The Continuous Update Project | Prof. Martin Wiseman

The Continuous Update ProjectBreast 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

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

Breast

Global variation in cancer incidence

Colorectum

Migration data

Cancer Incidence in Japan*

* Per 100,000, world population standard

Ca

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r In

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Hanahan & Weinberg (2011) Cell; Hanahan & Coussens (2012) Cancer Cell

Hallmarks of cancer

Two enabling characteristics for acquiring hallmarks

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

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)

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

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

CANCER FREQUENCY AND AGE

IMPACT OF OFFSPRING SIZE AND GROWTH ON CANCER RISK

Height and risk of CVD and cancer

CVD Cancer

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

CUP database

Research Team

Second Expert Report databases

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

Grading the evidenceDecreases risk

Increases risk

Strong evidence

Convincing

Probable

Limited evidence

Limited - suggestive

Limited – no conclusion

Strong evidence

Substantial effect on risk unlikely

Basis for recommendations

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

Prostate cancer

Prostate cancer – sub-types

Non-advanced

Advanced

Fatal

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

Issues for prostate cancer

Heterogeneity of diseaseScreen detectedAdvanced or aggressiveFatal

Characterisation of exposureLycopeneCalcium/dairy

Breast Cancer Survivors

Breast Cancer Survivors Included

Pre-menopausal women Post-menopausal women Incident in-situ breast cancer Incident invasive breast cancer

Criteria for Study Inclusion

Randomised controlled trials≥ 50 women≥ 6 months follow-upOnly 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

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

change, BMI Body composition Dietary supplements Physical activity

Timing of ExposuresPre-diagnosis Within 12 months following diagnosis

Period of intensive primary therapy (surgery, radiation, chemotherapy)

From 12 months after diagnosisPatients may be receiving targeted therapy

during this period (e.g. hormonal therapy, HER2neu, bone metastases prevention)

Data may extend 20 years or more

Outcomes Included

Total mortality

Breast cancer specific mortality

Second primary breast cancer

Outcomes Included

Total mortality

Breast cancer specific mortality

Second primary breast cancer

Not: recurrence, QoL, lymphoedema etc

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 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

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

• 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

Need for studies that control for confounding by clinical variables

Randomised controlled trialsCohort studies with accurate diagnostic &

treatment variables

Future Considerations

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.

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

Thank you!

Summary: Before diagnosis- BMI

Total mortality Breast cancer mortalitySecond 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) - -

Summary: Around diagnosis- BMI


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)

Summary: After diagnosis – BMI


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

Summary: physical activity Total mortality

Breast cancer mortality

EventsRR (95%CI)N, I2, P het


Before diagnosisTotal

H vs. L 5050.83 (0.62-1.12)2, 23%, p=0.25

3380.80 (0.59-1.10)2, 0%, p=0.88

Before diagnosis Recreational

H vs. L 28920.74 (0.67-0.83)8, 5%, p=0.39

17500.76 (0.61-0.95)7, 49%, p=0.06

After diagnosisTotal H vs. L 514

0.63 (0.41-0.97)3, 44%, p=0.16

2170.81 (0.48-1.36)2, 0%, p=0.63

Per 10 MET-h/week

5140.90 (0.79-1.03)3, 79%, p=0.009

- -

After diagnosisRecreational

H vs. L 23370.61 (0.50-0.74)5, 46% ,p=12

3920.71 (0.45-1.12)2, 33%, p=0.22

After diagnosisRecreational

Per 10 MET-h/week

23370.81 (0.73-0.90)5, 64%, p=0.03

- -

Summary: dietary fibre

Total mortalityBreast cancer mortality



Before diagnosis H vs. L 4170.50 (0.35-0.73)2, 0%, p=0.83

2 studiesNon-sig risk

Per 10g/d 4430.68 (0.55-0.84)3, 0%, p=0.41

After diagnosis H vs. L 10920.76 (0.58-0.98)3, 0%, p=0.99

3320.82 (0.57-1.20)3, 0%, p=0.95

Per 10g/d 10920.88 (0.78-0.99)3, 0%, p=0.97

3320.93 (0.80-1.07)3, 0%, p=0.64

Summary: isoflavones

Total mortality


Before diagnosis H vs. L 6240.87 (0.65-1.17)3, 59%, p=0.06

After diagnosis H vs. L 7940.70 (0.56-0.88)3, 8%, p=0.33

Per 10mg/d 7940.91 (0.83-1.00)3, 68%, p=0.05

Summary: total fat




Before diagnosis H vs. L (g/d) 6551.87 (0.76-4.57)3, 90%, p<0.001

5211.13 (0.71-1.77)4, 54%, p=0.09

Per 10g/d 1781.19 (1.01-1.41)4, 82%, p=0.001

- -

Per 10% energy 1781.82 (1.41-2.36)3, 0%, p=0.38

- -

After diagnosis H vs. L (g/d) 14361.08 (0.90-1.30)3, 24%, p=0.27

6481.19 (0.94-1.50)4, 0%, p=0.41

Per 10g/d - - 5751.01 (0.95-1.08)3, 24%, p=0.27

After diagnosis: saturated fat

Outcome AuthorYear

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. Q1g/d

1.23 (0.89-1.69)


Beasley 2011

Follow-up of cases from case-control study

137 13% vs. 7% energy

1.55 (0.88-2.75)


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

Summary: Alcohol


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

26761.00 (0.99-1.00)

12961.00 (0.97-1.02) - -

After diagnosis:High vs. Low

38270.89 (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)

The Continuous Update Project | Prof. Martin Wiseman

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