Lifetime exercise activity and breast cancer risk among post-menopausal women

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1 Article no. bjoc Lifetime exercise ctivity nd brest cncer risk mong post-menopusl women CL Crpenter, RK Ross, A Pgnini-Hill nd L Bernstein Deprtment of Preventive Medicine, University of Southern Cliforni School of Medicine, USC/Norris Comprehensive Cncer Center, 1441 Estlke Ave., MS-44, Los Angeles, CA, USA Summry Lifetime exercise ctivity hs been linked to brest cncer risk mong young women. However, no study hs specificlly evluted whether lifetime exercise ctivity is relted to the brest cncer risk of post-menopusl women. We conducted popultion-bsed cse-control study of post-menopusl white women (1123 newly dignosed cses nd 904 helthy controls) ged who lived in Los Angeles County, Cliforni, USA to evlute this reltionship. Although neither exercise ctivity from menrche to ge 40 yers, nor exercise fter ge 40 seprtely predicted brest cncer risk, risk ws lower mong women who hd exercised ech week for t lest 17.6 MET-hours (metbolic equivlent of energy expenditure multiplied by hours of ctivity) since menrche thn mong inctive women (odds rtio (OR) = 0.55; 95% confidence intervl (CI) ). Exercise ctivity ws not protective for women who gined considerble (> 17%) weight during dulthood. However, mong women with more stble weight, brest cncer risk ws substntilly reduced for those who consistently exercised t high levels throughout their lifetime (OR = 0.42; 95% CI ), those who exercised more thn 4 h per week for t lest 12 yers (OR = 0.59; 95% CI ), nd those who exercised vigorously (24.5 MET-hours per week) during the most recent 10 yers (OR = 0.52; 95% CI ). Strenuous exercise ppers to reduce brest cncer risk mong post-menopusl women who do not gin sizble mounts of weight during dulthood. Keywords: brest neoplsms; exercise; weight gin; post-menopusl women Strenuous physicl ctivity, known to influence ovrin hormone production, is potentilly modifible fctor tht could led to reduction in brest cncer risk. Mny studies of exercise nd brest cncer risk hve been conducted on premenopusl women (Bernstein et l, 1994; Chen et l, 1997; Gmmon et l, 1998), nd on pre- nd post-menopusl women (Frisch et l, 1985; Albnes et l, 1989; Vihko et l, 1992; Dosemeci et l, 1993; Dorgn et l, 1994; Mittendorf et l, 1995; D Avnzo et l, 1996; Coogn et l 1997; Thune et l, 1997; Mezzetti et l, 1998; Rockhill et l, 1998), nd one exclusively mong post-menopusl women (McTiernn et l, 1996). Obesity nd weight gin re importnt risk fctors for postmenopusl brest cncer (Hunter nd Willett, 1993; Hung et l, 1997). Strenuous exercise is ssocited with weight loss (Willimson et l, 1993), nd consequently, physicl ctivity, in ddition to influencing ovrin hormone production during the reproductive yers, my reduce post-menopusl brest cncer risk through the promotion of len body. Informtion on exercise ctivities throughout women s lives is necessry to ssess the reltive importnce of different potentil biologicl effects of exercise. Although we previously exmined lifetime history of exercise ctivity in reltion to premenopusl brest cncer risk (Bernstein et l, 1994), to dte no epidemiologicl study hs evluted this reltionship mong postmenopusl women. The present study exmines this reltion to Received 20 October 1998 Revised 11 Jnury 1999 Accepted 1 Februry 1999 Correspondence to: L Bernstein determine whether the ssocition vries by ges t which womn engges in exercise ctivity, nd weight chnge during dulthood. MATERIALS AND METHODS Subjects All white (including Hispnic) English-speking femle residents of Los Angeles County who were between the ges of 55 nd 64 yers t dignosis, nd born in the USA, Cnd, or Western Europe, were eligible to prticipte in this study. A totl of 2373 eligible brest cncer cse ptients identified by the University of Southern Cliforni Cncer Surveillnce Progrm, the popultionbsed cncer registry for Los Angeles County, were dignosed with primry invsive or in situ brest cncer between 1 Mrch 1987 nd 31 December We interviewed 1579 eligible ptients (67%). We were unble to interview the remining ptients, 230 (10%) of which were too ill or hd died; we could not locte 17 (1%); physicins denied us permission to contct 128 (5%); nd 419 (18%) refused to prticipte. One neighbourhood control subject ws individully mtched to 1506 interviewed cse ptients on birthdte (within 36 months) nd rce (hispnic, other white). To identify ech neighbourhood control subject, we utilized predefined wlk pttern for the neighbourhood where the cse ptient lived t the time of her dignosis. The medin number of housing units pproched per cse ws 25. We obtined complete wlk-pttern censuses of neighbourhoods for 636 cse ptients. For the remining 870 brest cncer 1852

2 Exercise nd post-menopusl brest cncer 1853 ptients, we were denied ccess to t lest one housing unit (medin = 4) in the wlk pttern. For 1205 brest cncer ptients, the first identified eligible control subject prticipted. For 227 others, the second eligible control subject prticipted fter the first refused; for 74 others, three or more eligible control subjects were identified. Study procedures to protect humn subjects were pproved by the University of Southern Cliforni Institutionl Review Bord, in ccord with ssurnces pproved by the US Deprtment of Helth nd Humn Services. Ech subject provided informed consent. Collection of dt In-person interviews for ech cse-control pir were generlly conducted by the sme femle interviewer. We obtined lifetime reproductive, orl contrceptive, hormone replcement therpy nd physicl exercise histories for ech prticipnt. We recorded informtion up to reference dte (12 months prior to the dte of the ptient s dignosis for ech cse nd her mtched control). We considered womn to hve first-degree fmily history of brest cncer if her mother, sister or dughter hd been dignosed with brest cncer. We recorded self-reported height nd weight t ge 18 nd t the reference dte. Body mss ws estimted by Quetelet s index (weight in kilogrms divided by height in metres squred). We creted vrible for per cent chnge in weight between ge 18 nd the reference dte. Women who lost or hd no weight chnge were designted the referent ctegory nd the remining women were divided into three groups ccording to whether they were below the 50th percentile vlue, below the 75th percentile, or bove the 75th percentile of control subjects. We collected informtion on physicl exercise ctivity in which women regulrly prticipted for t lest 2 h per week. We recorded the type of ctivity, ges strted nd stopped, nd hours per week spent exercising. For ech yer of life, we computed totl hours per week of ll exercise ctivities, llowing for sesonl ctivities. We ssigned metbolic equivlents of energy expenditure (MET) scores to ech ctivity (Ainsworth et l, 1993), multiplied the score by hours per week engged in tht ctivity, nd summed the MET-hour vlues cross ll ctivities for ech yer of subject s life. Eighteen MET-hours of ctivity is equivlent to 3 h of hrd vigorous exercise (MET = 6) such s jogging, field hockey nd erobics (Ainsworth et l, 1993). We constructed two risk periods to ssess exercise ctivity: menrche through ge 39 (premenopusl period) nd ge 40 to the reference ge (perimenopusl nd post-menopusl periods). Annul MET-hours per week reported for ech risk period were summed nd divided by totl yers in tht period. Cut-points were creted for these two vribles bsed on the joint distribution of verge MET-hours per week in the two periods. We lso used these cutpoints to evlute lifetime exercise ctivity (since menrche). In ll nlyses, the referent group ws women who were inctive during the relevnt risk period. We ssessed risk ccording to the totl yers ech womn exercised t lest 4 h per week, s this ws n importnt mrker in our study of younger women (Bernstein et l, 1994). We lso exmined risk in reltion to the verge METhours per week in the 10 yers before ech womn s reference dte, nd in the 10-yer period following menrche. Anlysis of dt We limited nlyses to post-menopusl women with known ges t menopuse nd complete covrite informtion (1165 cse ptients, 1169 control subjects) fter excluding subjects who were premenopusl (30 cses, 20 controls), who hd unknown menopusl sttus (one control), who never menstruted (one control), who hd hysterectomy without bilterl oophorectomy prior to their lst menstrul period (306 cses, 267 controls), who hd surgicl menopuse before ge 30 (31 cses, 22 controls), who hd nturl menopuse before ge 35 (seven cses, seven controls), who took orl contrceptives fter menopuse (31 cses, 15 controls), who were missing informtion on hormone replcement therpy (six cses, three controls), or who were missing mesurements on weight or height (three cses, one control). We recreted mtching strt for ech single yer of ge between 55 nd 64, nd five socioeconomic sttus strt (bsed on medin household income nd distribution of eduction of dults living in Los Angeles County during the 1980 census). The exct ge mtch resulted in exclusion of 101 control subjects younger thn 55 yers, nd 152 control subjects older thn 64 yers who originlly were within 36 months of the ge of their corresponding cse but outside the restricted ge rnge. An dditionl 42 cse ptients nd 12 control subjects were excluded becuse they fell into ge nd socioeconomic strt tht hd only cses or only controls. The nlyses re bsed on 1123 cse ptients (100 of whom hd in situ disese) nd 904 control subjects. We estimted odds rtios (OR), 95% confidence intervls (CI) for the odds rtio (bsed on the stndrd error of the log odds), nd tests for liner trend cross ordinl vlues of ctegoricl vribles by conditionl logistic regression methods. All reported P-vlues re two-sided. Heterogeneity of trends ws evluted using likelihood rtio test. RESULTS Tble 1 presents distributions nd undjusted OR for potentil confounding fctors of the ssocition between physicl exercise ctivity nd brest cncer risk. Brest cncer risk incresed with incresing levels of Quetelet s index t reference dte (trend P < 0.001), but ws unrelted to Quetelet s index t ge 18. Women who gined excessive weight between ge 18 nd reference ge were t greter risk of brest cncer thn those whose weight ws stble. Quetelet s index t reference ge ws highly correlted with per cent weight chnge between ge 18 nd reference ge (Person correltion, r = 0.75). OR estimtes for the extreme ctegories of the two vribles were similr. Both fmily history of brest cncer nd ge t first term pregnncy mong prous women were positively ssocited with brest cncer risk (Tble 1). Age t menrche nd ge t menopuse were not ssocited with risk. We included Quetelet s index t reference dte, ges t first full-term pregnncy, menrche nd menopuse, fmily history, nd interviewer in ll multivrite models ssessing the reltionship between physicl exercise ctivity nd brest cncer risk (Tbles 2, 3 nd 4). Durtion of use of hormone replcement therpy ws not relted to ny exercise ctivity vrible nd ws not included in the multivrite models. Neither verge MET-hours per week of physicl exercise ctivity in which womn engged between menrche nd ge 39 yers, nor tht in which she engged from ge 40 yers to the reference ge ws relted to brest cncer risk (Tble 2). Risk estimtes were similr to those shown in Tble 2 when both mesures were included in the sme model. However, brest cncer risk ws substntilly lower mong women who mintined high level of exercise ctivity (verging t lest 17.6 MET-hours per week)

3 1854 CL Crpenter et l Tble 1 Odds rtios (OR) nd 95% confidence intervls (CI) for potentil confounding fctors of the ssocition between physicl ctivity nd brest cncer risk mong post-menopusl women ged yers No. of No. of Trend Vrible cses controls OR (95% CI) P-vlue Quetelet s index t reference dte b < ( ) ( ) ( ) < Quetelet s index t ge 18 < ( ) ( ) ( ) 0.41 Percent chnge in weight from ge 18 to reference dte Negtive chnge to no chnge % ( ) % ( ) 29.2% ( ) Age t menrche < ( ) ( ) ( ) 0.90 Age t menopuse < ( ) ( ) ( ) ( ) 0.21 Age t first full-term pregnncy < ( ) ( ) ( ) ( ) c Nulliprous ( ) First-degree fmily history of brest cncer No Yes ( ) Don t know/dopted ( ) Weight (kg)/height 2 (m); b one yer prior to brest cncer dignosis for cses nd corresponding dte for controls; c trend test for prous women. throughout their lifetimes, from menrche to reference dte (OR = 0.55; 95% CI ), compred to those with lifelong inctivity (Tble 3). Exercise during the first 10 yers fter menrche ws not ssocited with brest cncer risk (Tble 2). Likewise, verge MET-hours of exercise per week in the 10-yer period preceding the reference dte ws not ssocited with risk (trend P = 0.32), lthough women who verged t lest 24.5 MET-hours per week hd modestly reduced risk (OR = 0.71; 95% CI ). Totl yers in which women exercised more thn 4 h per week (Tble 3) predicted brest cncer risk (trend P = 0.01). Women who mintined this ctivity level for 12 or more yers were 29% less likely to develop post-menopusl brest cncer thn women who never exercised t tht level. We exmined the effects of exercise ctivity mong women with weight chnge bove nd below the medin vlue of controls (17% increse in weight) in single logistic regression model to evlute effect modifiction (Tble 4). We included Quetelet s index t reference dt s continuous term in these nlyses. Within the group of women who mintined their weight (< 17% increse), three mesures of exercise were ssocited with reduced brest cncer risk, while none ws ssocited with risk mong women with greter weight gin. Among women with stble weight, those who exercised t lest 17.6 MET-hours per week throughout their lifetimes reduced their brest cncer risk by more thn 55% reltive to women who were inctive in both ge periods. Among women who mintined their weight, brest cncer risk declined with incresing number of yers the womn exercised more thn 4 h per week (trend P = 0.009); with risk reduced more thn 40% for those exercising t this level for t lest 12 yers since menrche. Risk ws reduced 48% for those who verged t lest 24.5 METhours over the 10 yers preceding the reference dte. Trends in risk for MET-hours of ctivity within 10 yers prior to reference ge (P = 0.06) nd trends in risk for lifetime MET-hours of ctivity (P = 0.005) differed between women with sizble weight gin ( 17%) nd women who mintined stble weight (< 17% gin). Trends in risk for yers of ctivity tht verged more thn 4 h per week did not differ between the two weight gin groups (P = 0.30). DISCUSSION Most risk fctors for femle brest cncer cn be understood s mesures of cumultive exposure of the brest to oestrogens nd progesterone. Women with erly menrche hve greter brest cncer risk thn those with lter menrche nd this risk fctor contributes substntilly to overll brest cncer risk in young women (Kelsey et l, 1993). Erly menrche represents more yers of exposure to ovrin hormones becuse it predicts more rpid onset of regulr ovultory menstrul cycles during dolescence nd higher circulting oestrogen levels lter in reproductive life (Vihko nd Apter, 1984; Apter et l, 1989). Women who experience erlier menopuse hve lower brest cncer risk thn those who stop menstruting lter (Kelsey et l, 1993). Weight gin s n dult nd post-menopusl obesity increse brest cncer risk fter the menopuse (Hunter nd Willett, 1993; Hung et l, 1997); this is likely due to greter oestrogen exposure in obese thn in thinner post-menopusl women (Key nd Pike, 1988; Potischmn et l, 1996; Thoms et l, 1997) becuse of the high levels of oestrone production occurring in dipose tissue (McDonld et l, 1978; Kirschner et l, 1981). Bsed on our understnding of the importnce of ovrin hormones to brest cncer risk, we hypothesized tht regulr prticiption in exercise ctivities sufficient to lter menstrul cycle ptterns nd ovultory sttus during reproductive yers should reduce brest cncer risk (Bernstein et l, 1992). Exercise my reduce womn s cumultive exposure to oestrogen by delying menrche (Frisch et l, 1980, 1981), lowering levels of serum oestrogen (Russell et l, 1984; Broocks et l, 1990), nd incresing the frequency of novultion (Russell et l, 1984; Bernstein et l, 1987). During womn s perimenopusl nd post-menopusl yers, exercise my reduce hormonl exposure through weight mintennce. In our previous cse-control study of women ged 40 or younger, we exmined lifetime exercise ptterns nd observed sizble reduction in brest cncer risk mong women who

4 Exercise nd post-menopusl brest cncer 1855 Tble 2 Odds rtios (OR) nd 95% confidence intervls (CI) for the ssocition between time-specific mesures of physicl exercise ctivity nd brest cncer risk mong post-menopusl women ged yers Time period of exercise ctivity No. of No. of Adjusted Trend Ctegory of ctivity cses controls OR OR 95% CI P-vlue First 10 yers fter menrche b (verge MET-hours c per week) No ctivity ( ) ( ) ( ) 0.43 From menrche to ge 39 d No ctivity ( ) ( ) ( ) ( ) 0.79 From ge 40 to reference dte ef No ctivity ( ) ( ) ( ) ( ) 0.46 From 10 yers prior to reference dte until reference dte g No ctivity ( ) ( ) ( ) ( ) 0.32 Odds rtio djusted for ctegories of body-mss index (Quetelet s index) t reference dte, ge t first full-term pregnncy, fmily history of brest cncer, ge t menrche, ge t menopuse, nd interviewer. b Adjusted model includes continuous term for verge MET-hours from 10 yers fter menrche until the reference dte. c Product between metbolic equivlent of energy expenditure nd hours of ctivity. d Adjusted model includes continuous term for verge MET-hours per week of exercise from ge 40 to reference dte. e One yer prior to brest cncer dignosis for the cses, nd corresponding dte for controls. f Adjusted model lso includes continuous term for verge MET-hours from menrche to ge 39. g Adjusted model lso includes continuous term for verge MET-hours of ctivity up to 10 yers prior to reference dte. Tble 3 Odds rtios (OR) nd 95% confidence intervls (CI) for the ssocition between lifetime mesures of physicl exercise ctivity nd brest cncer risk mong post-menopusl women ged yers Mesure of lifetime ctivity No. of No. of Adjusted Trend Ctegory of ctivity cses controls OR OR 95% CI P-vlue Exercise ctivity from menrche to the reference dte b (verge MET-hours c per week) No ctivity < ( ) ( ) 0.01 Yers engged in more thn 4 h per week of exercise ctivity d ( ) ( ) 0.01 Odds rtio djusted for ctegoricl terms for body-mss index (Quetelet s index) t reference dte, ge t first full-term pregnncy, fmily history of brest cncer, ge t menrche, ge t menopuse, nd interviewer. b One yer prior to brest cncer dignosis for the cses, nd corresponding dte for controls. c Product between metbolic equivlent of energy expenditure nd hours of ctivity. d Adjusted model lso includes continuous term for number of yers in which the verge mount of exercise ws 4 h per week or less.

5 1856 CL Crpenter et l Tble 4 Odds rtios (OR) nd 95% confidence intervls (CI) for ssocition between mesures of physicl exercise ctivity nd brest cncer risk mong post-menopusl women ged yers by percent dult weight chnge. Per cent weight chnge between ge 18 nd reference dte Time period of < 17.0% 17.0% Exercise ctivity Cses/ Trend Cses/ Trend Ctegory of ctivity Controls OR b 95% CI P-vlue Controls OR b 95% CI P-vlue From menrche to to reference dte (verge MET-hours c per week) No ctivity 214/ / < / ( ) 255/ ( ) / ( ) / ( ) 0.26 Number of yers engged in more thn 4 h of exercise ctivity per week d 0 356/ / / ( ) 106/ ( ) 12 54/ ( ) / ( ) 0.25 From 10 yers prior to Reference ge until reference dte 0 332/ / / ( ) 40/ ( ) / ( ) 47/ ( ) / ( ) 49/ ( ) / ( ) / ( ) 0.75 One yer prior to brest cncer dignosis for cses nd corresponding dte for controls. b Adjusted for ctegories of ge t first full-term pregnncy, fmily history of brest cncer, ge t menrche, ge t menopuse, interviewer, nd continuous term for Quetelet s index t reference dte. c Product between metbolic equivlent of energy expenditure nd hours of exercise ctivity. d Adusted model lso includes continuous term for number of yers in which the verge mount of exercise ws 4 h per week or less. e Adjusted model lso includes continuous term for verge MET-hours per week of exercise up to 10 yers prior to reference dte. verged t lest 3.8 h per week of exercise during their reproductive yers (Bernstein et l, 1994). These results led us to pursue whether exercise might ffect brest cncer risk mong postmenopusl women. Mesurement of lifetime exercise in this study hs enbled us to exmine ctivity ptterns in different wys. We summrized lifetime physicl ctivity into two time periods nd evluted whether exercise during the reproductive yers might ffect risk differently thn exercise in the perimenopusl nd post-menopusl yers. We lso evluted lifetime ctivity. Brest cncer risk ws pprecibly reduced mong women who exercised t high levels throughout their lifetime. Although ctivity in the first 10 yers fter menrche ws relted to reduced brest cncer risk in our study of younger women (Bernstein et l, 1994), we did not find this effect in the present study of post-menopusl women ged yers, unless women continued regulr exercise. A high exercise level during the 10-yer perimenopusl nd erly post-menopusl period ws modertely protective compred to inctivity during those yers, but the overll ssocition ws non-liner. Yers tht women exercised more thn 4 h per week, on the other hnd, ws strongly protective with cler dose response reltionship. Weight gin in dulthood is generlly ssocited with n incresed risk of post-menopusl brest cncer (Bllrd-Brbsh et l, 1990; Brinton nd Swnson, 1992; Brnes-Josih et l, 1995; Ziegler et l, 1996; Hung et l, 1997). Post-menopusl women who exercise hve lower circulting levels of oestrone (Nelson et l, 1988; Culey et l, 1989), nd this reltionship ppers to be independent of body mss (Culey et l, 1989). The effects of exercise ctivity in the present study vried ccording to mount of weight gined during dulthood. Exercise ws strongly ssocited with reduced post-menopusl brest cncer risk mong women whose weight gin during dulthood ws miniml, but ws not clerly ssocited with brest cncer risk mong women who gined greter mounts of weight. Two recent studies of physicl ctivity nd brest cncer risk lso exmined differences in risk reduction ccording to body mss (Coogn et l, 1997; Thune et l, 1997), with results generlly consistent with dt reported here. Occuptionl physicl ctivity ws mildly protective for brest cncer mong post-menopusl women in the study of Coogn et l (1997), but mong len women the protective effect ws stronger. In lrge prospective study of Norwegin women, n inverse ssocition between the highest level of self-rted ctivity score nd brest cncer risk ws observed with the most sizble reduction in risk mong women with len body-mss (Thune et l, 1997). Although correlted, weight chnge during dulthood nd obesity represent somewht different vribles. To ccount for potentil residul confounding from obesity, we djusted for bodymss index t the reference ge in ll nlyses tht evluted the effects of exercise nd weight chnge. We further exmined verge body-mss index vlues t the reference ge in ech ctegory of the ctivity vribles within ech weight gin ctegory. We found only slight differences between cse ptients nd control subjects. Results from the present study emphsize the complexity of the reltionship between exercise ctivity nd post-menopusl brest cncer risk. Erly exercise ctivity, if not sustined, does not pper to ffect post-menopusl brest cncer risk. However, lifetime exercise when mesured by verge MET-hours per week

6 Exercise nd post-menopusl brest cncer 1857 or by exercise tht verges more thn 4 h per week, s well s vigorous exercise of sizble durtion during the perimenopusl nd erly post-menopusl yers re modertely ssocited with reduced brest cncer risk. Such exercise, especilly when combined with mintennce of reltively stble weight during dulthood, substntilly reduces the risk of post-menopusl brest cncer. Our results pper to suggest tht mong women who mintin len body, exercise exerts seprte, independent effect on brest cncer risk. However, our body-mss mesure does not tke into ccount the reltive mounts of muscle mss nd body ft, which, even mong women with reltively stble weight, my vry ccording to ctivity level. As consequence, the protective effect of exercise my not be independent of the mount of dipose tissue. Future studies re needed to identify whether exercise ffects post-menopusl brest cncer risk by reducing the mount of dipose tissue, by independently lowering oestrogen levels, or by ffecting other less studied fctors such s insulin resistnce. ACKNOWLEDGEMENTS Funding for the study ws provided by grnt CA17054 from the Ntionl Cncer Institute nd the LK Whittier Foundtion, privte foundtion supporting biomedicl reserch. Dr Crpenter ws supported by the Stte of Cliforni Brest Cncer Reserch Progrm, 1FB0202, nd supplementl fellowship wrded by the USC/Norris Comprehensive Cncer Center. Cncer incidence dt hve been collected under Subcontrct 050L-8709-S1149 with the Contrctor, Public Helth Institute. 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