1) The document summarizes a presentation on the relationships between obesity, physical activity, and colorectal cancer risk and outcomes. 2) It discusses how increased BMI is an established risk factor for colorectal cancer in a gender- and site-specific manner, and how weight gain, especially in early adulthood, can increase colon cancer risk. 3) It also reviews how measurements of waist circumference and waist-to-hip ratio may be associated with colorectal cancer risk independent of BMI, and how analyses of cancer survival have shown mixed results depending on whether BMI is measured before or after cancer diagnosis.

1. IASO/WCRF Meeting, London 17th April 2013
Energy balance, adiposity, physical
activity, and colorectal cancer: clinical
perspectives
Andrew G Renehan PhD FRCS FRCS(GenSurg)
Department of Surgery, The Christie NHS Foundation Trust
MRC Health eResearch Centre
Faculty Institute of Cancer Sciences, University of Manchester
Manchester Academic Health Science Centre

2. “There are known knowns;
there are things we know that we know.
There are known unknowns; that is to say there are
things that, we now know we don't know.
But there are also unknown unknowns – there are
things we do not know, we don't know.”
US Secretary of Defense, Donald Rumsfeld, 2002
Message no. 1

3. Message no. 2
Influences of BMI:
pre-diagnosis ≠ post-diagnosis

4. Message no. 3
Will Rogers phenomenon
“When the Okies left Oklahoma and went to
California, the average intelligence of both
states went up”
Tumour stage migration

5. W-R phenomenon: effect on survival
Patients with anal cancer undergoing chemo-radiotherapy
Christie Hospital 1988-2011
0.00
0.25
0.50
0.75
1.00
Survival(%)
0 12 24 36 48 60
Time in months
1988 to 2003, N = 190
Cancer-specific survival
Node negative
Node positive
P = 0.002
n = 156
n = 34 (18%)
0 12 24 36 48 60
Time in months
Node negative
2004 to 2011, N = 206
Cancer-specific survival
0.00
0.25
0.50
0.75
1.00
Node positive
P = 0.576
n = 137
n = 69 (34%)
Pre-treatment
MR staging

6. Obesity & colorectal cancer risk

7. BMI and cancer risk
Renehan et al. Lancet 371; 569-578: 2008

8. By colorectal site & gender
21
17
1.24 (1.20, 1.28)
1.09 (1.05, 1.12)
No. of
studies RR (95% CI)RR (95% CI)
Colon
Rectum
MEN
Risk ratio
(per 5 kg/m2 increase)
Colon
Rectum
15
11
1.09 (1.04, 1.14)
1.01 (0.99, 1.04)
WOMEN
10.8 1 1.5
Harriss on behalf of C-CLEAR
Colorectal Dis 2009; 11:547-63.
P < 0.0001P < 0.0001

9. Implications of gender & site specificity
• Specificity – Bradford-Hill criteria of causality
• Biological implications
- gender-specific physiology
- site-specific molecular characteristics
Hucthins .... Quirke
JCO 2011

10. MS-stable MSI-low MSI-high
n 913/1376 149/230 188/274
OR (95% CIs)
per 5 kg/m2
1.38
(1.24-1.54)
1.33
(1.04-1.72)
1.05
(0.94-1.31)

11. Weight gain in adulthood

12. • 500,000 men & women
• baseline age: 63.1 years
• baseline collection: 1995 to 1996
• followed to 2007 (last update)
• detailed lifestyle & dietary cohort
• retrospective questionnaire: 18y; 35y; 50y

13. Weight gain in adulthood
Renehan et al.
Am J Epi 2012
0.5
0.8
1
2
3
Relativerisk[logscale]
-1 -.5 0 .5 1 1.5 2
Weight gain 18 to 62 yr)
Colon cancer risk in men
per
0.5 kg/y
0.5
0.8
1
2
3
Relativerisk[logscale]
-1 -.5 0 .5 1 1.5 2
weight gain [kg/year]
Weight gain 18 to 35 yr
per
0.5 kg/y

14. WC/ WHR & colorectal cancer risk
Abdominal adiposity may better reflect metabolic dysfunction

15. Issues: WC/WHR versus BMI is:
1. Stronger associations for cancer risk
2. WC ‘independent’ effect from BMI:
2.1 Adjustment for BMI residual WC effect
2.2 WC ‘independent’ effects within each BMI category
3. WC as a better ‘discriminator’ of risk that BMI
4. Different WC v BMI patterns of association by ethnic groups
Adapted from Huxley et al. Eur J ClinNutr 2010: 64:16-22
Considerations

16. Men Women
Cohort 129,731 238,546
age 52.8 51.1
Colon cancers 421 563
BMI (Q5 v Q1) 1.55
(1.12-2.15)
1.06
(0.79-1.42)
WC (Q5 v Q1) 1.39
(1.01-1.93)
1.48
(1.08-2.03)
WHR (Q5 v Q1) 1.51
(1.06-2.15)
1.52
(1.12-2.05)
Colon cancer risk: mean FU = 6.1 y

17. Waist circumference ≠ visceral adiposity
65yr M
WC = 111 cm
BMI = 32.6 kg/m2
SAT vol = 2291 cm3
VAT vol = 3049 cm3
56yr F
WC = 111 cm
BMI = 29.8 kg/m2
SAT vol =2904 cm3
VAT vol = 918 cm3
WC
WC

18. BMI, WC & WHR in the AARP cohort
Keimling, Renehan ......... Leitzmann submitted
Men Women
Cohort 124,261 79,220
age 63.3 62.9
Colon cancers 1471 683
BMI (per SD) 1.14
(1.08-1.20)
0.97
(0.90-1.06)
WC (per SD) 1.17
(1.08-1.26)
0.98
(0.87-1.11)
WHR (per SD) 1.09
(1.04-1.14)
1.00
(0.92-1.08)
Colon cancer risk: mean FU = 9.3 y
no difference
P < 0.001

19. Ni Mhurchu et al IJE 2004
(2 kg/m2 reduction in BMI)
EPIC v AARP: explanations
Asia Pacific Cohort Studies Collaboration

20. Summary on cancer risk
• Increased BMI is an established risk factor for
colorectal cancer in gender- & site-specific manner
• Stronger associations for MS-stable and MSI-low
colorectal cancer
• Weight gain, perhaps in early adulthood, is a risk
factor for colon cancer
• WC & WHR are also associated with increased
risk – whether or not better ‘risk predictor’ is unclear

21. BMI & cancer mortality & survival

22. Obesity & cancer mortality/survival: 2 cohort types
Inception cohort design/
pre-diagnosis (mortality)
Cohort
entry
Cancer
diagnosis Death
Exposure
Cancer
diagnosis
DeathTreatment cohort/
Post-diagnosis survival
Treatment
Exposure

23. Baseline BMI & colorectal cancer mortality
Calle et al. NEJM 2003; 348:1625-38

24. Baseline BMI & colorectal cancer mortality
Calle et al. NEJM 2003; 348:1625-38

25. Obesity, cancer mortality & survival:
pre- & post-diagnosis BMI
Cohort
entry
Cancer
diagnosis Death
Baseline
BMI
Pre-dx
BMI (b)
Post-dx
BMI
Pre-dx
BMI (a)
Post-dx
BMI(a)
Post-dx
BMI(b)

26. Post-diagnosis BMI & breast cancer survival
Niraula..............Goodwin Breast Cancer Res Treat 2012; 5 May
Cancer specific survival

27. Pre-diagnosis BMI & mortality
Kuipar (2010)
Cancer mortality
Campbell (2012)
Campbell (2012)
I2 = 0.0%
Authors (year)
Prizment (2010)
Kuipar (2010)
All cause mortality
Prizment (2010)
I2 = 0.0%
USA
USA
USA
Country
USA
USA
USA
WHI
CPSII
CPSII
Cohort
IWHS
WHI
IWHS
C&R
C&R
C&R
Site
colon
C&R
colon
171
851
380
Cases
289
265
493
1.17 (0.80, 1.71)
1.30 (1.06, 1.59)
1.35 (1.01, 1.80)
1.33 (1.16, 1.52)
RR (95% CI)
1.30 (0.94, 1.79)
1.19 (0.88, 1.61)
1.46 (1.15, 1.86)
1.29 (1.07, 1.55)
11.9 y
16 y FU
16 y FU
FU
up to 20 y
11.9 y
up to 20 y
1.17 (0.80, 1.71)
1.30 (1.06, 1.59)
1.35 (1.01, 1.80)
1.33 (1.16, 1.52)
RR (95% CI)
1.30 (0.94, 1.79)
1.19 (0.88, 1.61)
1.46 (1.15, 1.86)
1.29 (1.07, 1.55)
11.9 y
16 y FU
16 y FU
up to 20 y
11.9 y
up to 20 y
10.8 1 1.5 2
RR for
obese v normal
Analysis from time of diagnosis
“Pre-diagnostic obesity may be a modifiable risk factor
for death in colon cancer patients”

28. All cause Cancer-specific
Pre-diagnosis BMI 1.30
(1.06-1.59)
1.35
(1.01-1.80)
Post-diagnosis BMI 0.93
(0.75-1.17)
1.14
(0.81-1.60)
Mortality: obese versus normal

29. Will-Rogers phenomenon
Renehan, Crosbie, Campbell JNCI letter submitted
Pre-
diagnosis
Post-
diagnosis Difference
No. of patients 2303 1957 346 (15%)
Weights in kg
All patients 79.08 77.03 2.05
Pre-diagnosis BMI category
<18.5 kg/m2 55.13 55.17 -0.03
18.5 to 24.9 kg/m2 67.84 66.17 1.67
25.0 to 29.9 kg/m2 82.19 80.40 1.79
30.0 to 34.9 kg/m2 94.99 90.96 4.03
35.0 kg/m2 108.30 103.70 4.60

30. Will-Rogers phenomenon
Rectal
cancer
diagnosis
Banks ............. Renehan unpublished Greater Manchester Rectal Cancer Audit
Definitive
major
surgery
Chemo-
radiation
(5 wks)
10-12wks
N =
218
N =
156
Total 62(28%)
25(33%)
26(27%)
4(11%)
BMI
20-25 kg/m2
n = 76
BMI
25-30 kg/m2
n = 95
BMI
>30 kg/m2
n = 35
BMI
< 20 kg/m2
n = 12
7(58%)

31. “When the Okies left Oklahoma and went to
California, the average intelligence of both
states went up”
Post-diagnosis BMI migration
Will-Rogers phenomenon

32. BMI & endometrial cancer survival: ASTEC trial
0.00
0.60
0.70
0.80
0.90
1.00
Survival(%)
0 12 24 36 48 60
Time in months
Overweight
Normal weight
Obese II
Obese I
Obese III
Type I (oestrogen-sensitive) endometrial cancer, N = 1004
Increasing BMI
• endometrium only
• tumour grade
• LV permeation

33. Post-diagnosis BMI & renal cancer survival
Waalkes et al. Cancer Causes Control 2010; 21:1905-10
University Hospital series
• N = 1338
• Mean FU: 5.1 y
• a priori stratification
Obese II/III
Obese I
Normal
Underweight

34. The ‘Overweight Paradox’
Sinicrope et al. Cancer 2013
• ACCENT consortium
• 21 RCT trials
• 5-FU adjuvant chemo
• N = 25,291
• FU = 7.8 years
Men
HR for DFS:
0.94 (0.88-1.00)
36% of pop.

35. Summary on cancer mortality/survival
• Associations between excess adiposity and
cancer incidence may not directly extrapolate to
same direction associations after diagnosis
• Demonstrated ‘time-related biases’ related to
when BMI is measured v cancer outcome
• In some cancers, there may be some protective
effect of being overweight during treatment – the
‘overweight paradox’

36. Acknowledgements
Bern, Switzerland
Professor M Egger
Dr M Zwhalen
Aarhus, Denmark
Professor A Flyvbjerg
Professor J Frystyk
Regensburg, Germany
Professor M Leitzmann
Dr M Keimling
American Cancer Society
Dr PT Campbell
Erasmus/IARC
Professor JW Coebergh
Dr I Soerjomataram
Manchester (colorectal)
Whole team
Manchester (others)
Professor S Shalet
Professor P Clayton
Professor A Howell
Dr M Harvie
Professor G Evans
Professor H Kitchener
Dr E Crosbie
Manchester (epidemiology)
Professor I Buchan
Dr E Badrick
Dr M Carr

37. Thank you