IJC

International Journal of Cancer

Healthy lifestyle and risk of breast cancer among

postmenopausal women in the European Prospective
Investigation into Cancer and Nutrition cohort study
Fiona McKenzie1,2, Pietro Ferrari1, Heinz Freisling1, Veronique Chajès1, Sabina Rinaldi1, Jordi de Batlle1,
Christina C Dahm3, Kim Overvad3, Laura Baglietto4,5, Laureen Dartois6,7,8, Laure Dossus6,7,8, Pagona Lagiou9,10,11,
Dimitrios Trichopoulos10,11,12, Antonia Trichopoulou12, Vittorio Krogh13, Salvatore Panico14, Rosario Tumino15,
Stefano Rosso16, H. B(as) Bueno-de-Mesquita17,18,19, Anne May20, Petra H Peeters19,20, Elisabete Weiderpass21,22,23,24,
Genevieve Buckland25, Maria-Jose Sanchez26,27, Carmen Navarro27,28,29, Eva Ardanaz27,30, Anne Andersson31,
Malin Sund32, Ulrika Ericson33, Elisabet Wirfa€lt33, Tim J Key34, Ruth C Travis34, Marc Gunter19, Elio Riboli19,
Anne-Claire Vergnaud and Isabelle Romieu1
19

1
International Agency for Research on Cancer (IARC), Lyon, France
2
Centre for Public Health Research, Massey University, Wellington, New Zealand
3
Department of Public Health, Aarhus University, Aarhus, Denmark
4
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
5
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia
6
INSERM, Centre for Research in Epidemiology and Population Health (CESP), Villejuif, France
7
Paris South University, UMRS 1018, Villejuif, France
8
Institute Gustave Roussy, Villejuif, France
9
Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece
10
Department of Epidemiology, Harvard School of Public Health, Boston
11
Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece
12
Hellenic Health Foundation, Athens, Greece
13
Epidemiology and Prevention Unit, IRCCS Foundation, National Cancer Institute, Milan, Italy
14
Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
15
Cancer Registry and Histopathology Unit, “Civile - M.P.Arezzo” Hospital, Ragusa, Italy
16
Piedmont Cancer Registry, Centre for Epidemiology and Prevention in Oncology in Piedmont, Turin, Italy
17
National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
18
Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands
19
School of Public Health, Imperial College London, United Kingdom
20
Julius Center, University Medical Center Utrecht, Utrecht, The Netherlands

Key words: breast cancer, healthy index, lifestyle, prospective studies, Europe
Abbreviations: AICR: American Institute for Cancer Research; CI: confidence interval; EPIC: European Prospective Investigation into
Epidemiology

Cancer and Nutrition; ER: oestrogen receptor; HLIS: healthy lifestyle index score; HR: Hazard ratios; HRT: hormone replacement ther-
apy; OC: oral contraceptive; PR: progesterone receptor; WCRF: World Cancer Research Fund.
Additional Supporting Information may be found in the online version of this article.
Grant sponsor: Genesis Oncology Trust; Grant sponsor: European Commission (DG-SANCO), the International Agency for Research on
Cancer; Grant sponsor: Danish Cancer Society (Denmark); Grant sponsor: Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle
Generale de l’Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Grant sponsor: Deutsche
Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Grant sponsor: Hellenic Health
Foundation (Greece); Grant sponsor: Italian Association for Research on Cancer (AIRC) and National Research Council (Italy); Grant
sponsor: Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch
Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The
Netherlands); Grant sponsor: ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and
Health. (Norway); Grant sponsor: Health Research Fund (FIS) of the Spanish Ministry of Health (ISCIII RETICC RD06/0020/0091) the
Catalan Institute of Oncology, and the participating regional governments and institutions of Spain (Spain); Grant sponsor: Swedish Cancer
Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); Grant sponsor: Cancer Research UK,
Medical Research Council, Stroke Association, British Heart Foundation, Department of Health, Food Standards Agency, and Welcome Trust
(United Kingdom)
DOI: 10.1002/ijc.29315
History: Received 11 Apr 2014; Accepted 19 Sep 2014; Online 7 Nov 2014
Correspondence to: Fiona McKenzie, IARC, 150 cours Albert Thomas, Lyon 69008, France, Tel.: 133-4-72738389, Fax: 133-4-72738320,
E-mail: mckenzief@iarc.fr

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McKenzie et al. 2641

21
Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway
22
Department of Research, Cancer Registry of Norway, Oslo, Norway
23
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
24
Samfundet Folkh€alsan, Helsinki, Finland
25
Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
26
Andalusian School of Public Health, Granada Bio-Health Research Institute (Granada.IBS), Granada, Spain
27
CIBER Epidemiology and Public Health (CIBERESP), Spain
28
Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain
29
Department of Health and Social Sciences, Universidad de Murcia, Murcia, Spain
30
Navarre Public Health Institute, Pamplona, Spain
31
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
32
Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden
33
Department of Clinical Sciences in Malmo €, Lund University, Sweden
34
Cancer Epidemiology Unit, University of Oxford, United Kingdom

Breast cancer is the most common cancer among women and prevention strategies are needed to reduce incidence worldwide.
A healthy lifestyle index score (HLIS) was generated to investigate the joint effect of modifiable lifestyle factors on postmeno-
pausal breast cancer risk. The study included 242,918 postmenopausal women from the multinational European Prospective
Investigation into Cancer and Nutrition (EPIC) cohort, with detailed information on diet and lifestyle assessed at baseline. The
HLIS was constructed from five factors (diet, physical activity, smoking, alcohol consumption and anthropometry) by assigning
scores of 0–4 to categories of each component, for which higher values indicate healthier behaviours. Hazard ratios (HR) were
estimated by Cox proportional regression models. During 10.9 years of median follow-up, 7,756 incident breast cancer cases
were identified. There was a 3% lower risk of breast cancer per point increase of the HLIS. Breast cancer risk was inversely
associated with a high HLIS when fourth versus second (reference) categories were compared [adjusted HR 5 0.74; 95% confi-
dence interval (CI): 0.66–0.83]. The fourth versus the second category of the HLIS was associated with a lower risk for hor-
mone receptor double positive (adjusted HR 5 0.81, 95% CI: 0.67–0.98) and hormone receptor double negative breast cancer
(adjusted HR 5 0.60, 95% CI: 0.40–0.90). Findings suggest having a high score on an index of combined healthy behaviours
reduces the risk of developing breast cancer among postmenopausal women. Programmes which engage women in long term
health behaviours should be supported.

What’s new?
How much does behavior really affect cancer risk? These authors set out to measure just that. First, they created a Healthy
Lifestyle Index, which quantified five modifiable behaviors, such as smoking and physical activity. Then, using data from the
European Prospective Investigation into Cancer and Nutrition (EPIC), they assigned each participant a score between 0 and 4

Epidemiology
on each of the behaviors. It turned out that with each point added to a person’s Healthy Lifestyle Index score, breast cancer
risk fell by 3%, suggesting that public programs to help women maintain these behaviors could be worthwhile for cancer
prevention.

Breast cancer is the most common cancer among women
with an estimated 1.4 million new cases diagnosed worldwide
in 2008, almost one quarter of all female cancers. It is the
most common cancer in both developed and developing
regions; the highest reported incidence for breast cancer is in
Western Europe, with a rate of approximately 90 cases per
100,000 women.1
A number of established risk factors for breast cancer
have been identified, including age, reproductive history, hor-
mone levels/use, family history of breast cancer, breast den-
sity and adult attained height.2–6 In addition to these,
individual modifiable lifestyle factors have been shown to be
associated with breast cancer risk such as diet,7–10 physical
activity,11,12 smoking,13,14 alcohol consumption,15,16 and body
fatness.17,18 As people have a propensity to follow common
behavioral patterns,19 and such lifestyle factors are often clus-
tered, it seems prudent to investigate these lifestyle factors
jointly.
There is accumulating evidence associating combined life-
style factors, or patterns of behavior, to cardiovascular dis-
ease19,20 and diabetes,21 and most recently, to cancer.22,23 The
benefit of adhering to a healthy lifestyle has been quantified
specifically in relation to breast cancer risk for Mexican
women,24 where in a case–control study an 80% lower risk
was observed for postmenopausal women when comparing
breast cancer risk in the highest to the lowest quintile of a

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 2642
healthy lifestyle index constructed by means of principal
components.
There is mounting literature on the relationship between
nutrition and breast cancer. Several dietary components have
reported associations that are supported by a biological plau-
sibility25 but for which current evidence is too limited to per-
mit a probable causal judgement in their aetiological role.11
Fibre,26,27 folate,28 carbohydrates,29,30 and different fatty
acids31–34 have all been posited to affect breast cancer risk,
have all been reviewed,25,35,36 and all remain suggestive of a
causal relationship.37
A recent study assessed the association between concord-
ance with World Cancer Research Fund (WCRF)/American
Institute for Cancer Research (AICR) overall cancer preven-
tion guidelines and subsequent cancer risk, including breast
cancer, in the European Prospective Investigation into Cancer
and Nutrition (EPIC) cohort and reported a protective effect
of adhering to the guidelines.38 To further investigate breast
cancer risk and lifestyle behaviors in the EPIC cohort, a
breast cancer specific a priori health index was created based
on posited dietary components, high physical activity, avoid-
ance of smoking, no alcohol consumption and low BMI as
previously proposed,19,21,39 and then used to assess the asso-
ciation of a healthy lifestyle index with the risk of breast can-
cer in the study cohort.
Methods
Study population
EPIC is a large prospective cohort study across 23 centres in
10 European countries (Denmark, France, Germany, Greece,
Italy, the Netherlands, Norway, Spain, Sweden and the
United Kingdom).40 The cohort of 521,330 healthy men and
women recruited from 1992 to 2000, and aged between 25
and 70 years, was primarily designed to investigate the link
between nutrition, dietary habits and lifestyle and cancer
Epidemiology
incidence. Participants were enrolled from the general popu-
lation, within defined geographical or administrative areas,
with exceptions for France (national health insurance scheme
members), Utrecht and Florence (breast cancer screening
participants), Oxford (health conscious, mainly vegetarian,
volunteers) and some centres from Italy and Spain (blood
donor participants). The rationale for EPIC, study design and
methods have been described in detail elsewhere.40 The study
obtained ethical approval from participating centres and
IARC ethics committees. Informed consent was given by all
study participants.
Data collection and follow-up
Validated country-specific questionnaires were completed by
participants at baseline, including self-administered semi-
quantitative food frequency questionnaires or interviewer-
administered diet history questionnaires, and semi-
quantitative food frequency questionnaires to measure usual
intakes.41 In an 8% random sub-sample, standardized
interviewer-administered 24-hr recalls were collected in a cal-
Postmenopausal breast cancer risk
ibration study.42 Energy intake was estimated using the
harmonized EPIC nutrient database.43 Sociodemographic
information, physical activity, alcohol consumption, smoking
and medical and reproductive history were captured from
lifestyle questionnaires, and anthropometric measurements
taken at all centres (except Oxford and France, where they
were self-reported).40
Follow-up was done through cancer registries in Den-
mark, Italy, the Netherlands, Norway, Spain, Sweden and the
UK. For France, Germany and Greece, follow-up was done
via health insurance records, cancer/pathology registrations
and through participants and their next-of-kin. Follow-up
began at date of enrolment and ended at date of cancer diag-
nosis, death, or last complete follow-up (December 2004 to
June 2010, depending on the centre), whichever came first.
Breast cancer cases were defined as first primary invasive
breast tumours (coded C50.0 to 50.9 using the 10th Revision
of International Statistical Classification of Diseases). Infor-
mation on oestrogen receptor (ER) and progesterone receptor
(PR) statuses was provided by each centre on the basis of
pathology reports.
The original EPIC cohort comprised 367,993 women;
334,848 after the exclusion of women with prevalent and
recurring cancers or missing follow-up information (23,053),
missing dietary or lifestyle questionnaires (3,339), and those in
the top or bottom 1% of the ratio of energy intake to energy
requirement (6,753). Energy requirement is calculated as basal
metabolic rate times the moderate physical activity level of
1.55. The current study was based on data from 242,918 post-
menopausal women (premenopausal n 5 37,236), following
exclusions of women with in situ cases (1,349) and missing
data for the components of the lifestyle index (53,345), includ-
ing all women from Umea in Sweden and Norway, where
information on physical activity was not collected.
Index construction
Score for diet. Intakes of seven dietary factors were com-
bined for the diet score: cereal fibre, folate, the ratio of poly-
unsaturated to saturated fat, fatty fish (as a marker for
omega-3 fatty acids), margarine (as a marker for industrially
produced trans-fats), glycemic load and fruits and vegetables.
Consumption of dietary components were grouped into
country-specific deciles and scored from 0 to 9 (inverse for
trans-fat and glycemic load), with 0 being least healthy con-
sumption. Overall ranges for each dietary component are
shown in Supporting Information Table 1. The individual
scores were summed to a total diet score, and then categor-
ised into quintiles. For one centre (Potsdam, Germany),
which did not have food frequency data specifically for fatty
fish, consumption of total fish was weighted based on the
fatty fish proportions of total fish reported in 24-hr recalls of
the calibration study.42
Score for health index. The overall health index was deter-
mined by assigning scores of 0–4 to each individual variable
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McKenzie et al. 2643

Table 1. Distribution of postmenopausal women and breast cancer bles, and percentages for categorical variables. Cox propor-
cases by country in the European Prospective Investigation into Can- tional hazard regression models were used to estimate
cer and Nutrition cohort study, 1992–2000
associations between the healthy lifestyle index and breast
Age1 Follow-up cancer. Age was used as the primary time variable, with entry
Country Cohort (Median) Cases (Median) Person-years
time defined as age at study entry, and exit time as age at
Denmark 28,038 56.2 1,241 11.6 309,699 diagnosis of breast cancer or censoring (which ever occurred
France 62,766 51.6 2,310 9.9 576,428 first).
Germany 21,567 52.5 601 8.3 170,890 Hazard ratios (HR) and 95% confidence intervals (CI)
Greece 11,884 58.3 140 10.0 104,357 were stratified by centre, to control for centre-specific effects,
Italy 27,999 51.8 779 10.5 256,685
and 1-year age bands (age at study entry). Models were
adjusted by height (continuous), age at menarche (<12, 12–
Netherlands 20,210 55.0 684 11.7 218,174
14, >14, unknown), age at full term pregnancy (nulliparous,
Spain 21,719 50.0 332 10.5 196,607 <21, 21–30, >30, unknown), education (none/primary, sec-
Sweden 13,800 56.6 637 13.7 178,101 ondary/technical, university, unknown), oral contraceptive
UK 34,935 52.9 1,032 10.8 332,134 (OC) use (never, ever, unknown), hormone replacement ther-
Total 242,918 53.2 7,756 10.9 2,343,075 apy (HRT) use (never, ever, unknown), breastfeeding (never,
ever, unknown), total energy intake excluding alcohol (con-
1
Age at beginning of follow-up. tinuous). The healthy index was modelled as a continuous
and categorical variable (5, 6–10, 11–15, 16), using the
category, for which a higher point value indicates a healthier second lowest scoring group as the reference category. The
behavior. The health index ranged from 0 to 20. Healthiest test for trend was performed by assigning median values of
behavior was defined as never smoking (never 5 4, ex- each of the four categories of the index, which was then
smokers quit > 10 years 5 3, ex-smokers quit  10 years 5 2, modelled as a continuous variable. Heterogeneity of associa-
current  15 cigarettes/day 5 1, current > 15 cigarettes/day- tion by BMI and HRT was assessed with interaction terms
5 0), no consumption of alcohol (none 5 4, 0.1–4.9 (g/day)- and associated log likelihood ratio tests; no evidence of inter-
5 3, 5.0–9.9 (g/day) 5 2, 10.0–19.9 (g/day) 5 1, > 20 (g/ action was found. Separate models were fitted according to
day) 5 0), top quintile of physical activity based on recrea- the breast cancer hormone receptor status: ER positive and
tional and household metabolic equivalent tasks (5th PR positive, and ER negative and PR negative tumours, while
quintile 5 4, 4th quintile 5 3, 3rd quintile 5 2, 2nd censoring other combinations of tumour hormone receptors.
quintile 5 1, 1st quintile 5 0), BMI in the bottom quintile Two-sided p-values are provided with statistical signifi-
(1st quintile 5 4, 2nd quintile 5 3, 3rd quintile 5 2, 4th cance set at p < 0.05. All analyses were performed using Stata
quintile 5 1, 5th quintile 5 0) and a healthy diet i.e., high in version 11.
cereal fibre, folate, fatty fish, with a high ratio of polyunsatu-
rated to saturated fat, high intake of fruits and vegetables and Results
low in margarine/trans-fat and glycemic load (5th Among the total of 242,918 postmenopausal women, there

quintile 5 4, 4th quintile 5 3, 3rd quintile 5 2, 2nd
quintile 5 1, 1st quintile 5 0).
Statistical analysis. Menopausal status was provided at time
of recruitment; women were considered as postmenopausal
when they reported not having had any menses over the past
12 months, or when they reported bilateral ovariectomy.
Women with missing or incomplete questionnaire data, or
with reported previous hysterectomy, were considered post-
menopausal only if they were older than 55 years. Women
were considered with unknown menopausal status when they
were between 46 and 55 years of age, and had missing or
incomplete questionnaire data, or reported previous hysterec-
tomy (without ovariectomy). For these analyses, a cut-point
of 50 years (median age of menopause within EPIC) was
used for age of menopause among those women which were
pre and perimenopausal at recruitment, and this was consid-
ered as point of entry into the study.
Descriptive statistics are provided by cross tabulations
with medians and inter-quartile ranges for continuous varia-
Epidemiology
were 7,756 first primary incident breast cancer cases recorded
during a median follow-up time of 10.9 years and 2,343,075
accumulated person-years. The median age at start of follow-
up was 53.2 years. Table 1 shows the numbers of cohort par-
ticipants, median ages at entry, frequencies of breast cancer
cases, and follow-up years for each EPIC country in the
study.
Table 2 shows medians, or percentages, for each compo-
nent of the healthy lifestyle index, and for each covariate
characteristic. Across categories of the index score, total
energy intake was slightly higher among the healthy behavior
groups. The percentage of women educated below secondary
level increased among the healthy behavior groups, as did the
percentage of women who had ever breastfed. The frequency
of OC and HRT use declined across the least healthy to most
healthy behavior categories of the index.
Table 3 shows the scoring system used for the individual
components of the healthy lifestyle index, and the corre-
sponding HR and 95% CI for each component score and
breast cancer, adjusted for the other covariates. Healthy

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 2644 Postmenopausal breast cancer risk

Table 2. Characteristics of postmenopausal women in the European Prospective Investigation into Cancer and Nutrition cohort study accord-
ing to healthy lifestyle index category, 1992–2000
1 (5 points) 2 (6–10 points) 3 (11–15 points) 4 (16 points) All
Index component
Diet score (units) 24 (21–29) 29 (24–34) 34 (29–39) 40 (23–43) 32 (26–37)
Alcohol (g/day) 20.3 (10.6–31.7) 8.5 (1.9–17.9) 2.3 (0.3–8.0) 0.4 (0–2.6) 4.2 (0.6–12.2)
Physical activity (METS/week) 41 (29–59) 62 (40–90) 99 (66–136) 140 (107–167) 82 (51–123)
BMI (kg/m2) 27 (24–30) 25 (22–28) 24 (21–27) 22 (20–24) 25 (22–28)
Smoking (% ever) 96 70 34 12 49
Covariate
Age at entry (years) 53 (50–58) 53 (50–59) 54 (50–60) 53 (50–60) 53 (50–59)
Height (cm) 162 (158–166) 162 (158–166) 161 (156–165) 161 (157–166) 161 (157–166)
Age at menarche (years) 13 (12–14) 13 (12–14) 13 (12–14) 13 (12–14) 13 (12–14)
Age at full term pregnancy (years) 24 (21–27) 24 (22–27) 25 (22–27) 25 (23–28) 24 (22–27)
Energy intake (kcal/day) 1752 (1437–2122) 1837 (1518–2212) 1875 (1557–2250) 1916 (1588–2304) 1858 (1538–2234)
Nulliparity (%) 5 3 2 3 3
Education (% below secondary) 28 28 35 35 32
OC use (% ever) 62 59 52 47 55
HRT use (% ever) 33 30 26 23 27
Breastfeeding (% ever) 64 67 70 72 69

Values are medians (25th–75th percentiles) unless otherwise specified.

behaviors were inversely associated to breast cancer risk;
although not all components and score levels reached statisti-
cal significance.
Modelled as a continuous variable, there was a 3% lower
risk (adjusted HR 5 0.97, 95% CI: 0.96–0.98) of breast cancer
per point score of the index. Table 4 shows the crude and
adjusted HRs and 95% CIs for the association between the
healthy lifestyle index and breast cancer for all women, and
by tumour hormone status. For all women, there was a 26%
lower risk (adjusted HR 5 0.74, 95% CI: 0.66–0.83) of breast
Epidemiology
24-hr recall means. To account for possible misclassification
due to high-energy intakes, models were run based on the
residuals from the regression of dietary components on total
energy intake. These results (not shown) were not notably
different from the uncorrected models reported.
Sensitivity analyses were performed to assess the robust-
ness of the findings. Models were run separately for North-
ern, Central and Southern European based centres and no
material difference in results (not shown) were observed.
Reverse causality was tested through the exclusion of women

cancer in the fourth category of the index (most healthy)
compared to the second (reference) category of the index
score. Women in the first category (least healthy) had a 19%
greater risk of breast cancer compared to their counterparts
in the second (reference) category of the index score
(adjusted HR 5 1.19, 95% CI: 1.07–1.31). There was a lower
risk for women with both hormone receptor double positive
and double negative breast cancer, comparing the fourth cat-
egory to the reference category of the index score (adjusted
HR 5 0.81, 95% CI: 0.67–0.98 and 0.60, 95% CI: 0.40–0.90,
respectively).
To investigate the possibility of confounding by family
history of breast cancer, this was included, and models rerun
for those centres that had family history available (42% of
the women, n 5 102,579). There was no notable change in
results from the ones presented here.
To account for measurement errors in reporting food con-
sumptions, the dietary components were additionally rescaled
by country-specific differences between food frequency and
whose breast cancer diagnosis was within their first 2 years
of follow-up; these results (not shown) did not differ from
those of the entire cohort. Further analyses were performed
with the exclusion of women with a BMI of less than
18.5 kg/m2, and with the exclusion of energy intake under-
reporters, using the Goldberg cut-off for physical activity
level 1.14.44 Finally, the analyses were rerun with the exclu-
sion of former drinkers from the non-drinker category. None
of the sensitivity analyses materially altered results or
changed interpretation of findings.
Discussion
This study based on a large prospective cohort has found a
lower risk of breast cancer in postmenopausal women with
healthier lifestyles. Findings suggest that modification of
behavior resulting in a one point increase in the healthy life-
style index score correspond to a 3% lower breast cancer risk.
All individual components of the healthy lifestyle index
were significantly associated with breast cancer risk, except

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McKenzie et al. 2645

Table 3. Associations for healthy lifestyle index components and breast cancer risk among postmenopausal women in the European Prospec-
tive Investigation into Cancer and Nutrition cohort study, 1992–2000
Index component Score HR 95% CI p–trend
Diet
1st quintile (3–25) 0 1 Reference 0.005
2nd quintile (26–30) 1 0.93 0.87, 0.99
3rd quintile (31–34) 2 0.98 0.91, 1.06
4th quintile (35–39) 3 0.89 0.83, 0.95
5th quintile (40–63) 4 0.90 0.84, 0.97
BMI
5th quintile (29 1) 0 1 Reference <0.001
4th quintile (26–29) 1 0.91 0.84, 0.98
3rd quintile (24–26) 2 0.92 0.85, 0.99
2nd quintile (22–24) 3 0.87 0.80, 0.93
1st quintile (<22) 4 0.81 0.74, 0.87
Physical activity
1st quintile (<45 METs/week) 0 1 Reference 0.001
2nd quintile (45–69 METs/week) 1 0.97 0.91, 1.04
3rd quintile (69–96 METs/week) 2 0.94 0.89, 1.02
4th quintile (96–134 METs/week) 3 0.90 0.83, 0.97
5th quintile (134 1 METs/week) 4 0.87 0.80, 0.95
Alcohol
>20 (g/day) 0 1 Reference <0.001
10.0–19.9 (g/day) 1 0.91 0.85, 0.98
5.0–9.9 (g/day) 2 0.84 0.78, 0.91
0.1–4.9 (g/day) 3 0.81 0.76, 0.87
Never 4 0.84 0.78,0.93
Smoking
Current > 15 cigarettes/day 0 1 Reference 0.171
Current  15 cigarettes/day 1 0.87 0.79, 0.96
Ex–smokers quit  10 years 2 0.87 0.77, 0.99

Epidemiology
Ex–smokers quit > 10 years 3 0.91 0.82, 1.02
Never 4 0.87 0.78, 0.96

Stratified by study centre and age, and adjusted for height, age at menarche, age at first pregnancy, education, HRT, OC, breastfeeding, non–alcohol
energy intake, and other index components.

for the smoking component, which did not reach conven-
tional significance. Smoking, while the biggest risk factor for
cancer overall, is not an established risk factor for breast can-
cer. Although this exposure is frequently debated, smoking
has been found to be positively associated with breast cancer
in populations with high smoking prevalence,14 or long dura-
tions.45,46 The fact that not all components are equally related
to breast cancer risk implies that a factor which is less
strongly related dilutes out the effect of another one which is
more strongly related. However, the combined healthy life-
style index was overall more strongly associated with breast
cancer risk as compared to the individual components of the
index.
For the healthy lifestyle index, BMI was used as a measure
for overall body fatness. However, as there is evidence to sug-
gest that central adiposity may be a better predictor of post-
menopausal breast cancer,47 various anthropometric
measures were included in additional analyses. The use of
waist circumference, waist to hip ratio, or waist to height
ratio as a component in place of BMI did not materially alter
our results. Therefore BMI was used in the index for reasons
of data completeness.
Findings for the current study are consistent with two
previous studies, which found protective associations between
breast cancer and healthy lifestyle indexes. A relatively small
Mexican case–control study found that women in the highest

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 2646 Postmenopausal breast cancer risk

Table 4. Associations for the healthy lifestyle index and breast cancer risk among postmenopausal women in the European Prospective Inves-
tigation into Cancer and Nutrition cohort study, 1992–2000
Categorical index score
1 (5 points) 2 (6–10 points) 3 (11–15 points) 4 (16 points) p trend
Women 10,280 93,036 123,784 15,818
Cases 451 3,287 3,656 362
Unadjusted HR (95% CI) 1.18 (1.07, 1.30) 1 (Reference) 0.91 (0.87, 0.95) 0.75 (0.67, 0.83) <0.001
Adjusted HR (95% CI) 1.19 (1.07, 1.31) 1 (Reference) 0.90 (0.86, 0.95) 0.74 (0.66, 0.83) <0.001
Continuous adjusted HR (95% CI) per unit score 0.97 (0.96, 0.98)
ER1 and PR1 158 1,122 1,179 127
Unadjusted HR (95% CI) 1.22 (1.03, 1.45) 1 (Reference) 0.89 (0.82, 0.97) 0.82 (0.68, 0.99) 0.003
Adjusted HR (95% CI) 1.23 (1.04, 1.45) 1 (Reference) 0.89 (0.82, 0.97) 0.81 (0.67, 0.98) 0.002
Continuous adjusted HR (95% CI) per unit score 0.96 (0.95, 0.98)
ER– and PR– 45 315 317 26
Unadjusted HR (95% CI) 1.22 (0.89, 1.67) 1 (Reference) 0.88 (0.75, 1.03) 0.61 (0.40, 0.91) 0.013
Adjusted HR (95% CI) 1.23 (0.90, 1.69) 1 (Reference) 0.87 (0.74, 1.02) 0.60 (0.40, 0.90) 0.009
Continuous adjusted HR (95% CI) per unit score 0.96 (0.94, 0.99)

Stratified by study centre and age, and adjusted for height, age at menarche, age at first pregnancy, education, HRT, OC, breastfeeding, and non–
alcohol energy intake.

quintile of the a posteriori calculated healthy lifestyle index
had significantly lower odds of developing breast cancer than
their counterparts in the lowest quintile of the index (pre-
menopausal OR 0.50, 95% CI: 0.29–0.84; postmenopausal OR
0.20, 95% CI: 0.11–0.37).24 Their index considered healthy
behavior as being in the lowest tertile of the Western dietary
pattern, never consuming alcohol, smoking less than 100 cig-
arettes and practicing moderate and vigorous-intensity exer-
cise.24 More recently, a study based on the EPIC cohort
found a lower breast cancer risk for women in their highest
scoring category of a score based on adherence to WCRF/
Epidemiology
correlation in men and women among several food groups
examined.49 Finally, to avoid high correlations within and
between food groups, the number of indicator foods for an
index should be restricted to as few as possible. The highest
correlation of dietary components in the current study was
between folate and fruit and vegetables; nevertheless this was
included as the authors specifically wanted to capture the
importance of folate in relation to breast cancer.
There was no specific information on dietary supplemen-
tation available, particularly for folate and omega3 supple-
mentation. However, there was general information available,

AICR recommendations11 compared to their lowest category
(HR 5 0.84, 95% CI: 0.78–0.90).38 The components of this
index for all cancer were: body fatness, physical activity,
foods that promote weight gain, plant foods, red and proc-
essed meat, alcohol intake and breastfeeding.38 The breast
cancer specific health index used for the current study
resulted in an even greater risk reduction, and the association
between index and breast cancer risk was also able to be
investigated according to hormone receptor status.
The current study has several strengths, including the
large size and prospective design of the cohort, tumour hor-
mone receptor status and the detailed dietary and lifestyle
information. Nevertheless, consumption of fatty fish was used
as a marker for omega3 fatty acids in the construction of the
diet score, and information was not available for trans-fat in
the dataset; therefore, margarine was used as an indicator
because this food group has been described in the literature
as the main source for industrially produced trans fatty
acids.48 Margarine has been related to plasma elaidic acid (a
biomarker for trans-fat intake) in EPIC showing the strongest
whether vitamin or mineral supplements were taken without
stipulation of what those supplements contained. Sensitivity
analyses excluding women using unspecified supplements
showed similar results.
Although index components were equally weighted, there
is likely to be unintentional weighting due to some factors
being “recommended” items or those seen as positive like
physical activity while others are “moderation” items or those
perceived as negative like smoking. Recommended index
components are behaviors which are encouraged behaviors,
and as such, they may be unintentionally weighted through
their promotion more than behaviors which are discouraged,
such as the moderation index components.50
A further consideration in the interpretation of these
results is that EPIC participants are volunteers, and as such
this is not an ordinary population-based cohort. The cohort
is more likely to be healthier than the general population,
and therefore the estimates may be attenuated, providing an
underestimation of the association between healthy lifestyle
and breast cancer in Europe.

Int. J. Cancer: 136, 2640–2648 (2015) V

C 2014 UICC
McKenzie et al.
In conclusion, we evaluated the association between a
healthy lifestyle index (including healthy diet, moderate and
vigorous-intensity physical activity, avoidance of smoking
and alcohol consumption and low BMI) and the risk of
breast cancer among postmenopausal women, and found a
protective association of a healthy lifestyle among all
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