CHILDHOOD AND ADOLESCENT LIFESTYLE IS DRAMATICALLY RELATED TO LIFETIME CANCER RISK, BUT HOW DO THESE RISK FACTORS OPERATE?Graham A ColditzMay 11. 2017

OverviewEpidemiology shows rates of growth modify risk of pre and postmenopausal breast cancer

Animal models show cell proliferation slows after first full term pregnancy

Parity induce mammary epithelial cells – more stable

Prolactin levels lower

Medina 2005

Cell fate hypothesis¨ Mammary gland post

pubescent female, hormones stimulate proliferation of specific stem cell population, accompanied by molecular switch in these cells that results in persistent changes in regulatory loops governing proliferation and response to DNA damage

Ginger and Rosen 2003

Pike model

¨ Based on epidemiologic data postulated breast tissue age varied according to reproductive risk factors

¨ “To accommodate the higher incidence with late first birth, we add a constant “b” representing an increase in risk with FFTP

Pike et al Nature 1983

Department of SurgeryDivision of Public Health Sciences

Accumulating risk, multiple birth model

Rosner, Colditz, Willett, Am J Epidemiology 1994;139:826

Rat

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agin

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menarche birth birth birth menopause

Department of SurgeryDivision of Public Health Sciences

Accumulating risk, multiple birth model

Rosner, Colditz, Willett Am J Epidemiology 1994;139:826

9% /yr

2.5% /yr

Menarche 1st birth Menopause Current age

Rat

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Department of SurgeryDivision of Public Health Sciences

Parity and receptor status

Number of pregnancies inversely related to incidence of ER+PR+ breast cancer, unrelated to ER-PR-

Age at first pregnancy – menarche is directly related to risk or ER+PR- and ER- PR-RR per 20 years = 1.5

Rosner et al AJE 2013

Department of SurgeryDivision of Public Health Sciences

Why does early life matter

Consistent finding that age at menarche is not related to risk of breast cancer among women who develop benign breast disease (BBD)

For these women who developed BBD, breast ca risk accumulation before menarche is comparable to accumulation per year after menarche (9% / yr), whereas for women without BBD rate of increase is 9% after menarche vs 2% before menarche

Colditz and Rosner AJE 2000

Department of SurgeryDivision of Public Health Sciences

Life-course development of risk accumulation• Long-term effects of early radiation• Menopause – cessation of menstrual cycles leads to

slower risk accumulation• Menopause tells us hormones or accumulation

through premenopausal years must be important• Menarche and height point to early life as important

Department of SurgeryDivision of Public Health Sciences

Long-term effects of radiation in early life

Land et al. Radiation Research 2003

Atomic bomb survivors, 70,16540 year follow-up1059 cases

Department of SurgeryDivision of Public Health Sciences

Model of breast cancer developmentWellings-Jensen Model (JNCI 55:231, 1975)

Adapted from Allred

Time (decades)

TDLU

ADH DCIS IBC­Growth

CCH

Ds Adhesion& Polarity ­Diversity Invasion

Gertig et al 10+ years

Department of SurgeryDivision of Public Health Sciences

Birth, Childhood, Growth • Height velocity• Adiposity• Diet

Department of SurgeryDivision of Public Health Sciences

Understanding growth velocity (Stuart study)

Harvard Growth Study (HGS)Females born in 1930s and 1940s, followed to age 18

§ Age at menarche recorded to month§ Annual height measurements (identify year in which girl

experienced most rapid adolescent height growth)§ Mother interviewed annually on dietary intake over past 6

months while child being examined/measured, etc.

Department of SurgeryDivision of Public Health Sciences

Growth curve of one girl, HGSPeak height velocity = amount of greatest height gain in a single year

Berkey et al. Cancer 1999

Department of SurgeryDivision of Public Health Sciences

Peak height velocity

Berkey et al. Cancer 1999

Department of SurgeryDivision of Public Health Sciences

Predictors measured from birth through age 5, HGS

Age at menarche =12.8 (0.12) – 0.38 (0.12)height at age 3 to 5yr + 2.19 (0.91) vegetable protein ages 3 to 5 yr.

Peak height growth velocity = 14.2 + 4.25 (1.07) calories – 0.39 BMI ages 3 to 5yr + 2.08 (0.95) animal protein ages 3 to 5yr

Results consistent when repeated for exposures at age 10

Berkey, …, Colditz AJE 2000; 152:446-52

Department of SurgeryDivision of Public Health Sciences

Milk and growth velocityPreviously published from GUTS

§ Higher growth velocity increased risk of BBD (Berkey)§ Also, increased risk of pre and postmenopausal breast cancer§ Milk intake positively related to increase in peak height growth

velocity (Berkey CEBP 2009)

Now, meta-analysis of 12 controlled trials§ 0.4cm per year additional height growth for each 8oz

(cup) of milk consumed

De Beer. Dairy products and physical stature. Economics and human biology 2012;10:299-309

Department of SurgeryDivision of Public Health Sciences

Applying peak height growth velocity: Nurses’ Health Study and adolescent cohort (GUTS)

Higher peak height growth velocity (PHGV) associated with increased risk of pre and post menopausal breast cancer• Highest vs. lowest quintile of PHGV; 8.9cm/yr vs. <7.6

cm/yr; § RR=1.31 premenopausal breast cancer§ RR=1.40 postmenopausal breast cancer

For Benign Breast Disease same range in PHGV gave RR = 2.10 Berkey et al. Cancer 1999 & 2011

Department of SurgeryDivision of Public Health Sciences

Danish Cohort confirms growth velocity finding

• 141,393 girls, measured height annually in school• Linked to cancer registry• 3340 cases of breast cancer• Height increase age 8 to 14 positively related to

risk of breast cancer before age 50 and after§ RR per 5 cm = 1.15 (1.05, 1.27): age <50 yr.§ RR per 5 cm = 1.18 (1.07, 1.30): age 50+ yr.

Ahlgren et al. NEJM 2004; 351:1619-26

Department of SurgeryDivision of Public Health Sciences

Childhood adiposity related toEarlier menarche & lower growth height velocity• Significant inverse relation with all molecular

subtypes of breast cancer/ premenopausal and postmenopausal breast cancer§ Baer et al Tamimi et al

• Adiposity at age 7 associated with lower odds of dense breast.§ Anderson et al Breast Ca Res 2014

Department of SurgeryDivision of Public Health Sciences

Validated measure of childhood adiposity, age 5, 10

Significant decrease in risk of premenopausal and postmenopausal breast cancer for each unit increase in body size

Baer et al AJE 2010

Department of SurgeryDivision of Public Health Sciences

Relation to receptor statusInverse relation for adiposity at age 10 to 20 for • ER+ and ER- and for • Her2+ and Her2-• Stronger for ER- / PR-Replicated with central pathology testing of invasive breast cancer cases (Tamimi 2012), BMI at 18 inverse related to basal like BrCa

Effectsofobesityonbreastcancer

• Obesityiswell-establishedasariskfactorforpost-menopausalbreastcancer.

• Obesityisprotectiveforpre-menopausalbreastcancer

23

Cross-TREC Project CA155626, U54 CA155435, U54 CA155496, and PO1 CA 087969)

See Rosner,…., Colditz Br Ca Res Treat 2015 and forthcoming

Study Population• Prospective observational study of 77,232 women in the Nurses’ Health

Study, followed from 1980 to 2012, over 1,590,730 person-years with weight and other breast cancer risk factors updated every 2 years

• 4,965 incident invasive breast cancer cases

• ER/PR status obtained from pathology reports and medical records yielding• 2,412 ER+/PR+ cases• 662 ER-/PR- cases• 598 ER+/PR- casesCases with missing subtype data were censored at the time of diagnosis for subtype-specific analyses

24

0 10 18 30 47 Age(years)

Premenopausal Postmenopausal

50

+kg

Post-menopausalBreastCancerRisk -

1 0.80 0.98 1.36(weightchangefrom18toattained)

Adiposity

1.37(weightchangeaftermenopausaltoattained)

Reference:Rosner,B.,Eliassen,A.H.,Toriola,A.T.,Chen,W.Y.,Hankinson,S.E.,Willett,W.C.,...&Colditz,G.A.(2017).Weightandweightchangesinearlyadulthoodandlaterbreastcancerrisk. Internationaljournalofcancer, 140(9),2003-2014.

+kg+kg

Age(years)

-1

Pre-menopausalBreastCancerRisk

0.66 0.74 1.0

0 10 18 30 47 Age(years)

Premenopausal Postmenopausal

50

+kg

Post-menopausalBreastCancerRisk -

1 0.80 0.981.36 1.36(weightchangefrom18toattained)

Adiposity

1.37(weightchangeaftermenopausaltoattained)

Reference:Rosner,B.,Eliassen,A.H.,Toriola,A.T.,Chen,W.Y.,Hankinson,S.E.,Willett,W.C.,...&Colditz,G.A.(2017).Weightandweightchangesinearlyadulthoodandlaterbreastcancerrisk. Internationaljournalofcancer, 140(9),2003-2014.

+kg+kg

Age(years)

-1

Pre-menopausalBreastCancerRisk

0.66 0.74 1.0

ER-/PR-BreastCancerRiskRR/30kg

0.73(0.55-0.98)

0.70(0.46-1.05) Weightchangeunrelatedtorisk

Department of SurgeryDivision of Public Health Sciences

Other consistent relations TNBC• Lactation decreases risk of triple negative breast

cancer

• Short term weight gain increases risk• Premenopausal short term weight gain increased

risk of ER+/PR- and ER-/PR- but not ER+PR+ breast cancer

• Postmenopausal weight gain related to ER+PR+

Department of SurgeryDivision of Public Health Sciences

Mechanisms and prevention • What are the mechanisms underlying these

consistent findings• How can we harness these pathways for prevention?

Bernard Rosner, Catherine Berkey, Rulla Tamimi, Stuart Schnitt, Laura Collins, Jim Connolly, Tunji Toriola, Aliya Alimujiang, Siobhan SutcliffeBreast Cancer Research Foundation for support

Thank collaborators

Thank collaborators