Transcript Epidemiology and prevention of breast cancer

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
Long history of studying causes
1850’s family history
 1920’s reproductive risk factors
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– Lane-Claypon, 1926 case-control study
1950’s menopause
 1970 – onwards oral contracpetives,
postmenopausal hormones, diet,
physical activity, obesity, endogenous
hormones, SERMs
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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?
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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.
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.

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”
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Breast Cancer Average Annual
Incidence per 100,000 by age, 1982
1000
100
San Francisco
Japan
China
10
75
65
55
45
35
25
15
1
Age (years/female)
1930
1990
Seow A, et al Int J Epi 1996
Singapore breast cancer incidence by age and birth cohort
1908
1948
Seow 1996
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
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Risk factors
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Age
Gender
Family history
Benign breast
disease
Reproductive factors
Endogenous
hormones
Exogenous
hormones
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Adiposity
Diet
Physical activity
Alcohol
Radiation
Models of disease incidence
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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
Pike model
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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
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We translated this to mean the rate of
cell division and accumulation of
molecular damage on the pathway to
breast cancer
One Birth Model
Menarche
First birth
Rosner, Colditz, Willett, Am J Epidemiology 1994;139:824
Menopause
Age
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
Multiple Birth Model
Rosner, Colditz, Willett, Am J Epidemiology 1994;139:826
Application of models to NHS
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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
450
400
350
300
250
200
150
100
50
0
16%
27%
Age birth
35
Nulliparous
Age
Colditz and Rosner, Am J Epidemiology 2000;152:950-64
70
66
62
58
54
50
46
42
38
Age birth
20,23,26,29
34
30
Incidence/100,000
Pregnancy history
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
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Finland
Norway
Sweden
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
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Wu et al CEBP 2002
Age at menopause
400
Incidence/100,000
350
300
250
Menopause
age 45
Menopause
age 55
44%
200
150
100
50
0
30
35
40
45
50
55
60
Age
Colditz and Rosner, Am J Epidemiology 2000;152:950-64
65
70
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
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– who is target population
– how are they identified, counseled, etc.
– balance risks vs. benefits
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
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Risk of breast cancer by plasma estradiol levels:
By tumor receptor status
P for heterogeneity = < 0.001
6
5
4
3
2
1
0
1
2
3
ER+/PR+
Missmer et al, 2004
4
1
2
3
ER-/PR-
4
1
2
3
4
ER+/PR-
(case n = 152 ER+/PR+, 38 ER-/PR+, 33 ER-/PR-)
Body Mass Index and estrone
sulfate
250
200
150
Estrone sulfate
100
50
0
<21
21-22.9 23-24.9 25-28.9
Hankinson et a, JNCI 1995;87:1297-1302l
30+
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
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Eliassen JAMA 2006
Schairer et al
BCDDP cohort followed 46,355
postmenopausal women
 2082 cases of breast cancer
 Relative risk increased 0.01 (0.00020.03) per year of use for estrogen alone
 RR increased 0.08 (0.02-0.16) for E & P
 Increase in RR stronger among women
with BMI < 24.4 kg/m2
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JAMA 2000
Ross et al.
1879 postmenopausal cases and 1637
controls in LA county
 Estrogen alone associated with RR 1.06
(0.97-1.15) for 5 years of use
 E & P gave RR = 1.24 (1.07-1.45) per 5
years of use
 Among E & P sequential therapy gave
higher risk than continuous therapy
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JNCI 2000
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 1993-1998
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Intervention
Conjugated equine estrogen 0.625
mg/d, plus medroxyprogesterone
acetate, 2.5 mg/d, in 1 tablet (n=8506)
 Placebo (n=8102)
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Results at termination of trial
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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 (1.00-1.59)
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
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
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Large drop in breast cancer
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US SEER (national tumor registry program)
 California state
 New Zealand
 Germany
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US drop in prescribing
 Contribution of a decrease in screening has
been debated and ruled out as a cause for
drop
Dispensed outpatient PMH
prescriptions
34.5M ’92 to high of 87.5M 2000
Wysowski et al 2005
Clarke et al, California
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Kaiser data on prescribing
– 68% drop in E&P prescribing following release of
WHI results
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10% drop in breast cancer incidence
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For US women 50 to 69 (26 million women),
this is 8,200 fewer cases of breast cancer,
each year
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J Clin Oncology Nov 2006
Further SEER analysis
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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
Further analysis of California data
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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)
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
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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 postmenopausal women
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– Barriers to physical activity include
neighborhood safety, time and family
responsibilities, social pressures
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; 90:1371-88
JAMA 1999, JNCI 2004
Preventability
International variation in rates
 Variation in reproductive characteristics
 Growth and obesity
 Primary prevention randomized trials
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Social strategy to prevent breast
cancer
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Provider
– counseling on diet, activity, weight gain/loss
– identify “higher risk” for preventive interventions
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Balance risks and benefits
Regulation
– facilitate lactation, physical activity, ?diet
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Community
– lactation, physical activity, access to care
Goals for Prevention
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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
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No significant difference in
adverse events
Deaths
Placebo
Raloxifene
2.3%
1.7%
Thromboembolic 1.01%
disease
Endometrial
0.39%
cancer
Endometrial
0.29%
hyperplasia
1.72%
0.32%
0.37%
Risk vs. benefit: who should get a
SERM
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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
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For benefit (reduced breast cancer) to exceed
harm (thromboembolic events) incidence
must be greater than 380/100,000
Age and risk decile for
benefits to exceed risks
Age
D4
D6
D8
D9
D10
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
Incidence based on Rosner/Colditz model
Incidence per 100,000 women per year
50 to 64 year old population 5.1M eligible, 25%<65
Incidence, Number Needed to
Treat (for 5 years) to prevent
1 cases (top decile)
Age
50-4
55-9
60-4
65-9
Incidence
504
668
756
921
NNT
79
60
53
43
Assumes 50% reduction in Breast CA risk
Incidence per 100,000/yr.
Chen W, Rosner B, Colditz G. Cancer 2007
Next steps to prevention of
breast cancer
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Refine assessment of risk
– Stratify and provide appropriate counseling
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Balance risk and benefits
– Provide tools to aid weighing risks and benefits for
women
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Implement population strategies to change
behavior of providers, community, and even
regulations to reinforce behavior changes
(e.g., physical activity, weight control)