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 nd most common cause of cancer death – Estimated 39,520 breast cancer deaths in 2011 Over 2 million breast cancer survivors in US ACS,

2012 Estimated US Cancer Cases* *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, Men 848,170 Women 790,740 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 Prostate29% Lung & bronchus14% Colon & rectum9% Urinary bladder7% Melanoma of skin5% Kidney5% Non-Hodgkin 4% lymphoma Oral cavity3% Leukemia3% Pancreas3% All Other Sites18%

SEER

Age standardized incidence and mortality rates, 2008 Rates per 100,000 females Incidence Mortality

Krieger, N. Int. J. Epidemiol : ; doi: /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 factors  Age  Gender  Family history  Benign breast disease  Reproductive factors  Endogenous hormones  Exogenous hormones  Adiposity  Diet  Physical activity  Alcohol  Lactation  Radiation  Mammographic 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 Serum 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 – Short term increased risk with pregnancy Younger age at 1 st 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: 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 Day of menstrual cycle Estradiol, pmol/l, or progesterone, nmol/l x Mitotic rate Estradiol Progesterone Mitotic rate

adipose Androgens adrenals Postmenopause ovaries Estrogen Premenopause Estrogen

Estradiol by BMI Serum estradiol pmol/L < ≥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 ± ≥25kg LossNo ChangeGain p-trend<0.001 Relative Risk Eliassen, 2006

Weight Change After Menopause Relative Risk ≥10kg ± ≥10kg LossGain No 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: Age-adjusted incidence of invasive breast cancer, white women, age 45 to 74, California, 1996 to 2004

Serum estradiol pmol/L Menarche Lifetime Exposure to Estradiol PMH & Weight Menopause

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 : ; doi: /jnci/djh025 The distribution of ER and PR tumors among incident invasive breast cancer cases in the NHS ( ) 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<0.001p-trend=0.13 p-heterogeneity= Relative Risk

Weight Change After Menopause Loss No Change Gain p-trend<0.001p-trend=0.75 p-heterogeneity= Relative Risk 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+ tumors0.04 Cases/controls106/430196/643254/54889/ ( )2.3 ( )2.9 ( ) ER- tumors Cases/controls18/43044/64365/54830/ ( )3.0 ( )4.8 ( ) 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 , ,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) TypeNDefinition Luminal A1267ER+ &/or PR+ & HER2- & Grade 1&2 Luminal B321ER+ &/or PR+ & HER2- & Grade 3; ER+ &/or PR+ & HER2+ Her2-type113ER-/PR-/HER2+ Basal-like226ER-/PR-/HER2- & CK5/6+ or EGFR+ Unclassified95ER-/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 StudyN cases MenarcheParityBMI/WtHRTLactation Polish BCS (Yang et al, 2007) 804More with basal than LumA No Diff.Pre BMI ↑ Basal NE Carolina BCS (Millikan et al, 2008) 1424More with basal than LumA ↑ Parity with ↑ basal more than LumA No Diff.NE30% ↓ in basal LACE /Pathways study(Kwan et al 2009) 2544NENo Diff. Ever use with LumA 22% ↓ in basal NHS2,022More 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 StudyN cases MenarcheParityBMIHRTLactation Polish BCS (Yang et al, 2007) 804more with basal than LumA No Diff.Pre BMI ↑ Basal NE Carolina BCS (Millikan et al, 2008) 1424more with basal than LumA ↑ Parity with ↑ basal more than LumA No Diff.NE30% ↓ in basal LACE /Pathways study(Kwan et al 2009) 2544NENo Diff. Ever use with LumA 22% ↓ in basal NHS2,022No 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

Summary +:RR ; ++:RR ; +++:RR ; - :RR

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

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