Teresa Norat

Principal Investigator Continuous Update Project, Imperial College London

Diet and breast cancer survival: results of the Continuous Update Project

‘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

Second Expert Report (2007)

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

Specific foods Micro- and macro-nutrients Dietary patterns Alcohol Overweight, obesity, underweight, weight

change Body composition Dietary supplements Physical activity

Continuous Update Project Protocol

Breast Cancer Survivors Exposure/interventions

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

Total mortality Breast cancer specific mortality Second primary breast cancer Other cause-specific mortality, i.e.

cardiovascular

Continuous Update Project Protocol

Breast Cancer Survivors Outcomes

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

Continuous Update Project Protocol

Breast Cancer Survivors Study designs

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 data278 did not report on the associations of interest30 abstract/commentary9 meta-analyses94 irrelevant study design33 follow-up less than 6 months49 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

Nutrients Exposures

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

Other Exposures

Physical activity Total (work, home, commute, recreation) Recreational only

Body fatness Body mass index (kg/m2) Weight change

Randomised controlled trials

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)

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).

Barnett GC 2008

Hellmann 2010

Reding KW 2008

Harris HR 2012

Zhang S 1995

Dal Maso L 2008

0 5 10 15 20 25

Alcohol pre-diagnosis (drinks/week)

Overall (I-squared = 0.0%, p = 0.564)

Saxe GA (1999)

Dal Maso L (2008)

Zhang S (1995)

Hellmann (2010)

Reding KW (2008)

Harris HR (2012)

Barnett GC (2008)

Study

1.00 (0.99, 1.00)

1.01 (0.91, 1.13)

0.99 (0.96, 1.02)

0.93 (0.81, 1.07)

1.00 (0.98, 1.02)

0.97 (0.95, 1.00)

0.99 (0.95, 1.03)

1.00 (0.99, 1.01)

100.00

0.50

6.61

0.31

19.51

8.55

4.12

60.39

Weight

%

1.00 (0.99, 1.00)

1.01 (0.91, 1.13)

0.99 (0.96, 1.02)

0.93 (0.81, 1.07)

1.00 (0.98, 1.02)

0.97 (0.95, 1.00)

0.99 (0.95, 1.03)

1.00 (0.99, 1.01)

RR (95% CI)Per 1 drink/week

100.00

0.50

6.61

0.31

19.51

8.55

4.12

60.39

Weight%

1.9 1 1.2

Alcohol (before diagnosis) and total mortality

Linear dose-response meta-analysis of alcohol consumption (before diagnosis) and total

mortality

Alcohol (after diagnosis) and total mortality

Linear dose-response meta-analysis of alcohol consumption (twelve months or more after

diagnosis) and total mortality

Overall (I-squared = 50.2%, p = 0.074)

Flatt S (2010)

Study

Holmes MD (1999)

Barnett GC (2008)

Beasley JM (2011)

Kwan M (2010)

Ewertz M (1991)

0.98 (0.93, 1.03)

0.77 (0.61, 0.97)

1.01 (0.88, 1.15)

0.98 (0.96, 0.99)

0.94 (0.88, 1.00)

1.22 (0.86, 1.72)

RR (95% CI)

1.07 (0.96, 1.18)

100.00

4.61

10.91

40.78

25.83

2.17

Weight

15.70

0.98 (0.93, 1.03)

0.77 (0.61, 0.97)

1.01 (0.88, 1.15)

0.98 (0.96, 0.99)

0.94 (0.88, 1.00)

1.22 (0.86, 1.72)

RR (95% CI) Per 10 g/day

1.07 (0.96, 1.18)

100.00

4.61

%

10.91

40.78

25.83

2.17

Weight

15.70

1.6 1 1.2

Barnett GC 2008

Flatt S 2010

Ewertz M 1991

Beasley JM 2011

Holmes MD 1999

Kwan M 2010

0 10 20 30 40

Alcohol post-diagnosis (g/day)

Linear dose-response meta-analysis of alcohol intake before breast cancer diagnosis and breast cancer mortality

Overall (I-squared = 73.5%, p = 0.010)

Hellmann (2010)

Study

Dal Maso L (2008)

Harris HR (2012)

Reding KW (2008)

1.00 (0.97, 1.02)

1.01 (0.98, 1.03)

1.00 (0.99, 1.02)

1.02 (0.97, 1.08)

0.96 (0.93, 0.98)

100.00

26.13

33.62

14.22

26.03

Weight

1.00 (0.97, 1.02)

1.01 (0.98, 1.03)

1.00 (0.99, 1.02)

1.02 (0.97, 1.08)

0.96 (0.93, 0.98)

RR (95% CI) per 1 drink/week

100.00

26.13

%

33.62

14.22

26.03

Weight

1.9 1 1.1

Hellmann 2010

Dal Maso L 2008

Reding KW 2008

Harris HR 2012

0 5 10 15 20

Alcohol pre-diagnosis (drinks/week)

Alcohol (before diagnosis) and breast cancer mortality

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

Overall (I-squared = 65.2%, p = 0.057)

Study

Rohan T (1993)

Beasley JM (2011)

Kwan M (2010)

1.06 (0.79, 1.42)

RR (95% CI)Per 10 g/day

0.78 (0.55, 1.11)

1.06 (0.94, 1.20)

1.58 (1.00, 2.50)

100.00

Weight

29.58

47.61

22.81

1.06 (0.79, 1.42)

0.78 (0.55, 1.11)

1.06 (0.94, 1.20)

1.58 (1.00, 2.50)

100.00

%

Weight

29.58

47.61

22.81

1.6 1 1.7

Beasley JM 2011

Rohan T 1993

Kwan M 2010

0 10 20 30 40

Alcohol post-diagnosis (g/day)

Summary: Alcohol

Total mortalityBreast 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. Low2650 0.93 (0.82-1.06) 1329 1.18 (0.81-1.72) - -

Before : Per 1

drink/week2676

1.00 (0.99-1.00)1296

1.00 (0.97-1.02) - -

After diagnosis:

High vs. Low3827

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)

Dietary fibre

NOTE: Weights are from random effects analysis

Overall (I-squared = 0.0%, p = 0.968)

Beasley JM (2011)

Holmes MD (1999)

Study

Belle F (2011)

0.88 (0.78, 0.99)

0.87 (0.73, 1.04)

0.90 (0.73, 1.10)

0.87 (0.65, 1.16)

100.00

46.15

36.00

Weight

17.85

0.88 (0.78, 0.99)

0.87 (0.73, 1.04)

0.90 (0.73, 1.10)

RR (95% CI)Per 10 g/day

0.87 (0.65, 1.16)

100.00

46.15

36.00

%Weight

17.85

1.8 1 1.2

Linear dose-response meta-analysis of fibre intake (twelve months or more after diagnosis)

NOTE: Weights are from random effects analysis

Overall (I-squared = 0.0%, p = 0.643)

Rohan T (1993)

Study

Belle F (2011)

Beasley JM (2011)

0.93 (0.80, 1.07)

0.96 (0.80, 1.16)

0.94 (0.68, 1.29)

0.80 (0.58, 1.12)

100.00

59.97

%

20.75

Weight

19.28

0.93 (0.80, 1.07)

0.96 (0.80, 1.16)

0.94 (0.68, 1.29)

RR (95% CI)Per 10 g/day

0.80 (0.58, 1.12)

%Weight

1.6 1 1.2

Total mortality Breast cancer mortality

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/day443 (3) 0.68 (0.56-0.84)

0%, p = 0.41

Twelve months or more after diagnosis

High vs. Low1092 (3) 0.76 (0.58-0.98)

0%, p = 0.99332 (3) 0.82 (0.57-1.20)

0%, p = 0.95

Per 10 g/day1092 (3) 0.88(0.78-0.99)

0%, p = 0.97332 (3) 0.93 (0.80-1.07)

0%, p = 0.64

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)

99.43

0.57

100.00

98.90

1.10

100.00

15.49

49.64

33.59

1.28

100.00

Weight

%

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)

RR (95% CI)Per 3 serving/week

99.43

0.57

100.00

98.90

1.10

100.00

15.49

49.64

33.59

1.28

100.00

Weight

%

1.7 1 1.4

Fruits, total mortality

.

.

.

Pre-menopausalFink B (2006)Saxe GA (1999)

Subtotal (I-squared = 46.2%, p = 0.173)

Pre and post-menopausalFink B (2006)Saxe GA (1999)

Subtotal (I-squared = 0.0%, p = 0.715)

Post-menopausalBuck K (2011)Fink B (2006)McEligot A (2006)

Saxe GA (1999)Subtotal (I-squared = 22.4%, p = 0.276)

Study

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)

RR (95% CI)Per 7 serving/week

76.0223.98

100.00

89.0610.94

100.00

26.9850.809.74

12.48100.00

Weight

%

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)

76.0223.98

100.00

89.0610.94

100.00

26.9850.809.74

12.48100.00

Weight

%

1.6 1 1.7

Linear dose-response meta-analysis of fruits and vegetable intake (before diagnosis)

Fruits and vegetables

Isoflavones intake and total mortality

Meta-analysis of isoflavones intake (highest compared to lowest intake) and total mortality

Overall (I-squared = 59.4%, p = 0.061)

Fink B (2007)

Kang X premenopausal (2010)

Study

Boyapati SM (2005)

Kang X postmenopausal (2010)

0.87 (0.65, 1.17)

0.52 (0.33, 0.82)

1.05 (0.78, 1.71)

1.06 (0.79, 1.42)

0.88 (0.56, 1.24)

100.00

21.31

Weight

24.43

30.09

24.17

>7.48 vs 0-0.29 mg/d

Comparison

>42.3 vs <15.2 mg/d

T3 vs T1

>42.3 vs <15.2 mg/d

0.87 (0.65, 1.17)

0.52 (0.33, 0.82)

RR (95% CI)High vs low

1.05 (0.78, 1.71)

1.06 (0.79, 1.42)

0.88 (0.56, 1.24)

100.00

21.31

Weight

24.43

%

30.09

24.17

1.2 1 2

Overall (I-squared = 8.1%, p = 0.337)

Zhang Y (2012)

Shu X (2009)

Caan B (2011)

Study

0.70 (0.56, 0.88)

0.62 (0.42, 0.90)

0.79 (0.61, 1.03)

0.46 (0.20, 1.05)

100.00

31.84

60.88

Weight%

7.28

>28.83 vs <7.56 mg/d

>62.68 vs <=20 mg/d

Comparison

16.33-86.9 vs 0-0.07 mg/d

0.70 (0.56, 0.88)

0.62 (0.42, 0.90)

0.79 (0.61, 1.03)

RR (95% CI)High vs low

0.46 (0.20, 1.05)

100.00

31.84

60.88

7.28

1.2 11.5

Before diagnosis Twelve months or more after diagnosis

Overall (I-squared = 82.0%, p = 0.001)

Zhang S

Gregorio DI

Saxe GA

McEligot A

Author

1995

1985

1999

2006

Year

1.19 (1.01, 1.41)

1.13 (1.01, 1.28)

1.04 (1.00, 1.08)

1.15 (0.82, 1.61)

1.63 (1.31, 2.03)

RR (95% CI)Per 10 g/day

100.00

29.69

34.38

14.33

21.61

Weight

1.19 (1.01, 1.41)

1.13 (1.01, 1.28)

1.04 (1.00, 1.08)

1.15 (0.82, 1.61)

1.63 (1.31, 2.03)

100.00

%

29.69

34.38

14.33

21.61

Weight

1.492 1 2.03

Total mortalityLinear dose-response meta-analysis

Overall (I-squared = 53.5%, p = 0.091)

Dal Maso L

Nomura AM

Author

Kyogoku

Jain M

2008

1991

Year

1992

1994

1.13 (0.71, 1.77)

0.95 (0.75, 1.22)

1.42 (0.71, 2.86)

0.40 (0.10, 1.30)

1.89 (0.96, 3.70)

100.00

43.28

22.93

Weight%

10.06

23.73

T3 vs T1

High vs Low

Comparison

Q4 vs Q1

>=45.2 vs <=38.08%energy

1.13 (0.71, 1.77)

0.95 (0.75, 1.22)

1.42 (0.71, 2.86)

RR (95% CI)

0.40 (0.10, 1.30)

1.89 (0.96, 3.70)

High vs low fat

100.00

43.28

22.93

10.06

23.73

1.1 1 10

Fat intake before diagnosis

Breast cancer mortalityHighest vs lowest meta-analysis

Total mortalityHighest vs lowest meta-analysis

Fat intake twelve months or more after diagnosis

Breast cancer mortalityHighest vs lowest meta-analysis

NOTE: Weights are from random effects analysis

Overall (I-squared = 0.0%, p = 0.413)

Author

Holmes MD

Newman S

Beasley JM

Rohan T

Year

1999

1986

2011

1993

1.19 (0.94, 1.50)

1.44 (1.01, 2.04)

0.99 (0.65, 1.51)

0.92 (0.53, 1.60)

1.40 (0.66, 2.96)

100.00

Weight

43.33

29.63

17.54

9.51

Comparison

>=69.6 vs <53g/day

>77 vs <=77 g/day

mean 39 vs 23%energy

>108 vs <56 g/day

1.19 (0.94, 1.50)

RR (95% CI)High vs low

1.44 (1.01, 2.04)

0.99 (0.65, 1.51)

0.92 (0.53, 1.60)

1.40 (0.66, 2.96)

100.00

Weight%

43.33

29.63

17.54

9.51

1.338 1 2.96

Overall (I-squared = 24.4%, p = 0.266)

Ewertz M

Author

Beasley JM

Holmes MD

1991

Year

2011

1999

1.08 (0.90, 1.30)

0.96 (0.75, 1.22)

1.05 (0.79, 1.39)

1.34 (0.97, 1.85)

100.00

40.70

Weight%

32.73

26.57

Q4 vs Q1

Comparison

mean 39 vs 23%energy

>=69.6 vs <53g/day

1.08 (0.90, 1.30)

0.96 (0.75, 1.22)

RR (95% CI)High vs low

1.05 (0.79, 1.39)

1.34 (0.97, 1.85)

100.00

40.70

32.73

26.57

1.541 1 1.85

Fat intakeSummary

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/day178 (4) 1.19 (1.01-1.41)

82.0%, p=0.001

Twelve months or more after diagnosis

High vs. Low1436 (3) 1.08 (0.90-1.30)

24.4%, p = 0.27648 (4) 1.19 (0.94-1.50)

0%, p = 0.41

Per 10 g/day575 (3) 1.01 (0.95-1.08)

24.0%, p = 0.27

Saturated fat intake before diagnosis

and total mortality

Overall (I-squared = 31.8%, p = 0.231)

McEligot A

Author

Saxe GA

Zhang S

2006

Year

1999

1995

1.66 (1.26, 2.19)

2.02 (1.50, 2.70)

1.20 (0.56, 2.57)

1.45 (1.04, 2.03)

100.00

47.46

Weight

11.71

40.83

1.66 (1.26, 2.19)

2.02 (1.50, 2.70)

RR (95% CI)Per 10 g/day

1.20 (0.56, 2.57)

1.45 (1.04, 2.03)

100.00

47.46

%

11.71

40.83

1.37 1 2.7

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

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

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

Thanks! Continuous Update Project Panel

Anne Mc Tiernan and Inger Thune International scientific experts CUP team