1. Breast cancer prevention
Graham Colditz, MD, DrPH
Niess-Gain Professor, Dept. of Surgery
Washington University School of Medicine,
ACS Clinical Research Professor, and
Associate Director, Prevention and Control

2. Long history of studying causes
1850’s family history
1920’s reproductive risk factors
Lane-Claypon, 1926 case-control study
1950’s menopause
1970 – onwards oral contracpetives, postmenopausal hormones, diet, physical activity, obesity, endogenous hormones, SERMs
Contrast with study of TB where it has largely been removed from society
Study of cardiovascular epidemic – also largely solved

3. Do we know causes of breast cancer?
How do we frame this question?
Individual cases?
At the population level?
Does epidemiology guide prevention for individual women or inform population strategies?

4. Prevention
Prevention today refers mainly to lowering the risk of disease.
Risk of most chronic diseases can't be totally eliminated, it can still be significantly reduced.
If everyone in the US led a healthy lifestyle, 80% of the cases of heart disease and diabetes could be avoided, as could 70% the cases of stroke and over 50% of cancer.

5. Risk
Risk is a person's chance of getting a disease over a certain period of time.
There are many different ways to present risk.

6. Can we prevent breast CA?
YES
International variation
Migration
Common claim we do not know causes “ much of breast cancer epidemiology is not explained by known risk factors”

7. Breast Cancer Average Annual Incidence per 100,000 by age, 1982
Age (years/female)

8. 1930
1990
Seow A, et al Int J Epi 1996

9. Singapore breast cancer incidence by age and birth cohort
1908
1948
Seow 1996

10. Goals
Review risk factors in context of natural history/biology of the breast,
- focus on reproductive factors
- contribution of postmenopausal hormones
Potential for prevention
- SERMS (Selective Estrogen Receptor Modulators)
- diet, activity, weight loss (or control), breast feeding

11. Risk factors Age Gender Family history Benign breast disease
Reproductive factors
Endogenous hormones
Exogenous hormones
Adiposity
Diet
Physical activity
Alcohol
Radiation

12. Models of disease incidence
Can summarize risk factors and take account of temporal relations between risk factors and disease
Temporal relations often ignored in standard risk estimation and interpretation
Offers one approach to summarizing a range of etiologic pathways
- predict population or individual risk

13. Pike model
Factors associated with reduced risk of breast cancer were considered to lower the rate of breast tissue aging
Pike et. al., Nature 1983;303:767-70
We translated this to mean the rate of cell division and accumulation of molecular damage on the pathway to breast cancer

14. One Birth Model Rate of tissue aging Menarche First birth Menopause
Age
Rosner, Colditz, Willett, Am J Epidemiology 1994;139:824

15. Extensions to modeling
Includes time from birth to menarche
Allows the impact to the first birth to vary with age at first birth
Fits log incidence (Poisson regression) model giving terms that are interpretable
Contrast contribution of risk factors for receptor positive and negative breast cancer

16. Multiple Birth Model Rate of tissue aging
Rosner, Colditz, Willett, Am J Epidemiology 1994;139:826

17. Application of models to NHS
Observed that spacing of births was significantly related to reduced risk of breast cancer – the closer the births the lower the subsequent risk
A transient increase in risk was observed with first birth, but not subsequent births
Risk prediction and stratification now more accurate than Gail and other models

18. 16% 27% Colditz and Rosner, Am J Epidemiology 2000;152:950-64
Birth at 35 = 17% increase risk to age 70
Mult births = 27% reduction in risk to age 70
Colditz and Rosner, Am J Epidemiology 2000;152:950-64

19. Age at menarche Later age - lower risk
Age 15 vs age 11 gives 30% lower risk to age 70
Lack of physical activity associated with earlier menarche
Diet may play a role as might fewer childhood infections

20. Finland
Norway
Sweden

21. Impact of Menarche on Hormone levels
Singapore data
Breast cancer rates doubled
144 post menopausal women
Late menarche (after 17) 24% lower estradiol (circulating female hormone) than women with menarche before 17
Wu et al CEBP 2002

22. 44%
Colditz and Rosner, Am J Epidemiology 2000;152:950-64

23. Menopause Early menopause reduces risk
High circulating hormones levels after menopause increase risk, as does use of postmenopausal hormones
Anti-estrogens may have a role
who is target population
how are they identified, counseled, etc.
balance risks vs. benefits

24. Hormonal exposure after menopause
Obesity is related to poor survival
Tamoxifen reduces mortality among women with breast cancer
Tamoxifen and Raloxifene reduce risk of breast cancer in randomized controlled trials of breast cancer prevention

25. Risk of breast cancer by plasma estradiol levels:
By tumor receptor status
P for heterogeneity = < 0.001
Missmer et al, (case n = 152 ER+/PR+, 38 ER-/PR+, 33 ER-/PR-)

26. Body Mass Index and estrone sulfate
Hankinson et a, JNCI 1995;87: l

27. Weight and weight gain
Adult weight gain increases risk of breast cancer
Relation seen most clearly among postmenopausal women who never have used hormones
20 kg gain from age 18 associated with doubling in risk of breast cancer vs. stable weight

28. Eliassen JAMA 2006

29. Schairer et al BCDDP cohort followed 46,355 postmenopausal women
2082 cases of breast cancer
Relative risk increased 0.01 ( ) per year of use for estrogen alone
RR increased 0.08 ( ) for E & P
Increase in RR stronger among women with BMI < 24.4 kg/m2
JAMA 2000

30. Ross et al. 1879 postmenopausal cases and 1637 controls in LA county
Estrogen alone associated with RR 1.06 ( ) for 5 years of use
E & P gave RR = 1.24 ( ) per 5 years of use
Among E & P sequential therapy gave higher risk than continuous therapy
JNCI 2000

31. Women’s Health Initiative Design
A randomized controlled primary prevention trial
Planned duration 8.5 years
16,608 postmenopausal women 50 – 79 years of age with intact uterus at baseline were recruited by 40 clinical centers in

32. Intervention
Conjugated equine estrogen mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n=8506)
Placebo (n=8102)

33. Results at termination of trial
Mean duration of follow-up 5.2 years
290 cases of breast cancer
Risk increased with duration of use (sig. trend over time)
Overall RR vs placebo = 1.26 ( )
But, substantial noncompliance will bias results to null:
42% E&P and 38% placebo stopped study medication
RR in compliers = 1.49, p<0.001

34. International Agency for research on Cancer (IARC)
Classify agents as carcinogens after rigorous review of evidence, laboratory, animal, and human studies
Vol. 91 classifies combination estrogen plus progestin as carcinogenic to humans

35. Large drop in breast cancer
US SEER (national tumor registry program)
California state
New Zealand
Germany
US drop in prescribing
Contribution of a decrease in screening has been debated and ruled out as a cause for drop

36. Dispensed outpatient PMH prescriptions
34.5M ’92 to high of 87.5M 2000
Wysowski et al 2005

37. Clarke et al, California
Kaiser data on prescribing
68% drop in E&P prescribing following release of WHI results
10% drop in breast cancer incidence
For US women 50 to 69 (26 million women), this is 8,200 fewer cases of breast cancer, each year
J Clin Oncology Nov 2006

38. Further SEER analysis
Jemal et al used state of art analysis (joint point analysis) to evaluate trends in breast cancer over time
1975 to 2003 – 394,891 invasive cancers
Decrease in breast cancer largely confined to ER+ tumors in the 2003 downturn
Trend down strongest in women 55 to 64
In situ rates stable from 2000 to 2003
Rules out substantial screening impact
Jemal Breast Cancer Res May 2007

39. Further analysis of California data
California health interview survey
California tumor registry breast cancer
Classified CA counties into 3 levels based on 2001 E&P use
Breast cancer incidence declined
8.8% in counties with smallest decline
13.9% intermediate
22.6% largest E&P decline
No change in proportion of women having mammograms
Robbins and Clarke JCO 2007 (August)

40. Risk accumulation
Overall evidence points to accumulation of risk through the life course
SERMs may offer some potential to inhibit final stages of progression to cancer - prevention greatest among those with high estrogen levels
Lifestyle contributes to cumulative risk
No one intervention for prevention

41. Physical activity Evidence from more than 30 studies
Typical reduction in risk with 4 hours per week = 20% decrease in risk
Evidence present for pre and post- menopausal women
Barriers to physical activity include neighborhood safety, time and family responsibilities, social pressures

42. Cumulative rates of invasive and noninvasive breast cancers occurring in participants receiving placebo or tamoxifen. The P value are two-sided
Fisher et al, 1998; 90:

43. Application of SERM 35.6 million women in US ages 50-79
134,000 cases of breast cancer
74% of total incidence
Who should get a SERM?

44. JAMA 1999, JNCI 2004

46. Preventability International variation in rates
Variation in reproductive characteristics
Growth and obesity
Primary prevention randomized trials

47. Social strategy to prevent breast cancer
Provider
counseling on diet, activity, weight gain/loss
identify “higher risk” for preventive interventions
Balance risks and benefits
Regulation
facilitate lactation, physical activity, ?diet
Community
lactation, physical activity, access to care

48. Goals for Prevention Reduce exposure to hormones after menopause
Avoid postmenopausal hormones
Weight loss
Anti estrogens for those at high enough risk
Promote increase in physical activity
Manage alcohol intake

49. No significant difference in adverse events
Placebo
Raloxifene
Deaths
2.3%
1.7%
Thromboembolic disease
1.01%
1.72%
Endometrial cancer
0.39%
0.32%
Endometrial hyperplasia
0.29%
0.37%

50. Risk vs. benefit: who should get a SERM
35.6M women 50 to 79
134,000 incident cases/yr
Raloxifene would prevent 80,872 cases/yr
Raloxifene would cause 67,649 thromboembolic events
Based on 19/10,000 per year treated
For benefit (reduced breast cancer) to exceed harm (thromboembolic events) incidence must be greater than 380/100,000

51. Age and risk decile for benefits to exceed risks
50-4
185
233
302
357
504
55-9
246
309
401
474
668
60-4
278
349
453
536
756
65-9
339
425
552
654
921
6.4 M women should not take Raloxifene
30% of women under 65.
Incidence based on Rosner/Colditz model
Incidence per 100,000 women per year
50 to 64 year old population 5.1M eligible, 25%<65

52. Incidence, Number Needed to Treat (for 5 years) to prevent 1 cases (top decile)
Age
Incidence
NNT
50-4
504 79
55-9
668 60
60-4
756 53
65-9
921 43
Assumes 50% reduction in Breast CA risk
Incidence per 100,000/yr.
Chen W, Rosner B, Colditz G. Cancer 2007

53. Next steps to prevention of breast cancer
Refine assessment of risk
Stratify and provide appropriate counseling
Balance risk and benefits
Provide tools to aid weighing risks and benefits for women
Implement population strategies to change behavior of providers, community, and even regulations to reinforce behavior changes (e.g., physical activity, weight control)