Relationship between Established Breast Cancer Risk Factors and Risk of Seven Different Histologic Types of Invasive Breast Cancer

Transcription

1 946 Relatioship betwee Established Breast Cacer Risk Factors ad Risk of Seve Differet Histologic Types of Ivasive Breast Cacer Christopher I. Li, 1 Jaet R. Dalig, 1 Kathlee E. Maloe, 1 Leslie Berstei, 2 Polly A. Marchbaks, 3 Joatha M. Liff, 4 Bria L. Strom, 5 Michael S. Simo, 6 Michael F. Press, 2 Jill A. McDoald, 3 Giske Ursi, 2,7 Roald T. Burkma, 8 Deis Deape, 2 ad Robert Spirtas 9 1 Fred Hutchiso Cacer Research Ceter, Divisio of Public Health Scieces, Seattle, Washigto; 2 Departmet of Prevetive Medicie, Keck School of Medicie ad Norris Comprehesive Cacer Ceter, Uiversity of Souther Califoria, Los Ageles, Califoria; 3 Divisio of Reproductive Health, Ceters for Disease Cotrol ad Prevetio; 4 Rollis School of Public Health, Emory Uiversity, Atlata, Georgia; 5 Ceter for Cliical Epidemiology ad Biostatistics ad Departmet of Biostatistics ad Epidemiology, Uiversity of Pesylvaia, Philadelphia, Pesylvaia; 6 Divisio of Hematology ad Ocology, Karmaos Cacer Istitute at Waye State Uiversity, Detroit, Michiga; 7 Departmet of Nutritio, Uiversity of Oslo, Oslo, Norway; 8 Departmet of Obstetrics ad Gyecology, Baystate Medical Ceter, Sprigfield, Massachusetts; ad 9 Cotraceptio ad Reproductive Brach, Ceter for Populatio Research, Natioal Istitute of Child Health ad Huma Developmet, NIH, Departmet of Health ad Huma Services, Bethesda, Marylad Abstract Backgroud: Importat differeces i the cotributios of certai exposures to the risks of ductal versus lobular breast carciomas have bee observed, but few studies have evaluated the relatioships betwee established breast cacer riskfactors ad other histologic types. Methods: Iformatio o family history of cacer ad reproductive, hormoal, athropometric, ad lifestyle characteristics were collected i a multiceter populatio-based case-cotrol study cosistig of 3,463 ductal, 274 lobular, 261 ductal-lobular, 91 medullary, 77 tubular, 70 comedo, ad 61 mucious ivasive breast carcioma cases (ages years, ewly diagosed ) ad 4,682 cotrols. Associatios betwee each of these histologic types ad various exposures were evaluated usig polytomous regressio. Results: Heterogeeity i the risks of differet histologic types of breast cacer was observed for three exposures: meopausal hormoe use, body mass idex (BMI), ad alcohol cosumptio. Specifically, curret use of uopposed estroge was associated with a reduced riskof ductal carcioma ad icreased riskof comedocarcioma, ad curret use of estroge ad progesti was associated with elevated risks of ductal-lobular ad tubular carciomas. Amog postmeopausal wome, BMI was oly iversely related to riskof ductal-lobular carcioma, ad alcohol use was oly positively related to riskof lobular carcioma. Coclusios: Variatios i the associatios betwee kow breast cacer riskfactors ad riskof differet breast cacer histologies were observed. Although these fidigs require cofirmatio, ad the aalyses of some histologic groups were limited by small sample sizes, they provide some isight ito the differet etiologies of various histologic subtypes of breast cacer. (Cacer Epidemiol Biomarkers Prev 2006;15(5):946 54) Itroductio Numerous risk factors for breast cacer have bee idetified, icludig a family history of the disease ad reproductive, hormoal, athropometric, ad lifestyle characteristics (1). However, most of these factors are associated with but a modest icrease i breast cacer risk. This may partly be because breast cacer is a heterogeeous disease. Histology is oe meas of categorizig breast cacers that seems to have etiologic importace, give the results of several recet studies evaluatig differeces betwee ductal ad lobular breast carciomas. Specifically, whereas it is ow well established that use of combied estroge ad progesti hormoe therapy amog postmeopausal wome icreases breast cacer risk Received 11/14/05; revised 2/16/06; accepted 3/1/06. Grat support: Natioal Istitute of Child Health ad Huma Developmet ad Natioal Cacer Istitute through Emory Uiversity cotract N01-HD , Fred Hutchiso Cacer Research Ceter cotract N01-HD , Karmaos Cacer Istitute at Waye State Uiversity cotract N01-HD , Uiversity of Pesylvaia cotract N01-HD , ad Uiversity of Souther Califoria cotract N01-HD , ad Ceters for Disease Cotrol ad Prevetio itra-agecy agreemet Y01-HD The costs of publicatio of this article were defrayed i part by the paymet of page charges. This article must therefore be hereby marked advertisemet i accordace with 18 U.S.C. Sectio 1734 solely to idicate this fact. Requests for reprits: Christopher I. Li, Fred Hutchiso Cacer Research Ceter, 1100 Fairview Aveue North, M4-C308, P.O. Box 19024, Seattle, WA Phoe: ; cili@fhcrc.org Copyright D 2006 America Associatio for Cacer doi: / epi (2, 3), six (4-9) of seve (10) studies that have specifically reported o associatios betwee differet types of hormoe therapy ad risk of lobular (pure lobular ad/or mixed ductallobular tumors) versus ductal carciomas idicate that this associatio varies by histologic type (4-9). The six studies reportig a differece by histology fid that whereas use of combied hormoe therapy is associated with 2.0- to 3.9-fold icreases i risk of lobular carcioma, it has less of a effect o ductal carcioma risk. Five (4-8) of these six studies, i fact, foud that combied hormoe therapy is ot associated with a elevated risk of ductal carcioma. Oral cotraceptives (11, 12) ad alcohol use (13) also seem to be more strogly associated with a icreased risk of lobular carcioma tha with ductal carcioma. However, earlier reproductive evets, such as parity, age at first full-term pregacy, ad breast-feedig, seem to be similarly related to risk of ductal, lobular, ad mixed ductal-lobular tumors (14). I additio to differeces i their risk factor profiles ad pathologic features, umerous cliical (15) ad molecular (16-19) differeces betwee lobular ad ductal carciomas have bee well described. These ivestigatios have provided isight ito differeces i the etiologies of lobular compared with ductal tumors, ad they suggest that lobular carciomas are more hormoally resposive tha ductal carciomas. Few studies have evaluated the relatioship betwee established breast cacer risk factors ad other histologic types. Such Cacer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer

2 Cacer Epidemiology, Biomarkers &Prevetio 947 ivestigatios are importat because the etiologies of rarer histologic types of breast cacer, which accout for f7% of all cases i the Uited States (20), are largely ukow. We evaluated the relatioships betwee major kow risk factors for breast cacer ad seve differet histologic types of breast cacer i a large multiceter U.S. case-cotrol study. Materials ad Methods Details of the methods used i the Wome s Cotraceptive ad Reproductive Experieces Study have bee described previously (21). Briefly, a populatio-based case-cotrol study was coducted at five metropolita sites i the Uited States (Atlata, Detroit, Los Ageles, Philadelphia, ad Seattle). White ad Black wome ages 35 to 64 years without a history of i situ or ivasive breast cacer who were diagosed with ivasive breast cacer from July 1994 to April 1998 were eligible as cases. These wome were ascertaied by Surveillace, Epidemiology, ad Ed Results registry staff at four sites (Atlata, Detroit, Los Ageles, ad Seattle) ad by field ceter staff at oe site (Philadelphia). Cotrols were wome without a history of breast cacer who were idetified usig radom digit dialig. Cotrols were frequecy matched to cases withi strata of site, race, ad 5-year age group; 76.5% of eligible cases ad 78.6% of eligible cotrols participated i this study, for a total of 4,575 cases ad 4,682 cotrols (21). The study protocol was approved by each of the local istitutioal review boards at each of the sites where this study was coducted. Writte iformed coset was obtaied from all study subjects. All iterviews were coducted i perso, typically i subjects homes, usig stadardized procedures. The mai purpose of this study was to assess the relatioship betwee oral cotraceptives ad breast cacer risk, but selfreported iformatio o other possible risk factors for breast cacer were also obtaied. The data collected icluded a detailed family history of cacer, reproductive history, athropometric characteristics, use of meopausal hormoe therapy, lifetime smokig history, ad lifetime alcohol use. The methods used to assess alcohol use (22) i this study are described i detail elsewhere. Our questioig was limited to exposures that occurred before each subject s referece date. The referece date used for each woma with breast cacer was her diagosis date. The referece date assiged to each cotrol was the date of our first radom digit dialig cotact with her household. The histology of each breast cacer case was ascertaied from the data collected by each of the Surveillace, Epidemiology, ad Ed Results cacer registries through routie medical record abstractios (except i Philadelphia where these data were collected by field ceter staff). Cases were grouped ito the seve followig histologic categories based o the Iteratioal Classificatio of Diseases-Ocology codes assiged to their tumors, similar to how they have bee categorized previously (20). The categories icluded were ductal (Iteratioal Classificatio of Diseases-Ocology code 8500, = 3,463), lobular (code 8520, = 274), ductal-lobular (code 8522, = 261), medullary (codes 8510 ad 8512, = 91), tubular (codes 8211 ad 8201, = 77), comedo (code 8501, = 70), ad mucious (code 8480, = 61). The 278 wome with other Iteratioal Classificatio of Diseases-Ocology codes, represetig 6.1% of all cases, were excluded from all of our aalyses, leavig a total of 4,297 cases. We compared cases of each histologic type to cotrols usig multivariate polytomous logistic regressio (23). All aalyses were coducted usig Stata SE versio 8.2 (Stata Corp., College Statio, TX). Odds ratios (s) ad associated 95% cofidece itervals were calculated as estimates of the relative risk. All aalyses were adjusted for age, race, ad study site because cotrols were frequecy Table 1. Distributio of demographic characteristics amog cotrols ad cases with differet histologic types of breast cacer Factor Cotrols ( = 4,682), (%) ( = 3,463), (%) ( = 274), (%) ( = 261), (%) ( = 91), (%) ( = 77), (%) ( = 70), (%) Mucious ( = 61), (%) Age (y) (14.2) 560 (16.2) 16 (5.8) 25 (9.6) 21 (23.1) 7 (9.1) 15 (21.4) 5 (8.2) (17.8) 594 (17.2) 33 (12.0) 41 (15.7) 18 (19.8) 6 (7.8) 11 (15.7) 8 (13.1) (18.3) 587 (17.0) 48 (17.5) 41 (15.7) 16 (17.6) 13 (16.9) 19 (27.1) 13 (21.3) (17.6) 610 (17.6) 48 (17.5) 71 (27.2) 15 (16.5) 20 (26.0) 10 (14.3) 9 (14.8) (17.1) 589 (17.0) 51 (18.6) 45 (17.2) 13 (14.3) 16 (20.8) 8 (11.4) 11 (18.0) (15.0) 523 (15.1) 78 (28.5) 38 (14.6) 8 (8.8) 15 (19.5) 7 (10.0) 15 (24.6) Race White 3,021 (64.5) 2,220 (64.1) 193 (70.4) 195 (74.7) 27 (29.7) 62 (80.5) 39 (55.7) 47 (77.0) Black 1,661 (35.5) 1,243 (35.9) 81 (29.6) 66 (25.3) 64 (70.3) 15 (19.5) 31 (44.3) 14 (23.0) Site* Atlata (84.4) 47 (5.5) 43 (5.0) 10 (1.2) 5 (0.6) 21 (2.5) 7 (0.8) Detroit (88.5) 33 (5.4) 14 (2.3) 6 (1.0) 9 (1.5) 2 (0.3) 6 (1.0) Los Ageles 1, (75.1) 65 (5.6) 112 (9.6) 45 (3.8) 27 (2.3) 26 (2.2) 16 (1.4) Philadelphia (80.2) 47 (7.2) 27 (4.1) 22 (3.3) 11 (1.7) 13 (2.0) 10 (1.5) Seattle 1, (79.1) 82 (8.2) 65 (6.5) 8 (0.8) 25 (2.5) 8 (0.8) 22 (2.2) Educatio c <High school 444 (9.5) 308 (8.9) 27 (9.9) 19 (7.3) 7 (7.7) 5 (6.5) 8 (11.4) 6 (9.8) High school 1,350 (28.8) 998 (28.8) 70 (25.5) 75 (28.7) 31 (34.1) 23 (29.9) 24 (34.3) 18 (29.5) Tech school 1,495 (31.9) 1,134 (32.8) 78 (28.5) 76 (29.1) 41 (45.1) 27 (35.1) 20 (28.6) 18 (29.5) College 1,393 (29.8) 1,022 (29.5) 99 (36.1) 91 (34.9) 12 (13.2) 22 (28.6) 18 (25.7) 19 (31.1) Icome, US$ <10, (8.7) 332 (9.9) 21 (8.0) 18 (7.1) 9 (10.5) 2 (2.7) 12 (17.6) 3 (5.1) 10,000-19, (10.3) 322 (9.6) 22 (8.4) 22 (8.7) 14 (16.3) 10 (13.3) 7 (10.3) 5 (8.5) 20,000-34, (20.3) 691 (20.7) 52 (19.8) 43 (17.1) 16 (18.6) 13 (17.3) 12 (17.6) 9 (15.3) 35,000-49, (17.3) 599 (17.9) 50 (19.0) 49 (19.4) 22 (25.6) 16 (21.3) 12 (17.6) 8 (13.6) >50,000 1,978 (43.4) 1,400 (41.9) 118 (44.9) 120 (47.6) 25 (29.1) 34 (45.3) 25 (36.8) 34 (57.6) *Row percetages for cases oly are show (all other percetages show are colum percetages). cdata o educatio level were missig for oe cotrol, ad data o household icome were missig for 121 cotrols ad 119 ductal, 11 lobular, 9 ductal-lobular, 5 medullary, 2 tubular, 2 comedo, ad 2 mucious cases. Cacer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer

3 948 Breast Cacer Risk Factors ad Histologic Subtypes Table 2. Relatioship betwee family history of breast cacer ad risk of differet histologic types of breast cacer Cotrols ( = 4,426) ( = 3,302) ( = 263) ( = 246) ( = 84) ( = 72) ( = 68) Mucious ( = 57) First-degree family history of breast cacer: all wome No 3,940 2, (ref) (ref) (ref) (ref) (ref) (ref) (ref) Yes P c homogeeity = 0.77 ( )* ( )* ( )* ( ) ( )* ( )* ( ) Cotrols ( = 1,740) ( = 1,379) ( = 90) ( = 113) ( = 44) ( = 24) ( = 33) Mucious ( = 18) First-degree family history of breast cacer: premeopausal wome No 1,783 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) Yes P c homogeeity = 0.88 ( )* ( )* ( )* ( )* ( )* ( ) ( ) Cotrols ( = 1,703) ( = 1,232) ( = 145) ( = 115) ( = 22) ( = 33) ( = 19) Mucious ( = 26) First-degree family history of breast cacer: postmeopausal wome No 1,657 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) Yes P c homogeeity = 0.51 ( )* ( )* ( )* ( ) ( ) ( ) ( ) P iteractio b = 0.15 NOTE: All s are adjusted for age, race, ad study site. *P < cp homogeeity i the s across the six differet histologic types of breast cacer. bp iteractio betwee meopausal status ad first-degree family history of breast cacer i relatio to risk of differet histologic types of breast cacer based o likelihood ratio testig. matched to cases o these variables. Multiple variables (listed i Tables 1, 2, 3, ad 4) were evaluated separately as potetial cofouders of each of the associatios we evaluated. We adjusted our aalysis of age at first full-term birth (defied as ay pregacy lastig >26 weeks) for age at mearche ad first-degree family history of breast cacer (history of breast cacer amog a mother, sister, or daughter) ad our aalysis of umber of full-term births for age at first full-term birth because iclusio of these factors i the statistical model altered the s of iterest by >10% (24). Usig this 10% criterio, o other variables were idetified as cofouders of the other exposures we assessed. We also assessed heterogeeity across the s for each exposure across each of the six histologic types of breast cacer studied by testig the ull hypothesis that each of these s were equivalet to each other (test of homogeeity of s). Our assessmet of hormoe therapy use was limited to postmeopausal wome. We assessed the relatioships betwee differet histologic types of breast cacer ad firstdegree family history of breast cacer, BMI (kg/m 2 ), ad lifetime alcohol use for premeopausal ad postmeopausal wome separately, as their associatios with breast cacer risk have bee show to vary by meopausal status (1). The statistical sigificace of the iteractio betwee meopausal status ad these exposures was assessed usig a likelihood ratio test, comparig a model that icluded oly the mai effects of two exposures with that of a model that icluded the mai effects ad the iteractio term. We also evaluated iteractio terms for meopausal status ad reproductive factors ad meopausal status ad height, but these iteractio models did ot differ from the mai-effects models (P iteractio > 0.05). Results Cotrols ad ductal carcioma cases, which comprised 80.6% of all cases, had similar age ad racial distributios (Table 1). Cases with lobular, ductal-lobular, tubular, or mucious cacers teded to be 50 years of age ad older ad more commoly White compared with cotrol participats, whereas those with medullary or comedo carciomas teded to be youger ad more commoly Black tha cotrols. Cotrols ad ductal cases also were similarly distributed across study sites, but the distributio of other histologic groups differed somewhat by study site. I particular, greater proportios of wome i Seattle ad Los Ageles had ductal-lobular carcioma, ad greater proportios of wome i Los Ageles ad Philadelphia had medullary carcioma compared with breast cacer cases erolled at the other study sites. For the most part, educatio level was similar across the cotrol ad case groups, although lobular ad ductal-lobular cases were somewhat more likely, ad medullary carcioma cases were somewhat less likely to have had some college educatio. With respect to icome, cotrol subjects ad ductal carcioma cases were similar, although patiets with ductal-lobular or Cacer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer

4 Cacer Epidemiology, Biomarkers &Prevetio 949 mucious tumors teded to have higher icomes, whereas those with medullary or comedo carcioma teded to have lower icomes. A first-degree family history of breast cacer was associated with a 1.7- to 2.1-fold icrease i risk of each histologic type of breast cacer except for mucious carcioma (, 1.0; 95% CI, ; Table 2). I geeral, the magitude of these associatios was stroger whe the aalysis was restricted to premeopausal wome; although meopausal status was ot a statistically sigificat effect modifier of this relatioship (P = 0.15). Amog premeopausal wome, those with a firstdegree family history of breast cacer had 2.1- to 3.5-fold icreases i risk of all histologic types of breast cacer (although the risks associated with comedo ad mucious carciomas were withi the limits of chace). Amog postmeopausal wome with a first-degree family history of breast cacer, 1.6- to 2.1-fold icreases i risks of ductal, lobular, ductal-lobular, tubular, ad comedo carciomas (but ot of medullary or mucious carciomas) were observed, although the risks associated with tubular ad comedo carciomas were withi the limits of chace. Although some differeces i the risks associated with various reproductive factors were observed by histologic type (described below), it is oteworthy that statistically sigificat heterogeeity i these risks across histologies was ot observed for ay of these factors (Table 3). Compared with wome whose age at mearche was 11 years or youger, those whose age at mearche occurred at 14 years of age or older had a reduced risk of lobular carcioma (, 0.5; 95% CI, ) that was statistically differet from the risk estimate for ductal carcioma (P = 0.02). Later age at mearche was ot related to risk of ay other histologic type of breast cacer. The s for parous wome compared with ulliparous wome raged from 0.6- to 0.9-fold for ductal, lobular, ductal-lobular, tubular, ad comedo carciomas, although the associatios with lobular ad comedo carciomas were withi the limits of chace. Furthermore, compared with ulliparous wome, wome who had three or more live births had reduced risks of ductal, lobular, ductal-lobular, tubular, comedo, ad mucious carciomas, although the associatios with tubular, comedo, ad mucious carciomas were withi the limits of chace. Compared with wome who were 19 years of age or youger at first-term pregacy, those whose first-term pregacy was at age 25 years or older had elevated risks of lobular carcioma. A statistically differet differece i the risk estimates associated with age at first full-term pregacy for lobular versus ductal carciomas was observed (P = 0.004). Compared with wome who ever breast fed or breast fed for V1 moth, the s for those who breast fed for z12 moths raged from 0.4 to 0.7 for ductal, medullary, tubular, ad Table 3. Relatioship betwee reproductive factors ad risk of differet histologic types of breast cacer Risk factor Cotrols ( = 4,682) ( = 3,463) ( = 274) ( = 261) ( = 91) ( = 77) ( = 70) Mucious ( = 61) Age at mearche (y) V11 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) ,459 1, ( )* ( ) ( ) ( ) ( ) ( ) ( ) z ( ) ( )* ( ) ( ) ( ) ( ) ( ) P c homogeeity = 0.35 Parity Nulliparous (ref) (ref) (ref) (ref) (ref) (ref) (ref) Parous 3,868 2, ( )* ( ) ( )* ( ) ( )* ( ) ( ) P c homogeeity = 0.22 No. full-term pregacies b Nulliparous (ref) (ref) (ref) (ref) (ref) (ref) (ref) ( ) ( )* ( ) ( ) ( ) ( ) ( ) 2 1,355 1, ( ) ( )* ( ) ( ) ( )* ( ) ( ) z3 1,795 P c homogeeity = , ( )* ( )* ( )* ( ) ( ) ( ) ( ) Age at first full-term pregacy x V19 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) , ( ) ( )* ( ) ( ) ( ) ( ) ( ) ( ) ( )* ( ) ( ) ( ) ( ) ( ) z ( ) ( )* ( ) ( ) ( ) ( ) ( ) P c homogeeity = 0.15 Duratio of breast-feedig (mo) Never/<1 2,020 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) , ( )* ( ) ( ) ( ) ( ) ( ) ( ) z ( )* ( ) ( ) ( )* ( ) ( ) ( ) P c homogeeity = 0.32 Type of meopause Natural 1,379 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) Iduced ( )* ( ) ( ) ( ) ( ) ( ) ( ) P c homogeeity = 0.72 Age at atural meopause k V (ref) (ref) (ref) (ref) (ref) (ref) ( ) ( ) ( ) ( ) ( ) ( ) ( ) z ( ) ( ) ( ) ( ) ( ) ( ) ( ) P c homogeeity = 0.34 NOTE: Except where oted, all s are adjusted for age, race, ad study site. *P < cp heterogeeity i the s across the six differet histologic types of breast cacer. bs are adjusted for age, race, study site, ad age at first full-term pregacy. xs are adjusted for age, race, study site, age at mearche, ad first-degree family history of breast cacer. klimited to wome who had a atural meopause. Cacer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer

5 950 Breast Cacer Risk Factors ad Histologic Subtypes Table 4. Relatioship betwee use of postmeopausal hormoe therapy ad risk of differet histologic types of breast cacer HT use Cotrols ( = 2,029) ( = 1,424) ( = 146) ( = 109) ( = 26) ( = 36) ( = 22) Mucious ( = 30) Never (ref) (ref) (ref) (ref) (ref) (ref) (ref) Former ( )* ( ) ( ) ( ) ( ) ( )* ( ) Curret E ( )* ( ) ( ) ( ) ( ) ( )* ( ) Curret E + P ( ) ( ) ( )* ( ) ( )* ( ) ( ) P homogeeity c = NOTE: All s are adjusted for age, race, ad study site. Abbreviatios: E, uopposed estroge hormoe therapy; E + P, combied estroge ad progesti hormoe therapy. *P < cp heterogeeity i the s across the six differet histologic types of breast cacer. mucious carciomas. The results for tubular ad mucious carciomas may have bee due to chace. Wome who had a iduced or surgical meopause (bilateral oophorectomy) were at lower risk of all histologic types, with s ragig from 0.4 to 0.9, but the results for ductal carcioma were withi the limits of chace. Wome with later ages at meopause (ages z51 years) had 1.5- to 7.8-fold icreased risks of ductal-lobular, medullary, ad tubular carciomas, but these icreases could also be chace fidigs. Compared with ever users of postmeopausal hormoe therapy, former users of ay type of hormoe therapy ad curret users of uopposed estroge had elevated risks of comedo carcioma (, 4.4; 95% CI, ad, 4.1; 95% CI, , respectively) ad reduced risks of ductal carcioma (, 0.7; 95% CI, ad, 0.7; 95% CI, , respectively) but did ot have altered risks of ay other histologic type of breast cacer (Table 4). Curret users of a estroge plus progesti (combied) regime had 1.5-fold (95% CI, ), 2.9-fold (95% CI, ), 3.2-fold (95% CI, ), ad 3.0-fold (95% CI, ) elevated risks of lobular, ductal-lobular, tubular, ad comedo carcioma, respectively (although the associatios with lobular ad comedo carcioma were withi the limits of chace). The test for homogeeity of risk across histologic types associated with use of hormoe therapy idicated a sigificat differece i the s (P = ). Also oteworthy was that a statistically sigificat differece was observed whe the risk estimates for ductal-lobular tumors were compared with those of ductal tumors (P = 0.003). However, o differeces were observed whe the risk estimates for ductal-lobular tumors were compared with lobular tumors or whe lobular tumors were compared with ductal tumors. Height was positively associated with risk of ductal-lobular ad mucious carciomas (for the comparisos of wome z170 cm versus those V 160 cm, the risks were, 1.5; 95% CI, ad, 2.5; 95% CI, , respectively; Table 5). However, heterogeeity across histologic types was ot observed (P = 0.52), ad the risk estimates for ductal-lobular ad mucious carciomas were ot statistically differet from those for ductal carcioma (P = ad P = 0.07, respectively). Amog premeopausal wome, BMI was ot associated with risk of ay histologic type of breast cacer, except that wome i the highest BMI group had a reduced risk of tubular breast cacer. This result, however, was based o very few wome. Amog postmeopausal wome, those i the upper tertile of BMI compared with wome i the lowest tertile had a reduced risk of ductal-lobular carcioma (, 0.6; 95% CI, ). Furthermore, wome i the upper two tertiles seemed to have reduced risks of lobular, tubular, ad mucious carciomas, but these reductios were withi the limits of chace. A statistically sigificat heterogeeity i the risks of differet histologic types of postmeopausal breast cacer associated with BMI was observed (P = 0.008), ad the risk estimates for ductal-lobular carcioma were statistically differet from those for ductal carcioma (P = 0.003). Wome who cosumed seve or more alcoholic beverages per week had elevated risks of ductal, lobular, ad medullary carciomas whe compared with wome who ever drak alcohol (, 1.2; 95% CI, ;, 1.5; 95% CI, ; ad, 1.9; 95% CI, , respectively; Table 6). However, alcohol use amog premeopausal wome was ot associated with risk of ay histologic type of breast cacer. I cotrast, elevatios i risks of ductal, lobular, ductal-lobular, medullary, ad mucious carciomas were observed amog postmeopausal wome who cosumed seve or more alcoholic beverages per week relative to odrikers (although oly the risk estimate for lobular carcioma was statistically sigificat). These estimates varied sigificatly across histologic types (P = ), ad i particular, the risk estimates for lobular tumors differed from those for ductal tumors (P = ). Discussio Certai limitatios of our study should be cosidered whe iterpretig the results. First, this study was limited by relatively small umbers of medullary, tubular, comedo, ad mucious carciomas. I our aalyses of these tumors, there were five or fewer cases i some of our exposure categories, resultig i estimates with wide cofidece limits. However, previous studies have ot comprehesively assessed the relatioships betwee various risk factors for breast cacer ad risks of these histologic types. Compared with other studies of breast cacer, this study was relatively large as it icluded 4,575 cases. Nevertheless, this study should be viewed as hypothesis geeratig, ad its results should be iterpreted with cautio particularly because we coducted multiple comparisos with umerous exposures ad outcomes. Aother limitatio of this study is that we did ot perform idepedet or cetralized pathology reviews of the tumors, but istead relied o the diagoses made by local pathologists across each of the study sites as recorded by the local Surveillace, Epidemiology, ad Ed Results registry (Atlata, Detroit, Los Ageles, ad Seattle) or ascertaied by our field staff (Philadelphia). Misclassificatio of tumor histology may have resulted i some cases. For istace, it is uclear whether or ot the differeces i the proportios of these tumors diagosed across the differet study sites is due differeces i the demographic ad risk factor profiles of these populatios (e.g., differeces i racial distributios or patters of hormoe therapy use) or to differeces i pathologic practices across these sites. However, all aalyses are adjusted Cacer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer

6 Cacer Epidemiology, Biomarkers &Prevetio 951 Table 5. Relatioship betwee athropometric factors ad risk of differet histologic types of breast cacer Cotrols ( = 4,681) ( = 3,457) ( = 274) ( = 261) ( = 91) ( = 77) ( = 70) Mucious ( = 61) Height, quartiles (cm): all wome V160 1,493 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) ,955 1, ( )* ( ) ( ) ( ) ( ) ( ) ( ) z170 1, ( ) ( ) ( )* ( ) ( ) ( ) ( )* P homogeeity c =0.52 Cotrols ( = 1,825), ( = 1,427) ( = 92) ( = 123) ( = 47) ( = 25) ( = 35) Mucious ( = 20) BMI at referece date, tertiles (kg/m 2 ): premeopausal V (ref) (ref) (ref) (ref) (ref) (ref) (ref) ( ) ( ) ( ) ( ) ( ) ( ) ( ) z ( ) ( ) ( ) ( ) ( )* ( ) ( ) P homogeeity c =0.28 Cotrols ( = 1,804), ( = 1,304) ( = 151) ( = 119) ( = 25) ( = 36) ( = 19) Mucious ( = 28) BMI at referece date, tertiles (kg/m 2 ): postmeopausal V (ref) (ref) (ref) (ref) (ref) (ref) (ref) ( ) ( ) ( ) ( ) ( ) ( ) ( ) z ( ) ( ) ( )* ( ) ( ) ( ) ( ) P homogeeity c =0.008 NOTE: All s are adjusted for age, race, ad study site. *P < cp homogeeity i the s across the six differet histologic types of breast cacer. for study site. Additioally, we were able to iterview oly 76.5% of eligible cases ad 78.6% of all eligible cotrols. Our results could be biased if the wome we were uable to iterview differed from those who did participate with regard to the various exposures we collected. Fially, similar to all studies of this type, we caot rule out the possibility of recall bias because we relied o participats recall of their exposures. I this comprehesive assessmet of associatios betwee established breast cacer risk factors ad risk of seve differet histologic types of breast cacer, we observed some variatios by histology. A first-degree family history of breast cacer was associated with elevatios i risk of similar magitudes for all histologic types of breast cacer except for mucious carcioma, ad the magitudes of these risks were geerally higher amog premeopausal wome compared with postmeopausal wome. However, meopausal status was ot a statistically sigificat effect modifier of these associatios, ad heterogeeity i the risk estimates was ot observed across the differet histologic types we evaluated. Oly oe previous study has evaluated the relatioship betwee family history of breast cacer ad risk of differet histologic types of breast cacer (25). This was a iteratioal multiceter hospital-based casecotrol study coducted by the WHO. It cosisted of 1,924 ductal, 303 lobular, 72 medullary, 18 tubular, ad 52 mucious carciomas. Similar to our study, it foud that wome with a family history of breast cacer had 2.2- to 3.0-fold icreases i risk of ductal, lobular, ad medullary carciomas. However, it also observed that a family history of breast cacer was associated with a elevated risk of mucious but ot tubular carciomas, although the umber of tubular cases icluded was quite small. A importat limitatio of the WHO study is that details of the aalytic approach used to estimate these risks (ad whether or ot aalyses cosidered potetial cofoudig factors) ad their 95% CIs were ot reported. Give that both the WHO study ad our study had limited umbers of cases with rare histologic types of breast cacer, further studies are eeded to evaluate how a family history of breast cacer alters risks of differet histologic types of breast cacer. With respect to reproductive factors, parity ad a iduced meopause were each associated with reduced risks of all histologic types. However, our results suggest that lobular carciomas may be more strogly iflueced by certai reproductive characteristics, as both a early age at mearche ad a late age at first live birth were associated with elevated risks of lobular but ot of ductal carcioma. Both of these ages are related to importat periods of breast proliferatio ad differetiatio (26-28). Age at mearche marks the period of rapid breast growth ad developmet that occurs with puberty. Age at first live birth marks the time whe breasts become further differetiated i respose to the hormoal stimuli of pregacy. This primarily ivolves the further differetiatio of lobular structures i the breast, which results i a log-term reduced risk of breast cacer. Thus, there may be a biological basis for the statistical associatios we foud betwee these two factors with lobular carcioma, although our fidigs should be iterpreted with cautio as they require replicatio i additioal studies. Not surprisigly, our results are cosistet with the recet report by Ursi et al. (14) who used these same data i a detailed evaluatio of the relatioships betwee certai reproductive characteristics ad risks of ductal, lobular, ad ductal-lobular carciomas oly. Similar to our aalyses of these data, they foud o sigificat heterogeeity i the risks Cacer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer

7 952 Breast Cacer Risk Factors ad Histologic Subtypes of these three histologic types for parity, umber of full-term pregacies, or breast-feedig. Three other studies have also evaluated the relatioship betwee reproductive factors ad the risk of differet histologic types of breast cacer. Agai, it is difficult to compare the results of the WHO study to our results because of the way i which the aalyses coducted were preseted. However, i a case-oly aalysis i which they compared patiets with lobular or tubular carciomas to those with other carciomas, they observed that wome with lobular/tubular carciomas were more likely tha wome with other histologic types of breast cacer to have had a later age at first live birth. Otherwise, they observed o differeces i the reproductive characteristics of lobular/tubular cases to cases with other histologic types. The secod study is a populatio-based Daish cohort study that icluded 8,669 ductal, 963 lobular, 294 medullary, 187 tubular, ad 143 mucious carciomas (29). The fidigs of this study are partially cosistet with ours i the followig respects: parity was associated with a reduced risk of ductal carcioma; wome who had three or more live births had a reduced risk of ductal carcioma but ot of ay other histologic types of breast cacer; ad a later age at first live birth was oly associated with elevated risks of ductal ad lobular carciomas, ad the magitude of this associatio was stroger for lobular tha for ductal carciomas. Ulike our study, parity was also associated with a reduced risk of mucious but ot lobular carcioma. Fially, the third study was a populatiobased case-cotrol study of wome ages 65 to 79 years coducted i the Seattle area that oly compared ductal ( = 656) ad lobular/ductal-lobular ( = 196) histologies (12). The results of the preset study compared with this study are similar with respect to breast-feedig but ot with respect to age at mearche, parity, umber of full-term births, type of meopause, or age at meopause. However, because the age group evaluated i our populatio did ot overlap with the age group icluded i that Seattle study, ad this study grouped lobular ad ductal-lobular cases together, the two are ot directly comparable. Thus, additioal studies are eeded to further clarify the relatioships betwee reproductive characteristics ad risk of differet histologic types of breast cacer. The differeces i risks associated with hormoe therapy betwee ductal ad lobular cases has bee reported previously usig data from this study (7), ad these differeces are cosistet with several other reports i fidig that use of combied estroge plus progesti therapy is more strogly associated with a icreased risk of lobular ad/or ductal/ lobular carciomas tha with risk of ductal carcioma (4-9). Here, we exted these aalyses to additioal histologic types, ad we observed that curret use of combied estroge plus progesti therapy is associated with elevatios i risk of both tubular ad comedo carciomas. We also observed that curret use of uopposed estroge was associated with a icreased risk of comedo carcioma but ot other histologic types of breast cacer. These fidigs suggest that tubular ad comedo carciomas may be two other histologic types of breast cacer (i additio to lobular ad ductal-lobular carcioma) that are stimulated by the use of exogeous hormoes amog Table 6. Relatioship betwee alcohol use ad risk of differet histologic types of breast cacer Cotrols ( = 4,676) ( = 3,454) ( = 273) ( = 260) ( = 91) ( = 76) ( = 70) Mucious ( = 61) Alcohol use (driks/wk): all wome Never 2,682 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) <7 1,522 1, ( ) ( ) ( ) ( ) ( )* ( ) ( ) z ( )* ( )* ( ) ( )* ( ) ( ) ( ) P homogeeity c = 0.22 Cotrols ( = 1,826) ( = 1,426) ( = 93) ( = 123) ( = 47) ( = 25) ( = 35) Mucious ( = 20) 95% CI) Alcohol use (driks/wk): premeopausal wome Never 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) < ( ) ( ) ( ) ( ) ( ) ( ) ( ) z ( ) ( ) ( ) ( ) ( ) ( ) ( ) P homogeeity c = 0.55 Cotrols ( = 1,806) ( = 1,302) ( = 152) ( = 119) ( = 25) ( = 35) ( = 19) Mucious ( = 28) Alcohol use (driks/wk): postmeopausal wome Never 1, (ref) (ref) (ref) (ref) (ref) (ref) (ref) < ( ) ( ) ( ) ( ) ( ) ( ) ( )* z ( ) ( )* ( ) ( ) ( ) ( ) ( ) P homogeeity c = 0.04 P iteractio b =0.47 NOTE: All s are adjusted for age, race, ad study site. *P < cp homogeeity i the s across the six differet histologic types of breast cacer. bp iteractio betwee meopausal status ad alcohol use i relatio to risk of differet histologic types of breast cacer based o likelihood ratio testig. Cacer Epidemiol Biomarkers Prev 2006;15(5). May 2006 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer

8 Cacer Epidemiology, Biomarkers &Prevetio 953 postmeopausal wome. I additio, we observed that use of uopposed estroge was iversely associated with ductal carcioma risk. This is cosistet with the Wome s Health Iitiative radomized trial of uopposed estroge, which foud a early statistically sigificat reductio i risk of breast cacer overall, of early the same magitude, amog uopposed estroge users (30). I additio, as previously reported by Dalig et al. (7), this reductio i risk was somewhat more proouced amog users of uopposed estroge for z5 years. However, these fidigs should be iterpreted with cautio because we had limited statistical power to assess these associatios by rececy or duratio of use, ad these results require cofirmatio i additioal studies. Our assessmet of athropometric factors suggests that taller wome have elevated risks of ductal-lobular ad mucious carciomas, ad that obese postmeopausal wome had a reduced risk of ductal-lobular carcioma. The Seattle study of wome ages 65 to 79 years described above also evaluated these associatios amog ductal ad lobular cases (12). It observed that taller wome had icreased risks of both ductal ad lobular/ductal-lobular carciomas, ad that obese wome had a icreased risk of ductal but ot of lobular/ ductal-lobular carciomas. Our results are, therefore, icosistet with the Seattle study, but we are also curious because we did ot observe the well-reported associatios with BMI ad breast cacer risk; that is, that obese premeopausal wome have a reduced risk of breast cacer, whereas obese postmeopausal wome have a icreased risk (1, 31). The reasos why these associatios were ot observed are uclear, although they could be the result of recall bias as data o all athropometric factors were based o self-report oly ad queried weight 5 years before the established referece date for each woma. We did coduct additioal aalyses of BMI amog our larger histology groups (ductal ad lobular) ad foud that the directios of the risks associated with BMI did ot chage for these subtypes whe we used either fier categories (quartiles) or cliically relevat categories (z25 kg/m 2 for overweight, z30 kg/m 2 for obese). I additio, o iteractio betwee BMI ad postmeopausal hormoe use, which has bee reported i other studies (32), was observed. With respect to alcohol use, we observed that wome who cosumed seve or more alcoholic beverages per week over their lifetime had icreased risks of ductal, lobular, ductallobular, ad medullary carciomas. This relatioship seemed to vary by meopausal status, as alcohol use was ot associated with risk of ay histologic type of breast cacer amog premeopausal wome but was associated with icreased risks amog postmeopausal wome, particularly for lobular carcioma. A stroger associatio betwee alcohol use ad risk of lobular compared with ductal carcioma amog postmeopausal wome has bee observed previously (13). I additio, whereas differeces betwee risks of lobular ad ductal carciomas associated with alcohol use have already bee reported usig data from this study (22), this aalysis did ot evaluate risk amog the other histologic types separately. Although alcohol use has bee cosistetly show to cofer a modest icrease i risk of breast cacer (33), the magitude of this associatio does seem to vary by histologic type. Multiple hypotheses have bee proposed to explai the relatioship betwee alcohol use ad breast cacer risk. Oe of the mai hypotheses relates to the effects that alcohol has o icreasig hormoe levels i postmeopausal wome (34). Give that lobular carcioma seems to be more hormoally resposive compared with other histologic types of breast cacer, icludig ductal carcioma, because these tumors are more commoly estroge ad progesteroe receptor positive (35, 36), a stroger associatio betwee alcohol ad lobular carcioma is ot surprisig ad has ow bee observed i more tha oe study. Because this is oe of the first reports to documet may of these associatios, ad because we were limited by relatively small umbers of cases of certai histologic types, these results eed to be iterpreted with cautio. The aalyses preseted here should be viewed as hypothesis geeratig because the fidigs were based o multiple comparisos. However, where prior data exist, our results are geerally cosistet with the associatios reported. Thus, take as a whole, our study ad previous studies idicate that risk factor profiles may vary to some extet by histologic type. These variatios may poit to differeces i the etiologies of differet histologic types of breast cacer. A greater uderstadig of pathways leadig to differet breast cacer histologies may be a importat meas of advacig our kowledge of this heterogeeous disease. Ackowledgmets We thak the Ceters for Disease Cotrol for additioal staff ad computer support. Refereces 1. Berstei L. The epidemiology of breast cacer. Wome Cacer 1998;1S: Collaborative Group o Hormoal Factors i Breast Cacer. Breast cacer ad hormoe replacemet therapy: collaborative reaalysis of data from 51 epidemiological studies of 52,705 wome with breast cacer ad 108,411 wome without breast cacer. Lacet 1997;350: Chlebowski RT, Hedrix SL, Lager RD, et al. Ifluece of estroge plus progesti o breast cacer ad mammography i healthy postmeopausal wome: the Wome s Health Iitiative Radomized Trial. JAMA 2003;289: Li CI, Weiss NS, Staford JL, Dalig JR. 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10 Dowloaded from cebp.aacrjourals.org o November 25, America Associatio for Cacer Relatioship betwee Established Breast Cacer Risk Factors ad Risk of Seve Differet Histologic Types of Ivasive Breast Cacer Christopher I. Li, Jaet R. Dalig, Kathlee E. Maloe, et al. Cacer Epidemiol Biomarkers Prev 2006;15: Updated versio Access the most recet versio of this article at: Cited articles Citig articles This article cites 33 articles, 5 of which you ca access for free at: This article has bee cited by 12 HighWire-hosted articles. Access the articles at: alerts Sig up to receive free -alerts related to this article or joural. Reprits ad Subscriptios Permissios To order reprits of this article or to subscribe to the joural, cotact the AACR Publicatios Departmet at pubs@aacr.org. To request permissio to re-use all or part of this article, use this lik Click o "Request Permissios" which will take you to the Copyright Clearace Ceter's (CCC) Rightslik site.