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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

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Epidemiology of breast cancer


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    1. Epidemiology of breast cancer Rulla Tamimi, ScD Associate Professor of Medicine Harvard Medical School

    2. 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

    3. 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

    4. 2012 Estimated US Cancer Cases* 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% *Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Source: American Cancer Society, 2011.

    5. SEER

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

    7. Trends in breast cancer incidence in the US Krieger, N. Int. J. Epidemiol. 2008 37:627-637; doi:10.1093/ije/dyn055

    8. 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

    9. 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

    10. 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

    11. Risk factors

    12. 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

    13. Lifetime exposure to estradiol Serum estradiol pmol/l 500 400 300 200 100 0 0 10 20 30 40 50 60 70 80 Menopause Menarche

    14. Trend in age at menarche

    15. 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

    16. Colditz and Rosner, Am J Epidemiology 2000;152:950-64

    17. 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

    18. Duration of breast feeding Collaborative Group on Hormonal Factors in Breast Cancer, Lancet 2002

    19. 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

    20. Colditz and Rosner, Am J Epidemiology 2000;152:950-64

    21. 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

    22. Pike model of breast tissue ageing

    23. Hormones and breast cancer • Endogenous • Premenopausal • Postmenopausal • Exogenous

    24. 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??

    25. Estradiol, progesterone, and mitotic rate of breast epithelial cells Estradiol, pmol/l, or progesterone, nmol/l x 10 Mitotic rate 700 3.0 Mitotic rate 600 2.5 Progesterone 500 Estradiol 2.0 400 1.5 300 1.0 200 0.5 100 0 0.0 1 8 15 22 Day of menstrual cycle Based on data from Ferguson & Anderson et al 1981, Williams et al 1991

    26. Estrogen Estrogen Premenopause adrenals Postmenopause Androgens ovaries adipose

    27. Estradiol by BMI Serum estradiol pmol/L Endogenous Hormones Collaborative Group JNCI 2003 <22.5 22.5-24.9 25.0-27.4 27.5-29.9 ≥30.0 BMI

    28. 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

    29. Study-specific results for total estradiol Endogenous Sex Hormones Group, JNCI, 2002;94:617-29

    30. JNCI, 2002

    31. 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

    32. Colditz and Rosner, Am J Epidemiology 2000;152:950-64

    33. Weight Change Since Age 18 2.5 2.0 1.5 1.0 0.5 0.0 p-trend<0.001 Relative Risk ≥10kg 5-9.9 2-4.9 ±22-4.9 5-9.9 10-19.9 20-24.9 ≥25kg Loss No Change Gain Eliassen, 2006

    34. Weight Change After Menopause 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 p-trend=0.002 Relative Risk ≥10kg 5-9.9 2-4.9±22-4.9 5-9.9 ≥10kg No Change Loss Gain

    35. Postmenopausal hormone use by type and duration

    36. Risk post cessation of PMH Collins et al, Human Reproduction Update 2005

    37. Age-adjusted incidence of invasive breast cancer, white women, age 45 to 74, California, 1996 to 2004 Robbins, A. S. et al. J Clin Oncol; 25:3437-3439 2007

    38. Lifetime Exposure to Estradiol Serum estradiol pmol/L 500 400 300 200 100 0 0 10 20 30 40 50 60 70 80 Menopause Menarche PMH & Weight

    39. 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

    40. 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

    41. Collaborative Group on Hormonal Factors in Breast Cancer

    42. 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

    43. 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

    44. Incorporating pathology in breast cancer epidemiology

    45. 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

    46. 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). Colditz, G. A. et al. J. Natl. Cancer Inst. 2004 96:218-228; doi:10.1093/jnci/djh025

    47. Weight Change Since Age 18 ER+/PR+ ER-/PR- 4 3 2 1 Relative Risk p-trend<0.001 p-trend=0.13 p-heterogeneity=0.01 ----Loss---- No Change ------------Gain------------ ----Loss---- No Change ------------Gain------------

    48. Weight Change After Menopause ER+/PR+ ER-/PR- 2 1 Relative Risk p-trend<0.001 p-trend=0.75 p-heterogeneity=0.02 -------Loss------- No Change --------Gain------- -------Loss------- No Change --------Gain-------

    49. Association between mammographic density and ER status Yaghjyan et al, 2011

    50. Breast cancer subtypes Sorlie et al, 2003