Breast Cancer Epidemiology · BREAST CANCER EPIDEMIOLOGY although its possible adverse effect on fibrocystic breast disease (26) has not been entirely ruled out (27-35). Available

[CANCER RESEARCH 48, 5615-5623, October 15, 1988]

Perspectives in Cancer Research

Breast Cancer EpidemiologyJennifer L. Kelsey1 and Gertrud S. Berkowitz

Columbia University School of Public Health, New York, New York 10032 [J. L. K.J, and Mount Sinai School of Medicine, New York, New York 10029 [G. S. B.J

Established Breast Cancer Risk Factors

Various risk factors for breast cancer have been recognizedfor many years. Table 1 lists these established breast cancer riskfactors together with the approximate magnitude of the increasein risk associated with them (1). Among the demographicvariables, breast cancer incidence rates increase with agethroughout the life span in Western countries, although therate of increase is greater up to age 50 years than after 50 years.Breast cancer is more common among women in upper socialclasses than among women in lower social classes, amongwomen who have never been married than in women who havebeen married, among women living in urban areas than in ruralareas, among women living in the Northern United States thanin the Southern United States, and among whites than blacks,at least among those over 50 years of age.

Women in North American and Northern European countries have the highest risk for breast cancer, women in SouthernEuropean and Latin American countries are at intermediaterisk, and women in African and Asian countries have the lowestrisk. However, rapid rates of increase in incidence rates havebeen noted in recent years in many Asian, Central European,and some South American countries. Most of the increase thusfar has occurred in women under the age of 50 years, but it islikely that the increase will persist throughout life as theyounger generation ages. If the increases in incidence rates inyoung women in these previously low-risk countries continuethroughout their life span, then it is predicted that the annualworldwide incidence of breast cancer will be over 1,000,000cases by the year 2000 (2).

Among reproductive variables, the later the age at which awoman has her first full-term pregnancy, the higher is her riskfor breast cancer; the earlier the age at menarche and the laterthe age at menopause the higher is the risk; and, among womenwho have a premenopausal oophorectomy, the earlier the ageat which this occurs the lower is the risk. Also, among post-menopausal women, obesity is associated with an increase inrisk, probably because of the greater rate of conversion ofandrostenedione to estrone in the adipose tissue of obesewomen and the lower levels of sex hormone-binding globulinin obese than in nonobese women.

Evidence from many studies over the years has indicated thatlactation is negatively associated with subsequent breast cancerrisk only because the length of lactation is associated with thenumber of full-term pregnancies, which is in turn associatedwith age at first full-term pregnancy (1). However, a few recentstudies (3, 4) have suggested that lactation may have an independent protective effect against breast cancer in premenopausal women when effects of other risk factors are taken intoaccount in the statistical analysis. These recent findings meritfurther study. Some studies (5-8), but not others (9-11), have

Received 2/18/88; revised 7/5/88; accepted 7/11/88.' To whom requests for reprints should be addressed, at Division of Epide

miology. Columbia University School of Public Health, 600 W. 168th St., NewYork, NY 10032.

reported that a history of induced or spontaneous abortions isassociated with an increased risk for breast cancer. Occasionalreports that age at last pregnancy (12) or total number ofpregnancies (8, 10, 11, 13, 14) have independent effects onbreast cancer risk need to be evaluated in additional studies.

Other factors known to increase the risk for breast cancerinclude a family history of breast cancer, especially if it ispremenopausal or bilateral in a first-degree relative, a historyof cancer in one breast, a history of fibrocystic breast disease, ahistory of a primary cancer in the ovary or endometrium, anda history of radiation to the chest in relatively large doses.

It may be noted in Table 1 that most of the established riskfactors for breast cancer are associated with only a modestincrease in risk. In fact, the American Cancer Society (15) hasestimated that only about one-fourth of breast cancer cases canbe accounted for by known risk factors. Thus, much of theetiology is still unexplained, and hitherto unidentified riskfactors remain to be identified. Also, the mechanisms by whichmost of the established risk factors have their effects have notyet been elucidated. To what extent, then, is current researchfilling these gaps? What are the areas of greatest researchinterest at present?

Areas of Current Research Interest

Some current research is considering potential risk factorsthat have not been well studied in the past, including alcoholconsumption, cigarette smoking, caffeine consumption, exposure to DES,2 emotional stress, exposure to electric power, and

lack of physical activity. Other research seeks to obtain moredetailed knowledge about risk factors previously identified, suchas a family history of breast cancer, a history of benign breastdisease, and radiation. Risk factors for which previous epidemiolÃ³gica! data are not entirely consistent are also being studied, such as mammographie parenchyma! patterns. Still otherepidemiolÃ³gica! research seeks to clarify the role of agentsstrongly suspected from animals or other types of evidence tobe etiologically involved, but for which the human epidemiolog-ical evidence is weak or inconsistent. Included in this categoryare a high-fat diet, use of oral contraceptives, use of estrogenreplacement therapy, and endogenous hormones.

Cigarette Smoking, Caffeine, Emotional Stress, Electric PowerUse, and Physical Activity

Among the agents upon which interest has only recently beenfocused, cigarette smoking and caffeine consumption do notappear promising as potential etiological agents. Evidence fora protective effect of cigarette smoking ( 16), possibly mediatedthrough smoking-related changes in estrogen metabolism andage at menopause, has been contradictory and inconclusive(17-20), and at most the effect is small. Caffeine consumptiondoes not appear to be related to breast cancer risk (21-25),

2The abbreviation used is: DES, diethylstilbestrol.

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BREAST CANCER EPIDEMIOLOGY

although its possible adverse effect on fibrocystic breast disease(26) has not been entirely ruled out (27-35). Available evidencedoes not suggest that exposure to emotional stress increasesthe risk for breast cancer (36), and an association betweenelectric power use and breast cancer has been hypothesizedwithout supporting data (37).

A report (38) that women who are physically active at anearly age have a reduced risk for breast cancer needs to beevaluated in other studies. Physical activity would affect breastcancer risk through its effect on reproductive function, sinceevidence indicates that even moderate physical activity at anearly age decreases the frequency of ovulatory menstrual cycles(39) and that moderate physical activity in young adults depresses luteal progesterone levels (40).

Alcohol Consumption

A positive association between alcohol consumption andbreast cancer has now been reported in several, but not all,epidemiolÃ³gica! studies (18, 41-49) (see Table 2, for example).Although most studies have reported an increased risk of approximately 50%, this estimate is associated with levels ofconsumption ranging from fewer than three drinks per week(49) to three or more drinks per day (45). Similarly, the findingswith respect to type of alcoholic beverage have not been entirely

Table 1 Risk factors for breast cancer in female f

FactorAgeCountry

ofbirthSocioeconomic

classMaritalstatusPlace

ofresidencePlaceofresidenceRaceAge

at firstfull-termpregnancyOophorectomyBody

build,postmeno-pausalAge

atmenarcheAgeatmenopauseFamily

history ofpre-menopausalbilateralbreast

cancerHistoryof cancer inonebreastHistory

of fibrocystic diseaseAny

first-degreerelativewithbreastcancerHistoryof primary can

cer in ovary' orendo-metriumRadiation

to chestHigh

riskOldNorth

America,NorthernEu

ropeUpperNever

marriedUrbanNorthern

U.S.WhiteOlder

than30NoObeseEarlyLateYesYesYesYesYesLarge

dosesLow

riskYoungAsia,

AfricaLowerEver

marriedRuralSouthern

U.S.BlackYounger

than20YesThinLateEarlyNoNoNoNoNoMinimal

exposureMagnitude

of riskdifferential>Â»>Â»Â»>>>>Â»Â»Â»>>>Â»>Â»Â»Â»Â»Â»

* Adapted from Ref. 1. >Â». relative risk of >4.0; Â», relative risk of 2.0-4.0; >, relative risk of 1.1-1.9.

Table 2 Adjusted relative risk far breast cancer according to level of daily alcoholintake"

Alcohol intake(g/day)None

<1.51.5-4.95.0-14.9

alS.OAdjusted*

relative

risk1.0

1.00.91.31.695%

confidencelimits0.8-1.3

0.7-1.21.0-1.61.3-2.0

consistent (42,46-48). Unreliable reporting, inconsistent measurements of alcohol intake, and the difficulty of accuratelyquantifying alcohol consumption represent the most likely explanations for the varied results. Inappropriate control groupsand lack of assessment for the possible confounding effects ofother dietary factors in some studies may also have contributedto the inconsistent findings (50).

While future studies are unlikely to eliminate misclassifica-tion with respect to exposure, the use of standardized questionsfor measuring alcohol intake and consistent assessment ofpotentially confounding variables would help to resolve someof the conflicting findings. Other issues that merit attentioninclude the timing and duration of alcohol exposure. Drinkingbefore the age of 30, regardless of later consumption, was foundto increase the risk of breast cancer in one recent study (47).Further confirmation of this finding is needed to determinewhether the age at which drinking began is an important factor.

Whether it is the alcohol or some other characteristics ofwomen who drink alcoholic beverages that brings about thereported increase in risk remains uncertain. Knowledge of themechanism by which alcohol has its effect would make theassociation easier to interpret. Possible mechanisms that havebeen suggested include interference with cell membrane permeability in breast tissue (51), exposure to circulating cytotoxicproducts of ethanol (52), and altered hepatic function, which inturn could affect hormone metabolism (53). Furthermore, if aspecific component of alcohol can be implicated, this mightsuggest other agents with similar biochemical properties thatmight also be risk factors.

Use of Diethylstilbestrol during PregnancySeveral studies (54-57) have reported that women who used

DES during pregnancy subsequently have an elevated risk forbreast cancer (see Table 3). The magnitude of the relative risksin these studies has been around 1.5 and generally increaseswith increasing estimated dose of the DES. Although it wasnot possible in some of the studies to separate out the effect ofDES from an effect related to the reason DES was prescribed(in most cases, to prevent spontaneous abortion), the evidenceis suggestive of a causal association. Some would argue thatthis is of little significance because DES is no longer used forthe purpose of preventing spontaneous abortions. However,this observation may be important in that it suggests thatexposure to high doses of certain agents over a short but criticaltime period (e.g., during a period of rapid growth of breasttissue during pregnancy) may increase the risk for breast cancer.This would suggest that epidemiolÃ³gica! research into breastcancer etiology should pay more attention to potentially criticaltimes of exposure, even though the exposure may have been oflimited duration.

Genetic Studies

The extent to which the increased breast cancer risk amongwomen with an affected first-degree relative (58-67) is attrib-

Table 3 Relative risk for breast cancer according to time since exposure todiethylstilbestrol while pregnant"

Time sinceexposure(yr)0-9

10-1920-2930-39Relative

risk1.0

1.11.62.595%


0.7-1.81.0-2.41.1-5.8

Â°Adapted from Ref. 48.* Adjusted for age, menopausa! status, age at first birth, age at menarche,

maternal history of breast cancer, and parity.

All exposed 1.4 1.1-1.9Â°Adapted from Ref. 57.

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utable to genetic as opposed to environmental factors is notknown. Heredity has been found to be important in at leastsome families, however. In a few pedigrees, predisposition tobreast cancer development appears to be inherited in a dominant fashion (68). The recently reported finding that familieswith ataxia-telangiectasia, an autosomal recessive syndrome,have an excess of breast cancer lends further credence to thehypothesis of a genetic component in some families (69). Linkage analysis showing that the glutamate-pyruvate transaminaselocus may be linked to an alÃelethat increases susceptibility tobreast cancer (70, 71) has not been replicated in subsequentinvestigations (2, 72). However, the new DNA technology utilizing probes for possible marker genes may enable furtherelucidation of the role of genetics in breast cancer etiology.

Benign Breast Diseases

Since benign breast disease encompasses a broad spectrumof histological changes, breast cancer risk has been furtherevaluated according to the histopathological characteristics ofthe biopsy specimens (73-80). Growing evidence indicates thatthe elevation in breast cancer risk may be limited to womenwith proliferative disease (73, 76-80), particularly the smallproportion of women with atypical hyperplasia who have beenestimated to have approximately a 5-fold increased risk ofbreast cancer (76-80). Calcification in the biopsy specimens(73,80) and possibly large breast size (81) may further increasethe risk in women with proliferative disease. A family historyof breast cancer and late age at first birth (or nulliparity) havealso been suggested to be more important risk factors in womenwith proliferative disease than in those who have nonprolifera-tive lesions (80, 81).

Additional studies are needed to confirm the finding that therisk of breast cancer among women with benign breast diseasesis largely confined to the subgroups with proliferative disease.In addition, further assessment of interactions among breastcancer risk, proliferative disease status, and other establishedrisk factors may not only improve identification of high-riskgroups but also provide clues regarding underlying mechanisms.

Mammographie Parenchyma! Patterns

Wolfe (82, 83) proposed that mammographie parenchymalpatterns are highly predictive of subsequent breast cancer. Fourpatterns (Nl, PI, P2 and DY) were described on the basis ofthe relative amounts of fat, ducts, and densities seen on xero-mammograms. Although subsequent studies of Wolfe's classi

fication have not yielded consistent results (84-92), sufficientevidence exists to indicate that the most dense patterns (P2 andDY) are associated with relative risks of approximately thesame magnitude as well-established risk factors for breast cancer (93). The associations between parenchymal patterns andrecognized breast cancer risk factors have also been explored.Several studies have shown an inverse association with parity(87, 89, 94-98), a positive association with age at first birth(84,94-96,98,99), and an inverse association with body weight(92, 95, 99-101), but no consistent results have been observedfor other established breast cancer risk factors.

The existing data suggest that parenchymal patterns represent an additional risk factor but not a major marker for futureoccurrence of breast carcinoma. Since some of the inconsistentresults may reflect lack of standardized methods for classifyingmammograms (93), more rigorous adherence to Wolfe's system

may clarify some of the discrepancies. Additional studies of the

relationship between parenchymal patterns and other breastcancer risk factors, including the histopathological features ofbenign breast lesions, may further our understanding of the roleof mammographie patterns in breast cancer development.

Radiation

It is widely accepted that relatively high doses of ionizingradiation can cause breast cancer, but questions have remainedregarding the shape of the dose-response curve, the importanceof age at exposure, and the length of the latency period. Pastestimates have suggested a straight-line relation between doseand radiation-induced breast cancer (102-106) but, apart fromthe studies on atomic bomb survivors (107), empirical datademonstrating a breast cancer excess at low doses are lacking(108-110). With respect to age at exposure, it was traditionallybelieved that the susceptibility of the breast to the carcinogeniceffects of radiation was maximal between the ages of 10 and 20years while breast tissue is rapidly developing and decreasedafter age 30 with little or no risk before age 10 or after age 40(102-104,106, 111, 112). However, two groups of investigatorshave recently reported excess breast cancer risks among womenwho were below the age of 10 at the time of the exposure (113-115). Since the excess risk was not apparent until the womenhad reached the age at which breast cancer rates normallyincrease, these data also support the previous observation thatyounger women may have a longer latency period than olderwomen (106). Questions about the risk of low-dose exposure,age of exposure, and latency periods are of considerable interestin light of the frequent use of diagnostic radiography and thegrowing use of mammography for breast cancer screening.While current estimates suggest that diagnostic radiographyhas a small effect on the occurrence of breast cancer (116) andsubstantial evidence indicates that mammography screeningprograms reduce breast cancer deaths in women age 50 or older(117-121), further research needs to refine the risks of routineradiography as well as establish the risk-benefit ratio for mammography in younger women.

Diet

Dietary fat has long been suspected of playing a role in theetiology of breast cancer. This suspicion stems from animaldata (122, 123), marked international correlations between percapita fat "disappearance" data and breast cancer incidence and

mortality rates (124), migrant studies (125), and temporal increases in breast cancer incidence paralleling higher rates of fatintake (126, 127). However, many other factors could explainthese differences in breast cancer incidence rates over time andgeographic area, and the applicability of animal studies tohuman studies is uncertain. Thus, the results of these positivestudies should at most be considered suggestive.

In contrast, Table 4 shows results from one of the recentprospective cohort studies in which fat intake is slightly negatively associated with breast cancer risk. In general, epidemio-

Table 4 Age-adjusted relative risk of breast cancer according to quantitÃ©ofcalorie-adjusted intake of total faf

Quantile ofintake1

(low)234

5 (high)Age-adjusted

relativerisk1.0

0.80.90.80.895%


0.7-1.10.6-1.00.6-1.1

'Adapted from Ref. 138.

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logical case-control and cohort investigations have found eitherweak associations (either positive or negative) or no associationbetween fat intake and breast cancer risk (128-138). In thesestudies, however, measurement of diet may be so inadequatethat a real association may be missed. A study of vegetariannuns in the United Kingdom found that the nuns did not havelower breast cancer mortality rates than single women in thegeneral population (139), although perhaps other pertinentdifferences existed between the nuns and other women. Insummary, the role of a high fat diet in breast cancer etiology isuncertain, but if it is a risk factor, it is unlikely to be a strongone.

The effect of diet on endogenous hormones that may beinvolved in the pathogenesis of breast cancer has been explored,but the results thus far are either inconsistent or need furtherconfirmation (140-145). Recent studies (146, 147) have similarly failed to support the hypothesis that low dietary seleniumintake is associated with an increased risk of breast cancer(148).

It is also plausible that total calories consumed is the mostimportant dietary characteristic. Some animal evidence supports this possibility, and in humans total calories could influence breast cancer risk through its effect on obesity and age atmenarche (50).

If diet is related to breast cancer, not only will it be importantto identify the specific etiological components of diet but alsothe age at which such dietary constituents have their effect. Ifthe effect of diet is mediated by age at menarche, then little isto be gained (with respect to breast cancer risk) by changing thediet of older women. If the role of diet is primarily as a latestage promoter, then young women may indulge to their hearts'

content and alter their diet when they reach middle age. Designing epidemiolÃ³gica! studies to test dietary hypotheses isexceedingly difficult. Given the likely extent of measurementerror, observational studies are likely to be inconclusive. Giventhe probably small or moderate association at most betweendiet and breast cancer, randomized trials require such largesample sizes as to be almost prohibitively expensive. Thus, it isdifficult to suggest what directions epidemiolÃ³gica! studiesshould take. Further research elucidating biochemical and metabolic mechanisms may provide additional information aboutthe likelihood that a high-fat diet affects breast cancer risk.

Oral Contraceptives

Perhaps the greatest interest and greatest controversy inbreast cancer epidemiology has surrounded the questions ofwhether use of oral contraceptives and use of estrogen replacement therapy affect risk for breast cancer. Regarding oralcontraceptive use, almost all studies find that in the vast majority of women, oral contraceptive use neither increases nordecreases the risk for breast cancer (5, 10, 149-169). However,whether certain subgroups of women have their risk increasedif they use oral contraceptives is controversial. Among thesubgroups for which evidence is at least suggestive, but nevertheless inconsistent, are women with a history of biopsy-provedbenign breast disease (7, 149, 150, 160, 162, 170), women whouse oral contraceptives at an especially late age (46-55 years ofage) (166), and women who use oral contraceptives at anespecially early age (<20 years of age) and/or before their firstpregnancy (7, 10, 170-174). It is difficult to separate effects ofuse at an early age from use before the first pregnancy becausethese two variables are so highly correlated.

Particular concern (and controversy) has been focused on the

subgroup of women who use oral contraceptives very early intheir reproductive years. Some studies have shown an adverseeffect from use at an early age or use before the first pregnancy(7, 10, 170-174) (see Table 5, for instance), while others havenot (164, 175-178). In both camps, some studies have beenwell designed, while others have had methodological deficiencies. Various possible reasons for these discrepant results havebeen proposed, such as varying patterns of oral contraceptiveuse in different geographic regions ( 179,180), different calendaryears of introduction of oral contraceptives in various geographic regions and thus limitations of the possible latencyperiod in some areas ( 180-182), inadequate methods of analysis(179, 183-186), different oral contraceptive formulations indifferent time periods and places (179), differential responserates (187), greater surveillance for breast disease in oral contraceptive users (185), different methods of interviewing casesand controls (188,189), and inappropriate control groups (183).However, in our view, none of these explanations is likely toaccount for the differences among at least some of the betterdesigned studies, yet we are unable to suggest any better explanations. Recently, McPherson et al. (173) have presented datasuggesting that long-term use at an early age of compoundswith ethinylestradiol as the estrogen may be associated with anincrease in risk and that a latent period of 15-20 years is neededbefore the increase in risk is seen. This hypothesis needs to beevaluated in other sets of data that include sufficient numbersof women who have used oral contraceptives for relatively longperiods of time at a young age.

In addition, a recent Scandanavian study has reported anassociation with long-term use (>12 years) of oral contraceptives regardless of whether oral contraceptives were used beforethe first pregnancy (180). It has been suggested that oral contraceptive use began on a large scale earlier in Sweden thanelsewhere and that other geographic areas will show this increase in risk with long-term use when more time has elapsed.However, data from New Zealand, in which oral contraceptiveuse began earlier than in Sweden, do not show this increase inrisk with long-term use (178).

It appears to us that at least three important questionsremained unresolved with regard to oral contraceptives andbreast cancer: (a) Does very long-term use (for instance, 15years or more) increase the risk? (b) Does use at a very youngage increase the risk? (c) Do the specific constituents of theoral contraceptives make a difference? To answer these questions, more time is needed to allow assessment of risk in a largeenough number of women who have used specific oral contraceptives for very long periods of time or who started use at veryyoung ages. Use at very young ages could represent one of thecritical time periods mentioned above.

Estrogen Replacement Therapy

Likewise, the literature on use of estrogen replacement therapy and risk for breast cancer is inconsistent, and again the

Table 5 Relative risk of breast cancer in those younger than 45 years of ageaccording to duration of use for oral contraceptives before first full-term

pregnancy"

Duration ofuse(mo)Never

1-1223-48

>48Adjusted*

relative

risk1.0

1.02.02.695%


1.0-3.81.3-5.4

â€¢Adapted from Ref. 173.b Adjusted for age at first term birth, age at menarche, menopausa! status,

history of benign breast disease, and family history of breast cancer.

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elapse of additional time may be the main hope for resolvingthe controversy. Most studies (5, 149, 152, 153, 156, 190-196)have reported that estrogen replacement therapy does not increase the risk for breast cancer. Until recently, among thestudies that have noted an increased risk (197-201), the elevation in risk has for the most part been seen only in certainsubgroups. For instance, some investigators have found theincreased risk only among those who have had a bilateraloophorectomy (197, 199), while others have noted the increasedrisk only in women with ovaries intact (200, 201). Such inconsistencies suggest that these findings in specific subgroups areprobably attributable to chance. A few studies (197, 199, 201,202) have also noted that women with a history of biopsy-confirmed benign breast disease may be at particularly high riskif they also use estrogen, a finding difficult to interpret in lightof the uncertainty as to what benign breast disease really is.

Two recent studies (202, 203) were based on large enoughnumbers of women who had used estrogen replacement therapyfor 15 years or more that a possible effect in these very long-term users could be examined with some degree of power. Onestudy (202) reported a relative risk of 1.5 among women whoused estrogen for 20 years or more (see Table 6). The otherstudy (203), based on case and controls of ages 20-54 years,found a relative risk of 1.7 in women with a bilateral oophorectomy who had used estrogen for 15 years or more and a relativerisk of 2.0 in women who had undergone hysterectomy and hadone or two ovaries intact and who had a similar duration ofestrogen therapy. Numbers of very long-term users amongwomen undergoing natural menopause were not sufficient foran effect to be studied. Although the former study found asignificant trend with length of use, no such trend was apparentin the latter study. A trend with length of use was also noted ina case-control study from Italy (204), however. A few studies(195,197, 201) have also suggested slightly increased risks withincreasing doses of estrogen.

Current evidence thus indicates either that estrogen replacement therapy has no effect on breast cancer risk or that it hasa modest effect (i.e., relative risk of less than 2.0) in womenwho have used estrogen for long periods of time or who haveused estrogens at relatively high dosages. It is obviously important to determine whether or not risk is in fact somewhatelevated. Therefore, additional studies based on relatively largenumbers of women who have used estrogen replacement therapy for 15 years or more are of highest priority. Whetheraddition of progestin to estrogen has any effect on breast cancerrisk also needs to be carefully monitored, inasmuch as studiesto date have been inconclusive. Any effect of estrogen replacement therapy on breast cancer risk would have to be consideredin conjunction with the established protective effect of replacement estrogen against osteoporotic fractures and the establishedincreased risk for endometrial cancer, and the probably decreased risk for coronary artery disease.

Table 6 Adjusted relative risk for breast cancer according to number of years ofuse of estrogen replacement therapy*1

Yrofuse0<55-910-1415-19>20Adjusted*

relative

risk1.00.91.11.31.21.595%confidence

limits0.8-1.00.9-1.30.9-1.60.9-1.80.9-2.3

" Adapted from Ref. 202.* Adjusted for age, type of menopause, and interval since oophorectomy. P <

0.01 for test for trend among users.

Endogenous Hormones

Finally, epidemiological studies have also been concernedwith the possible etiological significance and usefulness asmarkers of risk of different patterns of circulating endogenoussteroid hormones and their metabolites, including estrone, es-tradiol, 2-hydroxyestradiol, estriol, androstenedione, testosterone, and progesterone, as well as blood levels of sex hormone-binding globulin and prolactin. Some recent evidence (205,206) suggests that studies of hormone levels in serum need tobe supplemented by measurements of hormone levels in breastfluid, since breast fluid estrogen levels may be 5 to 45 timeshigher than serum levels, and the levels in these different tissuesare not correlated. As more is learned about measurement andstorage issues and of how these hormones interact with eachother, it is hoped that a clearer picture of the role of endogenoushormones will emerge. Studies of levels and metabolism ofendogenous hormones and blood-borne steroid-binding proteins should lead to a better understanding of the mechanismsunderlying the relation of known risk factors, such as age atfirst birth, age of menarche, and age at menopause, to thedevelopment of breast cancer.

Some studies have sought to determine associations of riskfactors with development of tumors of different degrees ofdifferentiation and estrogen receptor status. Such studies couldshed light on the role of endogenous hormones in breast canceretiology. Results of studies through 1985 have been reviewedby Stanford et al. (207). Unfortunately, other than an increasingproportion of estrogen receptor-positive tumors with increasingage, a higher proportion of estrogen receptor-positive tumorsin whites than in blacks, and possibly a higher proportion ofestrogen receptor-positive tumors in postmenopausal womenthan in premenopausal women independent of age, resultsregarding other established and potential risk factors have beeninconsistent (207-214). Why different results have been obtained in various studies is unclear, but to date these studieshave not increased our understanding of the relationship between endogenous hormones and breast cancer or of the mechanisms of action of established risk factors. In fact, it remainsto be determined whether the estrogen receptor status of adiagnosed tumor is in any way influenced by exposures beforethe tumor developed or during early stages of tumor development, and whether the receptor status of a tumor reflects thereceptor status of the cells from which the tumor arose. Likewise, it is not known whether the estrogen receptor status ofnormal cells affects the likelihood of cancer following exposureto a carcinogenic agent.

The correlation between estrogen receptor status and progesterone receptor status is sufficiently high that it has beendifficult to separate any independent associations they mayhave with breast cancer risk factors (208).

Summary of Suggestions for Future Directions

This brief review of results of recent epidemiological investigations suggests some additional approaches for future studies. First, the studies of the DBS-exposed women and of oralcontraceptive users suggest that the timing of exposure may becritical, since the possible effect of both these hormonal agentsmay be limited to specific time periods of rapid breast development. Studies of other possible etiological agents should alsotry to focus more on exposures during critical time periods. Onthe other hand, if such a critical period does not exist inpostmenopausal women, then there may be little effect of

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hormones used at this time. Instead, exposure to higher thanaverage levels of estrogen from estrogen replacement therapyor through greater conversion to estrogen in adipose tissue inobese women may result in only a modest elevation in risk andonly after prolonged exposure, because of the relative inactivityof the breast at the time of exposure. Also, the effect of radiationand the possible effects of estrogen replacement therapy andoral contraceptives remind us of the long latency period thatmay be necessary before an effect is seen for at least someagents. Thus, studies with long-term follow-up and that includelong-term users are important in studies of effects of hormonesand other exposures.

Among the newly hypothesized etiological agents, it wouldseem that the possible protective effect of physical activitymerits further study. An effect of physical activity has not beenwell studied in the past, and possible biological mechanismshave been postulated. With regard to alcohol, assessment of theinfluence of age when consumption began and duration ofexposure as well as the identification of plausible mechanismsof action would aid in clarifying the role of alcohol consumptionin breast cancer etiology.

Ongoing studies of benign breast diseases are aimed at addressing the question of subgroups at particularly high risk, andongoing studies of radiation are addressing such questions asthe risks from low-dose exposures and the latency period following exposure. The results of these studies will be awaitedwith interest.

Since it is virtually certain that endogenous sex hormonesplay a role in breast cancer etiology, continued study of theirrole with new and improved measurement techniques is obviously of high priority. Likewise, in those cases of breast cancerin which marked familial aggregation is seen, newly developedprobes for marker genes will be useful.

Finally, it is also likely that exposures not studied to date areinvolved in breast cancer etiology, since known risk factors byno means account for the entire risk of breast cancer. Thus,new ideas are needed, particularly regarding exposures at critical time periods.

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3. McTiernan, A., and Thomas, D. B. Evidence for a protective effect oflactation on risk of breast cancer in young women. Am. J. Epidemici., 124:353-358. 1986.

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1988;48:5615-5623. Cancer Res Jennifer L. Kelsey and Gertrud S. Berkowitz Breast Cancer Epidemiology

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