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Epidemiology of breast cancer
Rulla Tamimi, ScD
Associate Professor of Medicine
Harvard Medical School
Outline
• Descriptive epidemiology• Established risk factors for breast cancer
– Epidemiologic data– Biologic mechanisms
• Incorporating pathology into breast cancer epidemiology– Examples from the Nurses’ Health Study
Breast Cancer
• The most common malignancy in the US– Estimated 230,480 new invasive cases in 2011
• 2nd most common cause of cancer death– Estimated 39,520 breast cancer deaths in 2011
• Over 2 million breast cancer survivors in US
ACS, www.cancer.org
2012 Estimated US Cancer Cases*
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2011.
Men848,170
Women790,740
29% Breast
14% Lung & bronchus
9% Colon & rectum
6% Uterine corpus
5% Thyroid
4% Non-Hodgkin lymphoma
4% Melanoma of skin
3% Ovary
3% Kidney
3% Pancreas
•20% All Other Sites
Prostate 29%
Lung & bronchus 14%
Colon & rectum 9%
Urinary bladder 7%
Melanoma of skin 5%
Kidney 5%
Non-Hodgkin 4% lymphoma
Oral cavity 3%
Leukemia 3%
Pancreas 3%
All Other Sites 18%
SEER
Age standardized incidence and mortality rates, 2008
0 20 40 60 80 100 120
China
India
Mexico
Columbia
Japan
Jordan
Brazil
Poland
Spain
Australia
Canada
UK
Sweden
Israel
France
New Zealand
USA
Rates per 100,000 females
IncidenceMortality
Krieger, N. Int. J. Epidemiol. 2008 37:627-637; doi:10.1093/ije/dyn055
Trends in breast cancer incidence in the US
Preventability
• International variation– 4-5 fold variability in rates worldwide
• Trends across time within countries
• Migration studies– Changes in rates in women moving from low
risk to high countries• Usually in 1-2 generations
– Vice versa
Long history of study
• 1880’s family history
• 1920’s reproductive risk factors
• 1950’s menopause
• 1970 – early 2000s– oral contraceptives, postmenopausal hormones,
diet, physical activity, obesity, endogenous hormones, SERMs
• 2000—onward– Incorporation of ER/PR and other tissue markers
Established Risk factorsAgeGenderFamily historyBenign breast diseaseReproductive factorsEndogenous
hormonesExogenous hormones
AdiposityDietPhysical activityAlcoholLactationRadiationMammographic
Density
Risk factors
Age at menarche
• Later age - lower risk
• Age 15 vs age 11 gives 30% lower risk
• Menarche represents the development of mature hormonal environment
• Factors associated with early menarche:– Lack of physical activity– Diet – Childhood infections
Lifetime exposure to estradiol
0 10 20 30 40 50 60 70 800
100
200
300
400
500Serum estradiol pmol/l
Menarche Menopause
Trend in age at menarche
Pregnancy and age at first birth
• Nulliparous women are at increased risk of breast cancer– Risk is evident after age 40-45– Short term increased risk with pregnancy
• Younger age at 1st full-term pregnancy is associated with reduced risk
Colditz and Rosner, Am J Epidemiology 2000;152:950-64
Lactation and reduced risk
• Strong evidence from many studies
• Recent US studies show even modern levels of breast feeding associated with lower risk
• Consistent dose response independent of parity
Duration of breast feeding
Collaborative Group on Hormonal Factors in Breast Cancer, Lancet 2002
Menopause
• Early menopause reduces risk• Women with bilateral oophorectomy
before age 45 had 50% reduced risk compared with women with natural menopause at 55+
• On average, 3% increase in risk with each year delay in menopause
• High circulating hormones levels after menopause increase risk
Colditz and Rosner, Am J Epidemiology 2000;152:950-64
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
• Breast tissue ageing…translates to mean the rate of cell division and accumulation of molecular damage on the pathway to breast cancer
Pike model of breast tissue ageing
Hormones and breast cancer
• Endogenous– Premenopausal– Postmenopausal
• Exogenous
Mechanisms for hormonal effects
• Stimulation of mitosis
– Increased chance of mutation being replicated
– More cells at risk of mutation
– Stimulation of tumor growth
• Genotoxic metabolites??
Estradiol, progesterone, and mitotic rate of breast epithelial cells
Based on data from Ferguson & Anderson et al 1981, Williams et al 1991
1 8 15 22
Day of menstrual cycle
0
100
200
300
400
500
600
700Estradiol, pmol/l, or progesterone, nmol/l x 10
0.0
0.5
1.0
1.5
2.0
2.5
3.0Mitotic rate
Estradiol
Progesterone
Mitotic rate
adipose
Androgens
adrenals
Postmenopauseovaries
EstrogenPremenopause
Estrogen
Estradiol by BMIS
erum
est
radi
ol p
mol
/L
<22.5 22.5-24.9 25.0-27.4 27.5-29.9 ≥30.0
BMI
Endogenous Hormones Collaborative Group JNCI 2003
Endogenous hormones and breast cancer collaborative group
Pooled analyses of prospective studies of endogenous hormones and breast cancer
Aims Precise estimates of risks Identify hormone most closely associated with risk
First meeting held in July 2000 in Oxford Collaborators: scientists from original studies; analysis group in
Oxford
Study-specific results for total estradiol
Endogenous Sex Hormones Group, JNCI, 2002;94:617-29
JNCI, 2002
Weight and weight gain
• Complex relationship by menopausal status• Premenopausal breast cancer:
– BMI is inversely associated with risk
• Adult BMI and weight gain increases risk of postmenopausal breast cancer– 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
Colditz and Rosner, Am J Epidemiology 2000;152:950-64
Weight Change Since Age 18
≥10kg 5-9.9 2-4.9 ±2 2-4.9 5-9.9 10-19.9 20-24.9 ≥25kgLoss No Change Gain
p-trend<0.001
Re
lati
ve
Ris
k
2.5
2.0
1.5
1.0
0.5
0.0
Eliassen, 2006
Weight Change After MenopauseR
ela
tiv
e R
isk
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0 ≥10kg 5-9.9 2-4.9 ±2 2-4.9 5-9.9 ≥10kg
Loss GainNo Change
p-trend=0.002
Postmenopausal hormone use by type and duration
Risk post cessation of PMH
Collins et al, Human Reproduction Update 2005
Robbins, A. S. et al. J Clin Oncol; 25:3437-3439 2007
Age-adjusted incidence of invasive breast cancer, white women, age 45 to 74, California, 1996 to 2004
0 10 20 30 40 50 60 70 800
100
200
300
400
500Serum estradiol pmol/L
Menarche
Lifetime Exposure to Estradiol
PMH & WeightMenopause
Oral contraceptives
• Combined data from 54 studies
• Current use increases risk (RR=1.24)
• Increased risk declines after stopping use
• No excess risk 10 or more years after stopping
Alcohol
• Increasing risk with increasing amount of alcohol consumed
• Consistent finding in over 50 studies
• Hormonal mechanism likely pathway
• 1 drink per day increases risk to age 70 by approximately 7% compare to never drinker
Collaborative Group on Hormonal Factors in Breast Cancer
Physical activity
• Evidence from more than 30 studies• Typical reduction in risk with 4 hours per
week = 20% decrease in risk• 2002—IARC concluded that there was
“convincing” evidence that physical activity reduced risk of breast cancer
• Mechanism may vary by period of life
Attributable risk
• Overall evidence points to accumulation of risk through the life course
• Estimated that 45-55% of breast cancer cases in the US can be explained by known factors• late AFB, nulliparity, family history, early menarche,
high SES, and BBD.
• Estimated that reproductive differences could explain half of the difference in rates between US and China
Incorporating pathology in breast cancer epidemiology
Heterogeneity of breast tumors
• Breast cancer is a heterogeneous disease– ER/PR– Known to influence prognosis and response
to treatment• Important for studying the epidemiology
of breast cancer• Estrogen and progesterone act through
the ER and PR• Helps understand the biology
Colditz, G. A. et al. J. Natl. Cancer Inst. 2004 96:218-228; doi:10.1093/jnci/djh025
The distribution of ER and PR tumors among incident invasive breast cancer cases in the NHS (1980-2000) by age at cancer diagnosis
ER-/PR- (square-hatched bars), ER-/PR+ (vertical-stripe bars), ER+/PR- (open bars), and ER+/PR+ (solid bars).
Weight Change Since Age 18
ER+/PR+ ER-/PR-
----Loss---- No Change
------------Gain------------ ----Loss---- No Change
------------Gain------------
p-trend<0.001 p-trend=0.13
p-heterogeneity=0.01
4
3
2
1
Re
lativ
e R
isk
Weight Change After Menopause
-------Loss------- No Change
--------Gain-------
p-trend<0.001 p-trend=0.75
p-heterogeneity=0.02
2
1
Re
lativ
e R
isk
-------Loss------- No Change
--------Gain-------
ER+/PR+ ER-/PR-
Association between mammographic density and ER status
Mammographic Density
<10% 10-24% 25-49% 50+% P-Het
ER+ tumors 0.04
Cases/controls 106/430 196/643 254/548 89/159
1.0 1.3 (1.0-1.8) 2.3 (1.8-3.1) 2.9 (2.0-4.3)
ER- tumors
Cases/controls 18/430 44/643 65/548 30/159
1.0 1.7 (1.0-3.0) 3.0 (1.7-5.4) 4.8 (2.4-9.4)
Yaghjyan et al, 2011
Breast cancer subtypes
Sorlie et al, 2003
Subtypes associates with survival
Sorlie et al, 2003
Breast cancer defined subtypes
Luminal A
Luminal B
Her2 type
Basal-like
Unclassified
More refined classification of tumors may help elucidate association between risk factors and breast cancer
?
Nurses’ Health Study Cohort
1976
121,700
1989
32,826
Blood sub-cohort
Nested case-control study
1993-Tumor block collection
1999-Blood & urine
Risk factors for molecular defined breast cancer
• Created tissue microarrays• IHC markers and grade to define subgroups• Invasive Cancers (2,022)
Type N Definition
Luminal A 1267 ER+ &/or PR+ & HER2- & Grade 1&2
Luminal B 321 ER+ &/or PR+ & HER2- & Grade 3; ER+ &/or PR+ & HER2+
Her2-type 113 ER-/PR-/HER2+
Basal-like 226 ER-/PR-/HER2- & CK5/6+ or EGFR+
Unclassified 95 ER-/PR-/HER2-/CK5/6-/EGFR-
Age at menarche associated with luminal A tumors
*
P-het=0.92
BMI at age 18 associated with all subtypes
Weight gain since 18 associated with luminal A and B subtype
P-het=0.05
Weight gain since 18 associated with Lum B more than Lum A
P-het=0.0007
Lactation associated with reduced risk of basal-like
tumors
*
Comparison to other studies examining these subtypes
Study N cases
Menarche Parity BMI/Wt HRT Lactation
Polish BCS (Yang et al, 2007)
804 More with basal than LumA
No Diff. Pre BMI ↑ Basal
NE NE
Carolina BCS (Millikan et al, 2008)
1424 More with basal than LumA
↑ Parity with ↑ basal more than LumA
No Diff. NE 30%↓ in basal
LACE /Pathways study(Kwan et al 2009)
2544 NE No Diff. No Diff. Ever use with LumA
22% ↓ in basal
NHS 2,022 More with LumA than others (NS)
More with LumA than others (NS)
Weight gain ↑ LumA and LumB
E+P with LumA and basal
40%↓ in basal
Comparison to other studies examining these subtypes
Study N cases
Menarche Parity BMI HRT Lactation
Polish BCS (Yang et al, 2007)
804 more with basal than LumA
No Diff. Pre BMI ↑ Basal
NE NE
Carolina BCS (Millikan et al, 2008)
1424 more with basal than LumA
↑ Parity with ↑ basal more than LumA
No Diff. NE 30%↓ in basal
LACE /Pathways study(Kwan et al 2009)
2544 NE No Diff. No Diff. Ever use with LumA
22% ↓ in basal
NHS 2,022 No Diff. No Diff. No Diff. E+P with LumA and basal
40%↓ in basal
Limitations across studies
• Small sample sizes• Differences in assessing markers
– Variability in tumor processing
• Different exposures assessed• Different study designs, analyses• Different study populations
Conclusions
• Traditional breast cancer risk factors demonstrate different relationships with subtypes– Many reproductive factors were associated
with luminal A– Consistent strong inverse association
between lactation and basal-like
• Classification of tumors may help elucidate the association between “possible” breast cancer risk factors
Reproductive Factors Hormonal Factors Nutritional/Lifestyle Factors Others FactorsObesity (>30 BMI vs. <25)Premenopausal-Postmenopausal+
Age at first birth (>35 vs.<20)++
Estrogen replacement (10+ years vs. none)+
Adult weight gain (postmenopausal)++
Family history (first-degree relative)b++
No. of births (0 vs. one child)+
Estrogen plus progesterone replacement (>5 years vs. none)++
Alcohol (one or more drink/day vs. none)+
Jewish heritage (yes vs. no)+
Age at menopause (5-year increment)+
High blood estrogens or androgens (postmenopause)+++
Height (>5 feet 7 inches)+ Ionizing radiation (yes vs. no)+
Physical activity (>3 hours/week)-
Early age at first period+ OC use (current vs. none)+
Family history (mother and sister)a+++
Breast-feeding (>1 year vs. none)-
High blood prolactin++ Benign breast disease (MD diagnosed)d++
Summary
+:RR1.1-1.4; ++:RR2.5-2.9; +++:RR3.0-6.9; - :RR0.7-0.8
Future Directions
• Pathologic and molecular classifications of breast tumors increasingly important for understanding the epidemiology of breast cancer
• Major challenges to overcome– Small numbers of rare/aggressive subtypes– Uniformity of marker evaluation across studies– Finding robust and reliable markers applicable to
large populations
Thank You