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