Diet and breast cancer survival: results of the Continuous Update Project (CUP). Presentation given by Teresa Norat, Principal Investigator Continuous Update Project, Imperial College London.

1. Diet and breast cancer survival:
results of the Continuous Update
Project
Teresa Norat
Principal Investigator Continuous Update Project, Imperial College London

2. Second Expert Report
(2007)
 ‘Food, Nutrition, Physical Activity, and the
Prevention of Cancer: a Global Perspective’
 Not possible to draw firm conclusions that apply
to cancer survivors specifically
 Evidence was emerging but not sufficiently
developed
 Panel concluded cancer survivors should aim to
follow the recommendations for prevention of
cancer

3. Continuous Update Project
Protocol
Breast Cancer Survivors
Populations
 In cancer, a person is considered to be a
survivor from the time of diagnosis until
the end of life
 Pre-menopausal women
 Post-menopausal women
 Incident in-situ breast cancer
 Incident invasive breast cancer

4. Continuous Update Project
 Specific foods
 Micro- and macro-nutrients
 Dietary patterns
 Alcohol
 Overweight, obesity, underweight, weight
change
 Body composition
 Dietary supplements
 Physical activity
Protocol
Breast Cancer Survivors
Exposure/interventions

5. Timing of Exposures
Included
 Pre-diagnosis
 Immediate 12 months following diagnosis
 Period of intensive primary therapy (surgery,
radiation, chemotherapy)
 After 12 months post-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

6. Continuous Update Project
Protocol
Breast Cancer Survivors
Outcomes
 Total mortality
 Breast cancer specific mortality
 Second primary breast cancer
 Other cause-specific mortality, i.e.
cardiovascular

7. Continuous Update Project
Protocol
Breast Cancer Survivors Study
designs
 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 randomized controlled
trials, or follow-up studies in breast cancer
survivors

8. Literature search
(New search for Continuous Update Project )
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

9. Nutrients Exposures
 Dietary:
 Fibre
 Folate
 Soy protein, isoflavones
 Total fat (g/d, % calories)
 Saturated fat
 Dietary patterns
 Alcohol

10. Other Exposures
 Physical activity
 Total (work, home, commute, recreation)
 Recreational only
 Body fatness
 Body mass index (kg/m2)
 Weight change

11. Randomised controlled trials
 Women’s Healthy Eating and Living (WHEL Study): diet high in vegetables
(daily intake of 5 servings plus 16 oz of vegetable juice), fruit (3
servings/day) and fibre (30 g/day) and low in fat (15-20% of energy intake
that was kept isocaloric) (Pierce, 2007); 3088 women (age 18-70 years)
 Overall survival: HR :0.91 (95% CI 0.72-1.15; p = 0.43).
 Disease-free survival HR 0.96 (95% CI 0.80-1.14).
 Women’s Intervention Nutrition Study (WINS): reducing dietary fat
intake to 15% of total energy intake (Chlebowski, 2006); 2437
women (age 48-79 years)
 Overall survival: HR 0.89 (95% CI 0.65-1.21)
 Relapse-free survival HR 0.76 (95% CI 0.60-0.98)

12. Alcohol (before diagnosis)
and total mortality
Harris HR 2012
Hellmann 2010
Barnett GC 2008
Dal Maso L 2008
Reding KW 2008
Zhang S 1995
0 5 10 15 20 25
Alcohol pre-diagnosis (drinks/week)
Linear dose-response meta-analysis of alcohol
consumption (before diagnosis) and total
Study
Harris HR (2012)
Hellmann (2010)
Barnett GC (2008)
Dal Maso L (2008)
Reding KW (2008)
Saxe GA (1999)
Zhang S (1995)
Overall
(I-squared = 0.0%, p = 0.564)
mortality
0.99 (0.95, 1.03)
1.00 (0.98, 1.02)
1.00 (0.99, 1.01)
0.99 (0.96, 1.02)
0.97 (0.95, 1.00)
1.01 (0.91, 1.13)
0.93 (0.81, 1.07)
1.00 (0.99, 1.00)
%
Weight
4.12
19.51
60.39
6.61
8.55
0.50
0.31
100.00
RR (95% CI)
Per 1 drink/week
%
.9 1 1.2

13. Alcohol (after diagnosis)
and total mortality
Linear dose-response meta-analysis of alcohol
consumption (twelve months or more after
diagnosis) and total mortality
Study
Beasley JM (2011)
Flatt S (2010)
Kwan M (2010)
Barnett GC (2008)
Holmes MD (1999)
Ewertz M (1991)
Overall
(I-squared = 50.2%, p = 0.074)
RR (95% CI)
0.94 (0.88, 1.00)
0.77 (0.61, 0.97)
1.22 (0.86, 1.72)
0.98 (0.96, 0.99)
1.01 (0.88, 1.15)
1.07 (0.96, 1.18)
0.98 (0.93, 1.03)
Weight
25.83
4.61
2.17
40.78
10.91
15.70
100.00
Per 10 g/day
%
.6 1 1.2
Beasley JM 2011
Flatt S 2010
Kwan M 2010
Barnett GC 2008
Holmes MD 1999
Ewertz M 1991
0 10 20 30 40
Alcohol post-diagnosis (g/day)

14. Alcohol (before diagnosis)
and breast cancer mortality
Linear dose-response meta-analysis of
alcohol intake before breast cancer
diagnosis and breast cancer mortality
Study
Harris HR (2012)
Hellmann (2010)
Dal Maso L (2008)
Reding KW (2008)
Overall
(I-squared = 73.5%, p = 0.010)
Weight
RR (95% CI)
per 1 drink/week
1.02 (0.97, 1.08)
1.01 (0.98, 1.03)
1.00 (0.99, 1.02)
0.96 (0.93, 0.98)
1.00 (0.97, 1.02)
%
14.22
26.13
33.62
26.03
100.00
.9 1 1.1
Harris HR 2012
Hellmann 2010
Dal Maso L 2008
Reding KW 2008
0 5 10 15 20
Alcohol pre-diagnosis (drinks/week)

15. Alcohol (after diagnosis) and
breast cancer mortality
Linear dose-response meta-analysis of alcohol
consumption (twelve months or more after
diagnosis) and breast cancer mortality
Study
Beasley JM (2011)
Kwan M (2010)
Rohan T (1993)
Overall
(I-squared = 65.2%, p = 0.057)
RR (95% CI)
Per 10 g/day
1.06 (0.94, 1.20)
1.58 (1.00, 2.50)
0.78 (0.55, 1.11)
1.06 (0.79, 1.42)
Weight
%
47.61
22.81
29.58
100.00
.6 1 1.7
Beasley JM 2011
Kwan M 2010
Rohan T 1993
0 10 20 30 40
Alcohol post-diagnosis (g/day)

16. 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)

17. Dietary fibre
Study
Linear dose-response meta-analysis of fibre intake (twelve
Beasley JM (2011)
Belle F (2011)
Holmes MD (1999)
Total mortality Breast cancer mortality
Overall
(I-squared = 0.0%, p = 0.968)
0.87 (0.73, 1.04)
0.87 (0.65, 1.16)
0.90 (0.73, 1.10)
0.88 (0.78, 0.99)
NOTE: Weights are from random effects analysis
Weight
46.15
17.85
36.00
100.00
RR (95% CI)
Per 10 g/day
%
.8 1 1.2
months or more after diagnosis)
Study
Beasley JM (2011)
Belle F (2011)
Rohan T (1993)
Overall
(I-squared = 0.0%, p = 0.643)
%
Weight
0.80 (0.58, 1.12)
0.94 (0.68, 1.29)
0.96 (0.80, 1.16)
0.93 (0.80, 1.07)
NOTE: Weights are from random effects analysis
19.28
20.75
59.97
100.00
RR (95% CI)
Per 10 g/day
%
.6 1 1.2

18. Dietary fibre
Summary
Total mortality Breast cancer mortality
N deaths
(studies)
RR (95%CI)
I2, Pheterogeneity
N deaths
(studies)
RR (95%CI)
I2, Pheterogeneity
Before diagnosis
High vs. Low
417 (2) 0.50 (0.35-0.73)
0%, p = 0.83
Per 10 g/day
443 (3) 0.68 (0.56-0.84)
0%, p = 0.41
Twelve months or more after diagnosis
High vs. Low
1092 (3) 0.76 (0.58-0.98)
0%, p = 0.99
332 (3) 0.82 (0.57-1.20)
0%, p = 0.95
Per 10 g/day
1092 (3) 0.88(0.78-0.99)
0%, p = 0.97
332 (3) 0.93 (0.80-1.07)
0%, p = 0.64

19. Fruits and vegetables
Linear dose-response meta-analysis of fruits and vegetable
Vegetables, total mortality
Pre-menopausal
Fink B (2006)
Saxe GA (1999)
Subtotal
.
(I-squared = 0.0%, p = 0.876)
Pre and post-menopausal
Fink B (2006)
Saxe GA (1999)
Subtotal
.
(I-squared = 0.0%, p = 0.866)
Post-menopausal
Buck K (2011)
Fink B (2006)
McEligot A (2006)
Saxe GA (1999)
Subtotal
(I-squared = 24.7%, p = 0.263)
.
Study
1.02 (0.96, 1.08)
0.96 (0.45, 2.02)
1.02 (0.96, 1.08)
1.00 (0.96, 1.03)
0.97 (0.70, 1.35)
1.00 (0.96, 1.03)
1.03 (0.93, 1.14)
0.99 (0.94, 1.03)
0.93 (0.87, 0.99)
0.95 (0.65, 1.39)
0.97 (0.93, 1.02)
%
Weight
99.43
0.57
100.00
98.90
1.10
100.00
15.49
49.64
33.59
1.28
100.00
RR (95% CI)
Per 3 serving/week
.7 1 1.4
Fruits, total mortality
Study
Pre-menopausal
Fink B (2006)
Saxe GA (1999)
Subtotal
.
(I-squared = 46.2%, p = 0.173)
Pre and post-menopausal
Fink B (2006)
Saxe GA (1999)
Subtotal
.
(I-squared = 0.0%, p = 0.715)
Post-menopausal
Buck K (2011)
Fink B (2006)
McEligot A (2006)
Saxe GA (1999)
Subtotal
(I-squared = 22.4%, p = 0.276)
.
RR (95% CI)
Per 7 serving/week
1.03 (0.87, 1.22)
0.41 (0.11, 1.52)
0.83 (0.38, 1.78)
0.98 (0.91, 1.05)
1.02 (0.83, 1.27)
0.98 (0.92, 1.05)
0.93 (0.81, 1.07)
0.97 (0.89, 1.05)
0.80 (0.62, 1.03)
1.11 (0.89, 1.38)
0.96 (0.88, 1.04)
%
Weight
76.02
23.98
100.00
89.06
10.94
100.00
26.98
50.80
9.74
12.48
100.00
.6 1 1.7
intake (before diagnosis)

20. Isoflavones intake and total
mortality
Meta-analysis of isoflavones intake (highest compared to
lowest intake) and total mortality
Study
Before diagnosis Twelve months or more after
Kang X premenopausal (2010)
Kang X postmenopausal (2010)
Fink B (2007)
Boyapati SM (2005)
Overall
(I-squared = 59.4%, p = 0.061)
1.05 (0.78, 1.71)
0.88 (0.56, 1.24)
0.52 (0.33, 0.82)
1.06 (0.79, 1.42)
0.87 (0.65, 1.17)
Weight
24.43
24.17
21.31
30.09
100.00
Comparison
>42.3 vs <15.2 mg/d
>42.3 vs <15.2 mg/d
>7.48 vs 0-0.29 mg/d
T3 vs T1
RR (95% CI)
High vs low
%
.2 1 2
Study
Zhang Y (2012)
Caan B (2011)
Shu X (2009)
Overall
(I-squared = 8.1%, p = 0.337)
0.62 (0.42, 0.90)
0.46 (0.20, 1.05)
0.79 (0.61, 1.03)
0.70 (0.56, 0.88)
Weight
%
31.84
7.28
60.88
100.00
Comparison
>28.83 vs <7.56 mg/d
16.33-86.9 vs 0-0.07 mg/d
>62.68 vs <=20 mg/d
RR (95% CI)
High vs low
.2 11.5
diagnosis

21. Fat intake before diagnosis
Linear dose-response meta-analysis
Author
McEligot A
Saxe GA
Zhang S
Gregorio DI
Year
2006
1999
1995
1985
Total mortality
Overall
(I-squared = 82.0%, p = 0.001)
RR (95% CI)
Per 10 g/day
1.63 (1.31, 2.03)
1.15 (0.82, 1.61)
1.13 (1.01, 1.28)
1.04 (1.00, 1.08)
1.19 (1.01, 1.41)
Weight
%
21.61
14.33
29.69
34.38
100.00
.492 1 2.03
Highest vs lowest meta-analysis
Author
Year
Dal Maso L
Jain M
Kyogoku
2008
1994
1992
Nomura AM
1991
Breast cancer mortality
Overall
(I-squared = 53.5%, p = 0.091)
0.95 (0.75, 1.22)
1.89 (0.96, 3.70)
0.40 (0.10, 1.30)
1.42 (0.71, 2.86)
1.13 (0.71, 1.77)
Weight
%
43.28
23.73
10.06
22.93
100.00
Comparison
T3 vs T1
>=45.2 vs <=38.08%energy
Q4 vs Q1
High vs Low
RR (95% CI)
High vs low fat
.1 1 10

22. Fat intake twelve months
or more after diagnosis
Total mortality
Highest vs lowest meta-analysis
Breast cancer mortality
Highest vs lowest meta-analysis
Author
Beasley JM
Holmes MD
Rohan T
Newman S
Year
2011
1999
1993
1986
Overall
(I-squared = 0.0%, p = 0.413)
NOTE: Weights are from random effects analysis
0.92 (0.53, 1.60)
1.44 (1.01, 2.04)
1.40 (0.66, 2.96)
0.99 (0.65, 1.51)
1.19 (0.94, 1.50)
Weight
17.54
43.33
9.51
29.63
100.00
Comparison
mean 39 vs 23%energy
>=69.6 vs <53g/day
>108 vs <56 g/day
>77 vs <=77 g/day
RR (95% CI)
High vs low
Weight
%
.338 1 2.96
Author
Beasley JM
Holmes MD
Ewertz M
Year
2011
1999
1991
Overall
(I-squared = 24.4%, p = 0.266)
1.05 (0.79, 1.39)
1.34 (0.97, 1.85)
0.96 (0.75, 1.22)
1.08 (0.90, 1.30)
Weight
%
32.73
26.57
40.70
100.00
Comparison
mean 39 vs 23%energy
>=69.6 vs <53g/day
Q4 vs Q1
RR (95% CI)
High vs low
.541 1 1.85

23. Fat intake
Summary
Total mortality Breast cancer mortality
N deaths
(studies)
RR (95%CI)
I2, Pheterogeneity
N deaths
(studies)
RR (95%CI)
I2, Pheterogeneity
Before diagnosis
High vs. Low
655 (3) 1.87 (0.76-4.57)
90.1%,p < 0.001
521 (4) 1.13 (0.71-1.77)
53.5%, p = 0.09
Per 10 g/day
178 (4) 1.19 (1.01-1.41)
82.0%, p=0.001
Twelve months or more after diagnosis
High vs. Low
1436 (3) 1.08 (0.90-1.30)
24.4%, p = 0.27
648 (4) 1.19 (0.94-1.50)
0%, p = 0.41
Per 10 g/day
575 (3) 1.01 (0.95-1.08)
24.0%, p = 0.27

24. Saturated fat intake before
diagnosis
and total mortality
Author
McEligot A
Saxe GA
Zhang S
Year
2006
1999
1995
Overall
(I-squared = 31.8%, p = 0.231)
2.02 (1.50, 2.70)
1.20 (0.56, 2.57)
1.45 (1.04, 2.03)
1.66 (1.26, 2.19)
Weight
47.46
11.71
40.83
100.00
RR (95% CI)
Per 10 g/day
%
.37 1 2.7

25. Issues Relevant to
Survivor Research
 Confounding effects of:
 Treatment types, efficacies, adverse effects
 Stage of disease
 Comorbidities
 Type of cancer
 Methodological:
 Assessing exposure
 Determining cause of death
 Determining and classifying recurrence
 Screening for second primary breast cancer
 Increasing length of survival

26. Summary
 Growing literature on nutrition, related factors,
& breast cancer survival
 Time of exposure is dynamic
 Various outcomes are important to study
 Data are sufficient for meta-analyses for
several variables but still limited
 Some evidence that a healthy diet (rich in plant
foods and low in saturated fats) may be related
to longer survival in breast cancer patients

27. Judgement
The Reports from World Cancer
Research Fund/American
Institute for Cancer Research
and the Systematic Literature
Reviews published on October
16 2014 in www.wcrf.org

28. Thanks!
 Continuous Update Project Panel
Anne Mc Tiernan and Inger Thune
International scientific experts
CUP team