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Risk factors for Breast Cancer Caroline Antoine

Menopause Clinic - OBGYN Department

CHU Saint-Pierre – Brussels

caroline_antoine@stpierre-bru.be

Belgian Menopause Society Symposium – October 2016

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BC incidence and mortality

rates • BC = first cancer in women worldwide (25%)

• Belgium: highest incidence in the world (35%)

• Incidence rates similar in the 3 regions of Belgium and stable over time

• BC mortality = first cause of death by cancer in women in Belgium in 2012 (20% of all cancer deaths)

• Mortality rates decrease by 2% annualy

Ferlay et al. IJC 2012; Cancer burden in Belgium 2004-2013, Belgian Cancer Registry, Brussels 2015

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BC risk factors

• Numerous BC risk factors: well established / still under study

• Most women with BC (75%) don’t have identified risk factors

• Some risk factors cannot be changed

(i.e. being a woman, age and personal or family history of BC, genetic, etc.)

• Others are related to lifestyle

(i.e. BMI, alcohol consumption, having children , use of OC, MHT, etc.)

• Some may be influenced by the environment

(i.e. age of menarche, having children, age at first child, …)

• Some are probably influenced by genetic and environmental factors

(i.e. breast density)

Falkenberry et al. Obstetrics and Gynecology Clinics of North America 2002, Singletary. Annals of Surgery 2003, Boyd et al. Lancet 2005

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BC risk factors

• Personal and family history of BC, having atypical hyperplasia or genetic predisposition have a pronounced impact on BC risk

• Behavioural risk factors for BC have a modest impact on BC risk

(they don’t have the same magnitude of effect as for instance, cigarette smoking for lung cancer: It has been estimated that in the UK, in 2010, 83.6% of lung cancers were due to tobacco whereas only 26.8% of BC were due to all lifestyle and environmental factors)

• Healthy life style should be promoted

Singletary. Annals of Surgery 2003, Parkin et al. BJC 2011, Cancer Research UK, accessed July 2016

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High risk factors > 4 fold

• Age

• BRCA mutation

• High risk family history without mutation

• Biopsy with atypical hyperplasia

• LCIS

• DCIS

• Personal history of invasive BC

• Therapeutic ionizing radiation

• Increased breast density at mammography (≥75%)

RR 5.8-6.5

RR 15-200

RR 1.4-13.6

RR 5.3

RR16.4

RR 17.3

RR 6.8

RR 5.2

RR 4.64 (95%CI 3.64-5.91)

Easton et al. Am J Hum Genetic 1995, Armstrong et al. NEJM 2000, Singletary. Annals of Surgery 2003, McCormack et al. Cancer Epidemiol Biomarkers Prev 2006

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Intermediate risk factors ≤ 2

• Obesity

• Reproductive factors – Early menarche

– Late menopause

– Age at FFTP

• Alcohol

• MHT

RR 1.58 (95%CI 1.40-1.79)

– RR 1.2-1.5

– RR 1.3-2.0

– RR 1.27 (95%CI 1.07-1.50)

RR 1.43 (95%CI 1.02-2.02)

RR 1.3-1.5

Armstrong et al. NEJM 2000, Singletary. Annals of Surgery 2003, Ma et al. Br Cancer Res 2006, McCormack et al. Cancer Epidemiol Biomarkers Prev 2006, Zhang et al. Am J Epidemiol 2007, Neuhouser et al. JAMA oncol 2015

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Factors decreasing the risk of BC

• Breastfeeding

• Multiparity

• Physical activity

RR 0.77 (95%CI 0.66-0.88)

RR 0.89 (95%CI 0.84-0.94)

RR 0.88 (95%CI 0,85-0,90)

Lynch et al. Recent Results Cancer Res 2011, Lambertini et al. Cancer Treat Rev 2016, Pizot et al. EJC 2016

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Being overweight or obese

• After menopause increases BC risk

(maybe because fat tissue produces an important part of estrogens)

• In post menopausal women with a normal BMI, gain weight (more than 5% of body weight) increases BC risk

• In pre-menopausal women, an increased BMI may be associated with a lower risk of BC (not found to be statistically significant in all studies)

A high BMI in post menopausal women is associated with a raise of insulin and IGFs. A high BMI in pre menopausal women is associated with a low circulating level of IGF-1. Findings unclear, need further investigations

Key et al. JNCI 2003, Singletary. Annals of Surgery 2003, Lukanova et al. Eur J Endocrinol 2004, Suzuki et al. Int J Cancer 2009, Fowke et al. Endocr Relat Cancer 2010, Parkin et al. BJC 2011, Cheraghi el al. PLoS One 2012, Neuhouser et al. JAMA Oncol 2015

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Alcohol consumption

• Increases BC risk

(in low (<1 drink/day) and high (≥3 drinks/day) levels of alcohol consumption, compared with abstainers)

• BC risk increases with a higher consumption and particularly in women who drink alcohol in excess

Hamajima et al – Collaborative Group on Hormonal Factors in Breast Cancer. BJC 2002, Zhang et al. Am J Epidemiol 2007, Chen et al. JAMA 2011, Schütze et al. BMJ 2011 – EPIC study, Cao et al. BMJ 2015

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Menopausal hormone therapy

• BC risk increases with MHT use:

• For 5 years or longer

• Combined MHT > Estrogens only therapy

• Greater risk if MHT initiated within 5 years of menopause

• Increased MHT duration of use

• Whatever the estrogen type and route of administration

• Continuous MHT > Sequential MHT

• Synthetic progestins > Micronized progesterone and dydrogesterone

Rossouw et al. 2002, Beral et al. 2003, Tjonneland et al. 2004, Chen et al. 2006, Stefanick et al. 2006, Anderson et al. 2006, Fournier et al. 2008, Prentice et al. 2008, Fournier et al. 2009, Lyytinen et al. 2009, Bakken et al. 2011, Beral et al. 2011, Fournier et al. 2014, Chlebowski et al. JAMA 2015

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Breastfeeding and number of births

• In the collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries:

• BC RR decreases by 4.3% (95% CI 2.9 – 5.8; p<0.0001) for every 12 months of breastfeeding

• BC RR decreases by 7.0% (95% CI 5.0 – 9.0; p<0.0001) for each birth

• BC risk is increased in women with a first birth late in life (after age 35 years)

Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 2002, Ma et al. Breast Cancer Res 2006

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Physical activity

• High level of physical activity reduces BC

• Risk protection does not seem to be influenced by the type of physical activity (occupational or non-occupational), adiposity, and menopausal status

• Risk protection increased with increasing amounts of physical activity without threshold effect

It is likely that physical activity is associated with decreased BC risk via multiple interrelated biologic pathways that may involve adiposity, circulating sex hormones levels , insulin resistance, adipokines, and chronic inflammation

Lynch et al. Recent Results Cancer Res 2011, Pizot et al. EJC 2016

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Breast density at

mammography • Women with a density of more than 75% of the breast have a 4-5 times

greater risk of BC

• Breast density is highly heritable

• BMI, parity, menopausal status and MHT are also associated with breast density

Boyd et al. NEJM 2002, Boyd et al. Lancet Oncol 2005, McCormack et al. Cancer Epidemiol Biomarkers Prev 2006

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Possible BC risk factors

• Insulin growth factor-1 (IGF-1)

• Type 2 diabetes

• Cigarette smoking / environmental tobacco exposure

• Oral contraception use

• Night shift work

• Medications • Metformin / Insulin / Sulfonylurea

• Biphosphonates

• Statins

• Anti hypertensive drugs

• NSAID

• Vitamine D

Del Giudice et al. Br C Res treat 1998, Boyle et al. BJC 2012, De Bruijn et al. Br J Surg 2013, Macacu et al. Br C Res 2015, Gong et al. Int J Cancer 2016

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Summary

• BC has numerous risk factors but most women with BC don’t have any of them

• BC risk factors with a pronounced impact on BC risk are inherited or can’t be changed

• About 25% of BC are attributable to lifestyle BC risk factors

• Healthy life-style should then be promoted

In the center of the city, in the center of life, with passion for care

In the center of the city, in the center of life, with passion for care