1.
The Continuous Update Project
Breast cancer survivors
and prostate cancer
World Cancer Research Fund International, London UK
Professor Martin Wiseman FRCP FRCPath FAfN
NIHR BRC Southampton and University of Southampton

2.
Who we are What we do
AICR (1982)
WCRF UK (1990)
WCRF Netherlands (1994)
WCRF Hong Kong (1997)
WCRF International (1999)
Fund research on the relationship of
nutrition, physical activity and body
weight to cancer risk
Interpret the accumulated scientific
literature to derive
Recommendations for Cancer
Prevention
Educate people through our national
Health Information programmes
Advocate effective policies to help
people and populations to reduce
their chances of developing cancer

3.
Breast
Global variation in cancer
incidence
Colorectum

4.
Migration data

5.
0
5
10
15
20
25
30
1960 1965 1970 -
'71
1973 -
'77
1979 -
'82
1983 -
'87
1988 -
'92
1995 1997
Colon
Breast
Cancer Incidence in Japan*
* Per 100,000, world population standard
CancerIncidence

6.
Hanahan & Weinberg (2011) Cell; Hanahan & Coussens (2012) Cancer Cell
Hallmarks of cancer
Two enabling characteristics for acquiring hallmarks

7.
WCRF/AICR EXPERT REPORT
The most authoritative
• New method
• Systematic reviews
• Review of evidence separate from
judgement
• Panel of international experts
• Predetermined criteria for judgements
– Epidemiology
– Mechanisms
• Flexibility
• Continuous update of evidence

8.
NUTRITION AND CANCERS
• ADIPOSITY
– BREAST (PM), COLORECTUM, ENDOMETRIUM,
OESOPHAGUS, PANCREAS, GALLBLADDER, KIDNEY, OVARY,
PROSTATE (ADVANCED)
• PHYSICAL (IN)ACTIVITY
– COLON, BREAST
• MEAT – RED AND PROCESSED
– COLORECTAL
• ALCOHOL
– MPL, BREAST, COLORECTUM, LIVER
• PLANT FOODS (F&V, PULSES, WHOLEGRAINS)
– MPL, OESOPHAGUS, STOMACH, COLORECTAL (DF), LUNG
• BREASTFEEDING
– BREAST (MOTHER), OBESITY (CHILD)

9.
The Panel emphasises the
importance of not smoking and of
avoiding exposure to tobacco smoke

10.
USA UK BRAZIL CHINA
Mouth, pharynx,
larynx
63 67 63 44
Oesophagus 63 71 50 33
Lung 36 33 36 38
Stomach 47 45 41 33
Pancreas 19 15 11 8
Gallbladder 21 16 10 6
Liver 15 17 6 6
Colorectum 50 47 41 22
Breast 33 38 22 11
Ovary 5 4 3 1
Endometrium 59 44 37 21
Prostate (advanced) 11 10 5 4
Kidney 24 19 13 8
Total for these
cancers
30 32 25 24
Total for all cancers 21 24 17 20
Estimates of
cancer
preventability by
appropriate diet,
nutrition,
physical activity
and body fatness

11.
CANCER FREQUENCY AND
AGE

12.
IMPACT OF OFFSPRING SIZE AND GROWTH
ON CANCER RISK

13.
Height and risk
of CVD and cancer
CVD Cancer

14.
Continuous Update Project: CUP
 Same process for systematically
reviewing evidence for 2007 Report
 Researchers at Imperial College London
– CUP database of epi research
– Systematically review the evidence
 Expert Panel
– Draw conclusions
– Make recommendations

15.
CUP database
Research Team
Second Expert Report databases

16.
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

17.
Grading the evidence
Decreases
risk
Increases
risk
Strong
evidence
Convincing
Probable
Limited
evidence
Limited -
suggestive
Limited – no
conclusion
Strong
evidence
Substantial
effect on risk
unlikely
Basis for recommendations

18.
Year Publication
2010 Breast
2011 Colorectum
2012 Pancreas
2013-14 Endometrium, ovary, breast cancer survivors, prostate
2015 Liver, bladder, kidney, gallbladder
2015-16 Stomach, oesophagus, lung
2016-17 Mouth, pharynx, larynx, nasopharynx, breast, colorectum
2017 Review Recommendations for Cancer Prevention
Publications timetable

19.
Prostate cancer

20.
Prostate cancer – sub-types
 Non-advanced
 Advanced
 Fatal

21.
Prostate cancer – advanced
 Advanced
– AJCC 1992 stage 3-4
– Advanced
– Advanced or metastatic
– Metastatic
– Whitmore/Jewett 3-4
– Fatal (prostate specific)
– High stage or grade
– Gleason 7 or more

22.
Issues for prostate cancer
Heterogeneity of disease
Screen detected
Advanced or aggressive
Fatal
Characterisation of exposure
Lycopene
Calcium/dairy

23.
Breast Cancer Survivors

24.
Breast Cancer Survivors Included
 Pre-menopausal women
 Post-menopausal women
 Incident in-situ breast cancer
 Incident invasive breast cancer

25.
Criteria for Study Inclusion
 Randomised controlled trials
≥ 50 women
≥ 6 months follow-up
Only 2 identified (both low-fat diet trials)
 Prospective cohort (follow-up) studies
 Primary analysis, secondary analysis or
ancillary analysis of randomised controlled
trials, or follow-up studies in breast cancer
survivors

26.
Exposures Included
 Specific foods
 Micro- and macro-nutrients
 Dietary patterns
 Alcohol
 Overweight, obesity, underweight, weight
change, BMI
 Body composition
 Dietary supplements
 Physical activity

27.
Timing of Exposures
Pre-diagnosis
 Within 12 months following diagnosis
Period of intensive primary therapy (surgery,
radiation, chemotherapy)
 From 12 months after diagnosis
Patients may be receiving targeted therapy
during this period (e.g. hormonal therapy,
HER2neu, bone metastases prevention)
Data may extend 20 years or more

28.
Outcomes Included
 Total mortality
 Breast cancer specific mortality
 Second primary breast cancer

29.
Outcomes Included
 Total mortality
 Breast cancer specific mortality
 Second primary breast cancer
 Not:
 recurrence, QoL, lymphoedema etc

30.
Literature search
(New search for CUP)
19831 unique records identified in Pubmed
and Embase until 30th June 2012 and 18
articles found in handsearch
897 full-text articles retrieved and
assessed for inclusion
319 articles on survival and health events
in women with breast cancer
18952 records excluded on the basis of
title and abstract
578 articles excluded for not fulfilling the
inclusion criteria
85 no original data
278 did not report on the associations
of interest
30 abstract/commentary
9 meta-analyses
94 irrelevant study design
33 follow-up less than 6 months
49 study smaller than 50 women
213 articles have mortality or any second
primary cancer as study endpoints
106 articles excluded on health events
other than death or second primary
cancer in women with breast cancer

31.
Issues Relevant to
Survivor Research
Confounding effects of
 Treatment types, efficacies, adverse effects
 Stage of disease
 Comorbidities
 Type of cancer
Methodological
 Determining cause of death
 Screening for second primary breast cancer
 Increasing length of survival

32.
• Various associations also found for:
– Physical activity
– Foods containing fibre
– Foods containing soy
– Total fat
– Saturated fatty acids
• Evidence not judged strong enough to
conclude causal effects

33.
Need for studies that control for
confounding by clinical variables
Randomised controlled trials
Cohort studies with accurate diagnostic &
treatment variables
Future Considerations

34.
Summary
 Although there were significant
associations between some exposures
and outcomes, incomplete adjustment for
potential confounders restricted the ability
to ascribe causality.
 CUP Panel concluded that evidence is
limited.

35.
CONCLUSIONS
• Nutrition (diet, body composition and physical
activity) is key determinant of global cancer patterns
• Evidence from epidemiology and mechanistic data
• CUP is refining knowledge of risk factors
– Heterogeneity of prostate cancer
– Body fatness and advanced prostate cancer
– Lycopene? Calcium/dairy?
– Body fatness and early life events are important for many
cancers
– Poor nutrition is an adverse diagnostic factor in breast
cancer – better studies needed to determine causality

36.
Thank you!

37.
Summary:
Before diagnosis- BMI
Total mortality
Breast cancer
mortality
Second primary
breast cancer
N
deaths
RR (95%CI)
N
deaths
RR (95%CI)
N
events
RR (95%CI)
High vs. Low 8318 1.41 (1.29-1.54) 9854 1.34 (1.23-1.46) 701 1.43 (0.87-2.34)
Underweight vs.
normal weight
4944 1.10 (0.92-1.31) 4479 1.02 (0.85-1.21) -
-
Per 5 kg/m2 6261 1.17 (1.13-1.21) 6600 1.17 (1.11-1.24) 701 1.21 (1.04-1.40)
Premenopause 644 1.25 (1.10-1.43) 1350 1.06 (0.85-1.32) -
-
Postmenopause 1103 1.16 (1.01-1.34) 2866 1.15 (1.05-1.25) -
-

38.
Summary:
Around diagnosis- BMI
Total mortality
Breast cancer
mortality
Second primary
breast cancer
N
deaths
RR (95%CI)
N
deaths
RR (95%CI)
N
events
RR (95%CI)
High vs. Low
BMI
16925 1.27 (1.16-1.38) 10063 1.36 (1.23-1.50) 3478 1.30 (1.14-1.48)
Premenopause 4604 1.28 (1.16-1.42) 586 0.96 (0.45-2.06) -
-
Postmenopause 4614 1.13 (1.03-1.23) 1067 1.57 (1.31-1.89) -
-
Underweight vs.
normal weight
2598 1.23 (0.93-1.63) 1455 1.52 (1.26-1.84) -
-
Per 5 kg/m2 5875 1.11 (1.06-1.17) 1918 1.18 (1.11-1.25) 3186 1.13 (1.06-1.21)

39.
Summary:
After diagnosis – BMI
Total mortality
Breast cancer
mortality
Second primary
breast cancer
N
deaths
RR (95%CI)
N
deaths
RR (95%CI)
N
events
RR (95%CI)
High vs. Low 2289 1.21 (1.06-1.38)
2 studies
Both  risk, 1 significant
No studies
Underweight vs.
normal weight
1361 1.29 (1.02-1.63)
Per 5 kg/m2 1703
1.08 (1.01-1.15)
4, 0%, p=0.52

40.
Summary: physical activity
Total mortality
Breast cancer
mortality
Events
RR (95%CI)
N, I2, P het
Events
RR (95%CI)
N, I2, P het
Before diagnosis
Total
H vs. L 505
0.83 (0.62-1.12)
2, 23%, p=0.25
338
0.80 (0.59-1.10)
2, 0%, p=0.88
Before diagnosis
Recreational
H vs. L 2892
0.74 (0.67-0.83)
8, 5%, p=0.39
1750
0.76 (0.61-0.95)
7, 49%, p=0.06
After diagnosis
Total H vs. L 514
0.63 (0.41-0.97)
3, 44%, p=0.16
217
0.81 (0.48-1.36)
2, 0%, p=0.63
Per 10 MET-
h/week
514
0.90 (0.79-1.03)
3, 79%, p=0.009
- -
After diagnosis
Recreational
H vs. L 2337
0.61 (0.50-0.74)
5, 46% ,p=12
392
0.71 (0.45-1.12)
2, 33%, p=0.22
After diagnosis
Recreational
Per 10 MET-
h/week
2337
0.81 (0.73-0.90)
5, 64%, p=0.03
- -

41.
Summary: dietary fibre
Total mortality
Breast cancer
mortality
Events
RR (95%CI)
N, I2, P het
Events
RR (95%CI)
N, I2, P het
Before diagnosis H vs. L 417
0.50 (0.35-0.73)
2, 0%, p=0.83
2 studies
Non-sig  risk
Per 10g/d 443
0.68 (0.55-0.84)
3, 0%, p=0.41
After diagnosis H vs. L 1092
0.76 (0.58-0.98)
3, 0%, p=0.99
332
0.82 (0.57-1.20)
3, 0%, p=0.95
Per 10g/d 1092
0.88 (0.78-0.99)
3, 0%, p=0.97
332
0.93 (0.80-1.07)
3, 0%, p=0.64

42.
Summary: isoflavones
Total mortality
Events
RR (95%CI)
N, I2, P het
Before diagnosis H vs. L 624
0.87 (0.65-1.17)
3, 59%, p=0.06
After diagnosis H vs. L 794
0.70 (0.56-0.88)
3, 8%, p=0.33
Per 10mg/d 794
0.91 (0.83-1.00)
3, 68%, p=0.05

43.
Summary: total fat
Total mortality
Breast cancer
mortality
Events
RR (95%CI)
N, I2, P het
Events
RR (95%CI)
N, I2, P het
Before diagnosis H vs. L (g/d) 655
1.87 (0.76-4.57)
3, 90%, p<0.001
521
1.13 (0.71-1.77)
4, 54%, p=0.09
Per 10g/d 178
1.19 (1.01-1.41)
4, 82%, p=0.001
- -
Per 10% energy 178
1.82 (1.41-2.36)
3, 0%, p=0.38
- -
After diagnosis H vs. L (g/d) 1436
1.08 (0.90-1.30)
3, 24%, p=0.27
648
1.19 (0.94-1.50)
4, 0%, p=0.41
Per 10g/d - -
575
1.01 (0.95-1.08)
3, 24%, p=0.27

44.
After diagnosis: saturated fat
Outcome Author
Year
Study design Number of
events
Contrast RR
(95% CI)
Total
mortality
Beasley
2011
Follow-up of
cases from case-
control study
525 13% vs. 7%
energy
1.40 (1.06-1.87)
Total
mortality
Holmes
1999
Cancer survivors
of a cohort study
(NHS)
378 Q5 vs. Q1
g/d
1.23 (0.89-1.69)
Breast
cancer
mortality
Beasley
2011
Follow-up of
cases from case-
control study
137 13% vs. 7%
energy
1.55 (0.88-2.75)
Breast
cancer
mortality
Rohan
1993
Follow up of
cases from case-
control study
112 ≥45 vs <20g/d 1.65 (0.73-3.75)
For each of total mortality and breast cancer
mortality there were only two studies

45.
Summary: Alcohol
Total mortality
Breast cancer
mortality
Second primary/
contralateral
breast cancer
N deaths RR (95%CI) N deaths RR (95%CI)
N
events
RR (95%CI)
Before
diagnosis:
High vs. Low
2650 0.93 (0.82-1.06) 1329 1.18 (0.81-1.72) - -
Before :
Per 1
drink/week
2676 1.00 (0.99-1.00) 1296 1.00 (0.97-1.02) -
-
After
diagnosis:
High vs. Low
3827
0.89 (0.72-1.09)
403 1.22 (0.88-1.69) 2347 1.19 (0.96-1.47)
After
diagnosis:
Per 10g/d
3779 0.98 (0.93-1.03) 403 1.06 (0.79-1.42) 2347 1.01 (0.99-1.03)