Background Because physical activity may affect hormonal concentrationsand energy balance, we decided to investigate whether everydayexercise is related to the risk of breast cancer.
Methods During 1974 to 1978 and 1977 to 1983, a total of 25,624women, 20 to 54 years of age at entry, enrolled in health surveysand answered questionnaires about leisure-time and work activity.
Results During a median follow-up of 13.7 years, we identified351 cases of invasive breast cancer among the 25,624 women inthe cohort. Greater leisure-time activity was associated witha reduced risk of breast cancer, after adjustments for age,body-mass index (the weight in kilograms divided by the squareof the height in meters), height, parity, and county of residence(relative risk, 0.63; 95 percent confidence interval, 0.42 to0.95), among women who exercised regularly, as compared withsedentary women (P for trend = 0.04). In regularly exercisingwomen, the reduction in risk was greater in premenopausal womenthan in postmenopausal women, and greater in younger women (<45years at study entry) than in older women (>45 years) (relativerisk, 0.38; 95 percent confidence interval, 0.19 to 0.79). Instratified analyses the risk of breast cancer was lowest inlean women (body-mass index, <22.8) who exercised at leastfour hours per week (relative risk, 0.28; 95 percent confidenceinterval, 0.11 to 0.70). The risk was also reduced with higherlevels of activity at work, and again there was a more pronouncedeffect among premenopausal than postmenopausal women.
Conclusions Physical activity during leisure time and at workis associated with a reduced risk of breast cancer.
Vigorous physical training1,2,3,4,5 and even moderate exercise6,7,8,9can interrupt the menstrual cycle, perhaps by suppressing thepulsatile release of gonadotropin-releasing hormone.10,11 Thiseffect of physical activity may lower a woman's cumulative exposureto estrogen and progesterone, thereby inhibiting carcinogenesisin the breast.12,13,14,15,16,17,18,19,20,21,22 Energy balancemight also influence the risk of breast cancer. Caloric restrictionin rodents reduces the proliferative activity of the mammaryglands23 and inhibits carcinogenesis.24,25 However, the effectof energy balance, as indicated by energy intake, body-massindex (the weight in kilograms divided by the square of theheight in meters), and energy expenditure, on the risk of breastcancer has not been examined thoroughly in humans.
In this study we evaluated the influence of physical activity,both at work and during leisure time, on the risk of breastcancer in a cohort of 25,624 premenopausal and postmenopausalwomen. Data on parity, dietary factors, and body-mass indexallowed adjustment for potentially confounding factors, andreassessment of physical activity after three to five yearsgave an indication of the effect of sustained physical activityon the risk of breast cancer.
Methods
Study Population
From 1974 to 1978, the National Health Screening Service invitedpeople in three counties in Norway (Oppland, Sogn og Fjordane,and Finnmark) to participate in a survey of risk factors forcardiovascular disease. All women who were 35 to 49 years ofage and a random sample of 10 percent of those who were 20 to34 years of age were invited. In four municipalities in Finnmarkall women who were 20 to 34 years of age were invited. A comprehensivedescription of these populations has been published previously.26A total of 31,556 women were invited to participate, and 28,621(91 percent) actually did.
All women in this survey as well as a random sample of womenwho were 20 to 39 years of age were invited to participate ina second survey three to five years later (1977 to 1983). Ofthese 34,378 women, 31,209 (91 percent) participated.27 Thissecond survey was used as the base line, because no informationon parity and dietary factors was collected during the firstsurvey.
Each woman received a written invitation to participate, togetherwith a one-page questionnaire. The participants were asked toanswer the questionnaire and bring it to the clinical examination.At screening, trained nurses checked the questionnaire for inconsistenciesregarding physical activity and menopausal status, measuredweight and height, and collected blood samples.
During screening in the second survey, the participants wereasked to fill out a food-frequency questionnaire, to be returnedby mail. After one reminder, 25,892 (83 percent) returned thequestionnaire. The energy and fat intakes for each woman werederived from the sum of all food consumed. The semiquantitativefood-frequency questionnaire that we used has been describedin detail and validated.28,29
Assessment of Physical Activity
Self-reported categories of physical activity during leisurehours in the year preceding each survey were assessed when thewomen entered the study and graded from 1 to 4 according tothe participant's usual level of physical activity. A gradeof 1 was assigned to those whose leisure time was spent reading,watching television, or engaging in other sedentary activities;a grade of 2 to those who spent at least four hours a week walking,bicycling, or engaging in other types of physical activity;a grade of 3 to those who spent at least four hours a week exercisingto keep fit and participating in recreational athletics; anda grade of 4 to those who engaged in regular, vigorous trainingor participating in competitive sports several times a week.The self-reported level of physical activity during work hoursin the preceding year was also graded on a four-point scale.A grade of 1 was assigned to those whose work was mostly sedentary;a grade of 2 to those whose job involved a lot of walking; agrade of 3 to those whose job required a lot of lifting andwalking; and a grade of 4 to those engaged in heavy manual labor.
Two identical assessments of leisure-time activity were madeat an interval of three to five years, and the results werecombined for all groups. Women who reported moderate (grade2) or regular (grade 3 or 4) exercise during leisure time inthe first survey and regular exercise (grade 3 or 4) in thesecond survey were characterized as being consistently physicallyactive. Women who were sedentary (grade 1) during leisure timein both surveys were characterized as being consistently sedentary.The women who were neither consistently sedentary nor consistentlyactive during leisure time were characterized as being moderatelyactive.
Follow-Up and Identification of Cases of Breast Cancer
We followed a total of 25,707 women who had not been given adiagnosis of cancer before our base-line survey (1977 to 1983).We used the participants' national 11-digit personal identificationnumbers to identify every incident case of breast cancer reportedto the Cancer Registry of Norway and Statistics Norway throughthe end of follow-up (December 31, 1994). A total of 98 percentof the cases were verified histologically. Women in whom cancerdeveloped (n = 72) or who died (n = 11) within the first yearof the study were excluded from the analyses to account forthe possibility that undiagnosed cancer or severe illness mightinfluence the level of physical activity. Through a linkageto the Central Population Register at Statistics Norway, weobtained information concerning the reproductive history ofeach woman, including the date of birth of each liveborn childthrough December 31, 1992, and deaths in the cohort throughDecember 31, 1994.
The ultimate study cohort consisted of 25,624 women who participatedin both surveys (age range, 20 to 69 years) during 359,930 person-yearsof follow-up.
Statistical Analysis
Base-line variables were adjusted for age and compared by analysisof covariance. Cox proportional-hazards regression analysiswas carried out to investigate the simultaneous effect of physicalactivity and covariates on the incidence of breast cancer. Tocalculate the risk of breast cancer, women were observed forthe development of breast cancer from entry into the study tothe date of diagnosis of any cancer, the time of death, or theend of follow-up, whichever event came first. In the analysis,grades 3 and 4 of leisure-time activity were merged becauseof the small numbers of women with a grade of 4 in both surveys(48 women in the first survey and 57 in the second survey).As a reference group we used women who were sedentary at workor during leisure time.
In the analyses, we adjusted for age at entry (a continuousvariable), county of residence, number of children, age at birthof first child, intake of total fat and energy, and body-massindex. Women who reported that they were premenopausal at baseline were treated as premenopausal until they reached the ageof 50 during follow-up, at which time they were considered postmenopausal.Women who reported that they were postmenopausal at base linewere treated as postmenopausal.
Because there were few women with breast cancer who were sedentaryboth at work and during leisure time, the effect of this combinationon the risk of breast cancer could not be analyzed. All significancetests were two-tailed, and the level of significance was setat 5 percent. The analyses were performed with the SAS statisticalpackage version 6.11.
Results
There were 351 incident cases of breast cancer (100 among premenopausalwomen and 251 among postmenopausal women) among 25,624 women.The mean length of follow-up was 14.0 years (median, 13.7),and the median age at diagnosis was 54.7 years (range, 36.3to 68.0).
Table 1 gives the base-line characteristics of the participants.Two thirds of the women reported moderate activity during leisuretime, whereas 15 percent exercised regularly. Only 14 percentreported being sedentary at work, whereas 20 percent reportedlifting and 5 percent reported doing heavy manual labor. Womenwho reported regularly exercising during leisure time did notdiffer from women who were inactive during their leisure timewith respect to age at entry or number of children, but theytended to be taller and to have a lower body-mass index, a relativelylow ratio of total cholesterol to high-density lipoprotein (HDL)cholesterol in serum, lower serum triglyceride levels, and higherHDL cholesterol levels. Women whose work involved lifting orheavy manual labor had a higher body-mass index and more childrenthan those engaged in sedentary work. Energy intake was positivelyrelated to physical activity, but the association was more pronouncedwith work activity than with leisure-time activity.
Table 1. Base-Line Characteristics of the Women According to the Level of Physical Activity in the 1977–1983 Survey.
We analyzed other possible age-adjusted risk factors for breastcancer at base line and found a 28 percent increase in riskfor each additional 6 cm of height and a 13 percent reductionin risk for each child. An older maternal age at the birth ofa first child was associated with a borderline increase in risk,whereas body-mass index (in the group as a whole or in the subgroupsof premenopausal and postmenopausal women), energy intake, andtotal fat intake did not influence the overall risk of breastcancer (data not shown).
Table 2 shows the relation between the level of leisure-timeor work activity and the overall risk of breast cancer. Afteradjustment for age and with the sedentary group as the referencegroup, the relative risk of breast cancer was reduced amongwomen whose jobs involved walking, lifting, or heavy manuallabor. Adjustments for other factors (body-mass index, countyof residence, number of children, and height) in addition toage changed the risk estimates only slightly. Further adjustmentsfor age at first birth or dietary factors (energy intake, totalfat intake, and fiber intake) did not influence our estimatesof relative risk and were omitted from the final model. A 52percent reduction in risk was observed among the women who reporteddoing heavy manual labor (relative risk, 0.48; 95 percent confidenceinterval, 0.25 to 0.92). The overall adjusted risk of breastcancer decreased in a dose–response manner with increasingactivity level during leisure time (P for trend = 0.04). Womenwho exercised at least four hours a week during leisure timehad a 37 percent reduction in the risk of breast cancer (relativerisk, 0.63; 95 percent confidence interval, 0.42 to 0.95).
Table 2. Adjusted Relative Risk of Breast Cancer According to the Level of Physical Activity during Leisure Time and at Work in the 1977–1983 Survey.
When the group was divided according to menopausal status (Table 3),a consistently inverse association was observed betweenthe level of leisure-time activity and the premenopausal riskof breast cancer; the adjusted relative risk declined to 0.77(95 percent confidence interval, 0.46 to 1.27) and further to0.53 (95 percent confidence interval, 0.25 to 1.14) as the levelof activity increased (P for trend = 0.10). A weaker associationwas observed between the level of leisure-time activity andthe postmenopausal risk of breast cancer. The inverse associationbetween the level of activity at work and the risk of breastcancer was also pronounced among premenopausal women; amongpremenopausal women whose jobs involved lifting or heavy manuallabor, the relative risk was 0.48 (95 percent confidence interval,0.24 to 0.95).
Table 3. Adjusted Relative Risk of Breast Cancer According to Menopausal Status and the Level of Physical Activity in the 1977–1983 Survey.
We also divided the cohort into women who were younger than45 years of age at entry and those who were 45 or older. Amongthose younger than 45 years at entry for whom data were complete(of whom breast cancer developed in 138; mean age at diagnosis,48.3 years), the adjusted relative risk declined to 0.80 (95percent confidence interval, 0.52 to 1.22) and further to 0.38(95 percent confidence interval, 0.19 to 0.79) as the levelof activity during leisure time increased (P for trend = 0.01).The respective adjusted relative risks were 1.03 (95 percentconfidence interval, 0.72 to 1.48) and 0.84 (95 percent confidenceinterval, 0.51 to 1.39) (P for trend = 0.54) among those forwhom data were complete who were 45 years of age or older atentry (of whom breast cancer developed in 208; mean age at diagnosis,58.2 years). These values indicate that physical activity hada protective effect, particularly with respect to the risk ofbreast cancer before and soon after menopause.
We examined models stratified according to body-mass index (Table 4).Among lean (body-mass index, <22.8), regularly exercisingwomen, the risk of breast cancer was reduced by 72 percent (relativerisk, 0.28; 95 percent confidence interval, 0.11 to 0.70). Nosuch association was observed in the middle or upper thirdsof body-mass index among regularly exercising women. In modelsstratified according to both body-mass index and menopausalstatus, this association was seen among both premenopausal andpostmenopausal lean women (data not shown).
Table 4. Adjusted Relative Risk of Breast Cancer According to Body-Mass Index and the Level of Physical Activity during Leisure Time in the 1977–1983 Survey.
In the second survey 61.2 percent of the participants reportedthe same level of leisure-time activity as in the first survey,23.5 percent reported an increased level, and 15.3 percent reporteda reduced level. By combining these two assessments of leisure-timeactivity, we observed that the relative risk declined to 0.23(95 percent confidence interval, 0.09 to 0.60) as the levelof sustained activity increased in lean (body-mass index, <22.8)women (P for trend = 0.002) (Table 5). This protective effectacross increasing levels of sustained leisure-time activitywas observed in both lean premenopausal women (relative risk,0.23; 95 percent confidence interval, 0.06 to 0.88; P for lineartrend = 0.02) and lean postmenopausal women (relative risk,0.24; 95 percent confidence interval, 0.06 to 0.96; P for lineartrend = 0.03).
Table 5. Adjusted Relative Risk of Breast Cancer According to Body-Mass Index and Overall Level of Physical Activity during Leisure Time in the 1974–1978 and 1977–1983 Surveys.
Discussion
Our results support the idea that physical activity protectsagainst breast cancer, particularly among premenopausal andyounger postmenopausal women. Activity during both leisure timeand work reduced the overall risk. There was a significant inversedose–response relation between leisure-time activity andthe risk of breast cancer. The protective effect was evidentamong lean premenopausal and postmenopausal women, and repeatedassessment emphasized the preventive effect of physical activity.
The overall reduction in the risk of breast cancer among activewomen is consistent with findings in other cohort15,17 and case–control19,20,21,22studies, but at variance with the findings of a few others.30,31In one of these discrepant studies,31 most of the women wereolder than in the present study and breast cancer was diagnosedmainly among postmenopausal women. In the other,30 physicalactivity at college was assessed 35 to 70 years before the diagnosisof breast cancer, and no adjustments were made for potentialconfounding factors. Our finding of a protective effect of work-relatedactivity on the risk of breast cancer is also in agreement withother studies.18,32,33
Precise assessment of physical activity is difficult in a population-basedcohort. The accuracy of the levels of leisure-time activityreported on the questionnaire that we used has been validatedpreviously.34,35,36 Since the level of leisure-time activitycorrelates with the degree of physical fitness,34,36 our observationthat recreationally active women tended to be leaner than inactivewomen and had serum lipid profiles associated with regular exercisestrengthens the validity of our assessments. Energy intake wasalso positively related to both leisure-time and work activities,particularly work activities.
Repeated assessment of leisure-time activity is important inany analysis of the effect of sustained activity on the riskof breast cancer. The protective effect was notable among leanwomen who were consistently active during their leisure time.In combining the two assessments for each woman, we may alsohave increased the precision of our assessment of physical-activitylevels, but we cannot differentiate the effect of sustainedactivity from any misclassification.
The population-based approach and the high participation ratein our study reduced selection bias. The almost complete reportingof incident cases of breast cancer also strengthens our results.Age at menarche was not available and could have confoundedour results, but this is not likely, since an increased riskof only 4 percent was observed for each year of earlier ageat menarche in a similar study population in Norway.37
Information about the use of hormonal contraceptives was notavailable, although recent meta-analyses suggest that thereis only a small increase in the risk of breast cancer amongthe youngest women who commonly use hormonal contraceptives.38It is probable that this information would not have confoundedour results to any large extent.
How does physical activity influence the development of breastcancer? The propensity to be physically active may be inherited,39so the genotype may influence both physical activity and thepredisposition to breast cancer. Social and cultural influenceson exercise and energy balance seem to be more important thangenetic factors,39,40 which points to leisure-time activityas an independent and modifiable variable with regard to itseffect on the risk of breast cancer.
A reduction in the cumulative exposure to cyclic estrogens andprogesterone may in part explain the preventive effect of bothleisure-time and work activity. Over the long term, vigoroustraining and moderate leisure-time activity may decrease estradioland progesterone secretion,3,6,41 reduce the length of the lutealphase,10,42 induce anovulation,7,8,41,43 delay menarche,4,5and cause secondary amenorrhea.2,12
Physical activity influences energy balance, and experimentalstudies have shown that calorie restrictions inhibit mammarycarcinogenesis.24,25,44 Anthropometric measures such as height,body-mass index, and weight gain have been used as biomarkersof calorie intake, and increased values have been reported tobe risk factors for breast cancer in humans.45,46,47,48 A dietinvolving a high energy intake has also been associated withearly age at menarche,5,49 and this finding supports the hypothesisthat increased net energy may increase the cumulative hormonallevels that are of importance for carcinogenesis of the breast.Women who were active during leisure time reported only a slightlyhigher total energy intake than sedentary women, and they tendedto be leaner, indicating that their net available energy waslower. The greater protective effect of leisure-time activityagainst breast cancer in lean women indicates that there maybe an optimal energy balance that inhibits mammary carcinogenesis.
Triglycerides are known to displace estradiol from its tightbinding to the sex hormone–binding globulin, which isfound in low levels in obese women,50 and thus triglyceridesincrease levels of free estradiol. Serum levels of triglycerideswere higher in sedentary women than in women who were more activeduring their leisure time; thus, exposure to estrogen may begreater in inactive women. This underscores the importance ofavoiding obesity if physical activity is to have an optimalinhibitory effect on the risk of breast cancer.
Supported by a grant (90033-001) from the Norwegian Cancer Society.
We are indebted to the participants, the National Health ScreeningService, and the Cancer Registry of Norway.
Source Information
From the Institute of Community Medicine, University of Tromsø, Tromsø (I.T., T.B., E.L.), and the Cancer Registry of Norway, Oslo (M.G.) — both in Norway.
Address reprint requests to Dr. Thune at the Institute of Community Medicine, University of Tromsø, N-9037 Tromsø, Norway.
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