trackedusing
Googlep.540
EARTHSYSTEMSPast climates
givevaluablecluestofuture
warmingp.537
AVIANINFLUENZAShift expertise
totrack mutationswhere
they emergep.534
Raisestandardsfor
preclinical cancer research
C. Glenn Begley and LeeM. Ellisproposehow methods, publicationsand
incentivesmust changeif patientsaretobenefit.
Manylandmark findings in preclinical oncology researchare not reproducible, inpart because of inadequate cell linesand animal models.
S.GSCHMEISSNER/SPL
COMMENT
29 MARCH 2012 | VOL 483 | NATURE | 531

13. OBITUARYWylieVale
andan elusivestress
hormonep.542
HISTORYOFSCIENCEDescartes’
lost letter trackedusing
Googlep.540
EARTHSYSTEMSPast climates
givevaluablecluestofuture
warmingp.537
AVIANINFLUENZAShift expertise
totrack mutationswhere
they emergep.534
Raisestandardsfor
preclinical cancer research
C. Glenn Begley and LeeM. Ellisproposehow methods, publicationsand
incentivesmust changeif patientsaretobenefit.
E
fforts over the past decade to
characterizethegeneticalterations
inhumancancershaveledtoabetter
understandingof molecular driversof this
complexset of diseases.Althoughweinthe
cancer fieldhopedthat thiswouldleadto
moreeffectivedrugs,historically,our ability
totranslatecancer researchtoclinical suc-
cesshasbeenremarkablylow1
.Sadly,clinical
trialsinoncologyhavethehighest failure
ratecomparedwithother therapeuticareas.
Giventhehighunmet needinoncology,it
isunderstandablethat barrierstoclinical
development maybelower thanfor other
diseaseareas,andalarger number of drugs
withsuboptimal preclinical validationwill
enter oncologytrials.However,thislowsuc-
cessrateisnot sustainableor acceptable,and
investigatorsmust reassesstheir approachto
translatingdiscoveryresearchintogreater
clinical successandimpact.
Manyfactorsareresponsiblefor thehigh
failurerate, notwithstandingtheinher-
entlydifficult natureof thisdisease. Cer-
tainly, thelimitationsof preclinical tools
such asinadequatecancer-cell-lineand
mousemodels2
makeit difficult for even
Manylandmark findings in preclinical oncology researchare not reproducible, inpart because of inadequate cell linesand animal models.
S.GSCHMEISSNER/SPL
2 9 M A RC H 2 0 12 | V O L 4 8 3 | N A T U R E | 5 3 1
COMMENT
© 2012MacmillanPublishersLimited.All rightsreserved
29 MARCH 2012 | VOL 483 | NATURE | 531
• Reproducibility
• Relevance of model
• Relevance of exposure
• Relevance of dose
• Route of administration
• Publication bias

14. Mechanisms Protocol Development
Group
External Experts
 Stephen Hursting (chair)
 Andrew Dannenberg
 Johanna Lampe
 Henry Thompson
 Steven Clinton
 Nikki Ford - associate member
WCRF Team
 Martin Wiseman
 Susan Higginbotham
 Rachel Thompson
 Rachel Marklew
 Kate Allen
 Deirdre McGinley-Gieser

15. HALLMARKS OF CANCER
Classic Hallmarks
• Sustaining proliferative
signaling
• Evading growth suppressors
• Resisting cell death
• Enabling replicative
immortality
• Inducing angiogenesis
• Activating invasion and
metastasis
Emerging hallmarks
• Deregulating cellular
energetics
• Avoiding immune
destruction
Underpinning
characteristics
• Genome instability
• Inflammation
Hanahan and Weinberg 2011

16. Mechanisms
Reviews to be systematic and peer
reviewed
Reviews conducted by exposure
Feasibility test of final draft protocol by
external group, including peer review
External review team should have
expertise in informatics, stats, cancer
biology, cancer site, nutrition
Molecular, cellular, physiological…

17. Thank you!