AMERICAN JOURNAL OF EPIDEMIOLOGY
Vol. 132, No. 1
Copyright © 1990 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Printed in U.S.A.
Original Contributions
STEPHANIE J. LONDON,12 GRAHAM A. COLDITZ,3 MEIR J. STAMPFER,1-3 WALTER C. WILLETT, 134 BERNARD A. ROSNER,36 KAREN CORSANO,3 AND FRANK E. SPEIZER3 London, S. J. (U. of Southern California Medical School, Los Angeles, CA 90033), G. A. Colditz, M. J. Stampfer, W. C. Willett, B. Rosner, K. Corsano, and F. E. Speizer. Lactation and risk of breast cancer in a cohort of US women. Am J Epidemiol 1990;132:17-26. The relation between lactation and risk of breast cancer was examined in a cohort of 89,413 parous female US registered nurses aged 30-55 years and free from cancer in 1976 who provided information on total duration of lactation in 1986. Between 1976 and 1986, 1,262 cases of breast cancer occurred during 785,958 person-years of follow-up. There was no independent association between lactation and the risk of breast cancer. After adjustment for age and parity, compared with women who had never lactated, the relative risks (and 95% confidence intervals (Cl)) were 0.95 (95% Cl 0.84-1.08) for women with 24 months (test for trend: z = -0.80, p = 0.42). The association did not differ by age or menopausal status. These results do not confirm reports that relatively short durations of lactation reduce the risk of breast cancer among younger women. breast feeding; breast neoplasms; lactation; risk
Reproductive factors, including age at first birth, parity, and age at menarche, influence the risk of breast cancer; an association with lactation has long been postulated, but uncertainty remains (1). In 1970, MacMahon et al. (2) found no important association between lactation and the risk of breast cancer after adjusting for
parity in data from a series of international case-control studies. Subsequently, lactation was generally not regarded as an independent risk factor in studies of breast cancer. Recently, however, several authors have reported that lactation, even of relatively short duration, is associated with reduced risk of breast cancer (3), particularly
Received for publication June 23,1989, and in final form January 22, 1990. Abbreviation: Cl, confidence interval. 1 Department of Epidemiology, Harvard School of Public Health, Boston, MA. 2 Current address: University of Southern California Medical School, Los Angeles, CA. 3 Channing Laboratory, Departments of Medicine and Preventive Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. 4 Department of Nutrition, Harvard School of Publie Health, Boston, MA. 6 Departments of Medicine and Preventive Medi-
cine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. Reprint requests to Dr. Stephanie J. London, University of Southern California Medical School, Parkview Medical Building, B-306, 1420 Pablo Street, Los Angeles, CA 90033. This work was supported by research grants CA 40356 and CA 40935 and an Institutional National Research Service Award (CA 09001) from the National Institutes of Health. The authors acknowledge the expert help of Gail Cammarata, Suewei Chiang, Barbara Egan, Doreen Hurd, Marion McPhee, and Donna Vincent.
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LACTATION AND RISK OF BREAST CANCER IN A COHORT OF US WOMEN
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LONDON ET AL.
MATERIALS AND METHODS
The Nurses' Health Study cohort The Nurses' Health Study was established in 1976 when 121,700 female nurses aged 30-55 years and residing in one of 11 larger US states returned a mailed questionnaire (9, 10). On biennial follow-up questionnaires, participants provided information on risk factors for breast cancer and reported the occurrence of breast cancer and other major illnesses. Ascertainment of exposures The initial questionnaire in 1976 included information on parity, age at first birth, age at menarche, personal and family history of breast cancer, history of benign breast disease, weight, height, oral contraceptive use, and menopausal status. Follow-up questionnaires were mailed to cohort members in 1978, 1980, 1982, 1984, and 1986 to update information on parity, menopausal status, weight, and benign breast disease. In 1980, alcohol intake was assessed using a semiquantitative food frequency questionnaire (11, 12). In 1986, we inquired about the total number of months of breast feeding for all births combined using the following categories: never, 48 months, and unknown. Thus, we obtained data on lactation retrospectively and data on other
potential breast cancer risk factors prospectively. Ascertainment of cases On each follow-up questionnaire, we inquired as to whether breast cancer had been diagnosed during the previous 2 years. We telephoned nonrespondents to the 1982 and 1986 questionnaires to ask about the diagnosis of breast cancer and other medical events since 1976. Most deaths were identified by the next of kin or by postal authorities in response to follow-up questionnaires. We used the National Death Index to identify deaths among nonrespondents to each follow-up questionnaire, and we estimate the mortality follow-up to be 98 percent complete (13). For each case of breast cancer identified (for decedents, from the next of kin), we sought permission to obtain hospital records and pathology reports. Pathology reports were obtained for 93 percent of women reporting breast cancer between 1976 and 1986. We excluded the 0.4 percent of records that failed to confirm the diagnosis. Because the accuracy of self-report was extremely high (99.6 percent), we included the 7 percent of reported cases for whom we did not obtain pathology reports. Population for analysis From the baseline population in 1976, we excluded women with a prior history of cancer (other than nonmelanoma skin cancer) on the 1976 questionnaire (n = 3,427). We also excluded women who did not report lactation history on the 1986 questionnaire (n = 16,936, including 1,588 known to have died prior to June 1, 1986). Because the exposure of interest was lactation, we limited the analysis to parous women, thus eliminating nulliparous women (n = 8,928) and those with missing parity information (n = 1,254). Breast cancer might affect a woman's likelihood of breast-feeding children born after the diagnosis. However, we did not know when, prior to 1986, women had
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among younger women (4-6). Yuan et al. (7) observed a protective effect only for long-term lactation among women in China. However, in the only prospective study, Kvale and Heuch (8) found no relation between breast cancer and lactation. Given the continuing controversy on the relation between lactation—a potentially modifiable factor—and the risk of breast cancer, we undertook an analysis within the Nurses' Health Study, a large cohort of US women.
LACTATION AND BREAST CANCER RISK
and the return of the 1978 questionnaire was allocated to each participant without a diagnosis of breast cancer. Lactation status was ascertained only in 1986; other covariates were ascertained on multiple questionnaires beginning in 1976. For the initial follow-up interval, person-time was allocated according to each participant's lactation status (reported in 1986) and to levels of other covariates reported in 1976. For subsequent 2-year intervals, person-time was similarly assigned according to the covariates, other than lactation, updated at the beginning of each 2-year interval by follow-up questionnaires. If a given questionnaire was not returned, we used the most recently updated covariate status to assign person-time for the subsequent follow-up interval. For the intervals from 1980 to 1986, person-time also was classified according to intake of alcohol recorded in 1980. Subjects who developed breast cancer accrued person-time time only up to the reported date of that diagnosis. These subjects, as well as those who developed other cancers (exclusive of nonmelanoma skin cancer), were excluded from subsequent follow-up intervals. Thus, the base population for any 2-year interval was always Because data on pregnancies were up- free of cancer. dated every 2 years, varying numbers of We calculated an incidence rate for each women met the inclusion criteria (no chil- category of exposure status by dividing the dren under age 4 and no subsequent births) number of incident breast cancers by the at the beginning of each 2-year follow-up person-time of follow-up. The relative risk cycle. Between the return of the 1978 and was used as a measure of association; 1986 questionnaires, an additional 17,931 women who had never breast-fed served as women met the eligibility criteria and en- the reference group. Relative risks were tered into the analysis during at least one adjusted for age in 5-year intervals, and 95 follow-up interval. Added to the 71,482 percent confidence intervals were calcuwomen in the baseline population, this gave lated (14). us a total of 89,413 women included beTo control simultaneously for age and tween 1976 and 1986. other potential confounders, we used a proportional hazards model (15). The coData analysis variates included parity, age at first birth, We first performed stratified analyses age at menarche, family history of breast using person-time denominators. During cancer, history of benign breast disease, the first time interval (1976-1978), person- menopausal status, years since menopause, time equal to the number of months be- oral contraceptive use, and body mass actween the return of the 1976 questionnaire cording to Quetelet's index (weight (kg)/
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breast-fed. We thought that any woman with a child under 4 years of age at the time of the return of the 1976 questionnaire, as well as any woman with a later birth, might have breast-fed after 1976, and therefore we excluded these women from the baseline population (n = 11,735). If we did not know whether a woman had a child under age 4 or subsequently gave birth, we excluded her unless she met one of the following criteria: age 45 or older, history of tubal ligation, or menopause; this resulted in the exclusion of 7,938 women. (In the cohort as a whole, less than 0.1 percent of pregnancies of more than 6 months' duration occurred among women 45 or over at the beginning of a follow-up interval.) Because we applied the exclusion criteria equally to all women regardless of whether they developed breast cancer, we ensured that cases and noncases were included only if their total duration of lactation reported in 1986 was already completed and eliminated the possibility of a bias due to reduced breast feeding after a diagnosis of breast cancer. After the exclusion of a total of 50,218 women (many of whom were excluded for more than one reason) at baseline, 71,482 parous women met the eligibility criteria for inclusion in the study population.
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LONDON ET AL. 2
RESULTS
In 1986, 37 percent of the cohort had never lactated, 35 percent had lactated for up to 7 months, 10 percent had lactated for 7-11 months, 12 percent had lactated for 12-23 months, and 6 percent had lactated for 24 months or more. Between 1976 and 1986, 1,262 incident cases of breast cancer occurred during 785,958 person-years of follow-up.
When adjusting for age alone, we observed a weak, nonsignificant inverse association between lactation and the risk of breast cancer in all women, regardless of menopausal status (the relative risk for >24 months of lactation, relative to never lactation, was 0.89 (95 percent confidence interval (CI) 0.69-1.15); test for trend: z = -1.70, p = 0.09) (table 1). However, adjustment for parity using categories of one, two, three, and four or more births essentially eliminated this association (the relative risk for >24 months of lactation, relative to never lactation, was 0.98 (95 percent CI 0.76-1.28); test for trend: z = -0.80, p = 0.42) (table 1). Adjustment for age at first birth, singly or in combination with family history of breast cancer, history of benign breast disease, age at menarche, oral contraceptive use, and menopausal status, did not materially alter the age- and parityadjusted relative risks (table 1). We examined the association between duration of lactation and breast cancer by menopausal status and observed no important association among either premenopausal or postmenopausal women (table 1). We examined further the parity-adjusted association between lactation and breast cancer among all women regardless of menopausal status within each of five age categories: 30-39, 40-44, 45-49, 50-54, and >55 years (table 2). Although we did not find an important association within any age group, there was a slight and nonsignificant decrease in risk with increasing lactation only among the 50-54 age group (table 2). Terms for the interaction of age and lactation both as ordinal and categorical terms were not significant. We found no material association among all women under age 55 considered together (the relative risk, adjusted for age and parity, for 24 or more months of lactation compared with never lactation was 0.92 (95 percent CI 0.68-1.25); test for trend: z = -0.83, p = 0.41) (data not shown). The association between breast cancer and duration of lactation did not vary substantially within levels of parity (table 3)
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height (m) ). To test for linear trend, we divided the regression coefficient for lactation (coded as an ordinal variable) by its standard error and compared the resulting test statistic with a standard normal distribution. We prospectively evaluated possible confounding by alcohol intake among women otherwise eligible for the analysis who provided detailed dietary information in 1980 (415,172 person-years; 769 cases). We performed the analysis within the entire cohort and separately among premenopausal and postmenopausal women. We classified a woman as postmenopausal as of the return of a questionnaire with a report of natural menopause or hysterectomy with bilateral oophorectomy. In addition, we classified women reporting hysterectomy without bilateral oophorectomy as postmenopausal at the age when natural menopause had occurred in 90 percent of the cohort—54 years for current cigarette smokers and 56 years for nonsmokers. We classified a woman reporting hysterectomy without bilateral oophorectomy as premenopausal if she was a nonsmoker under 48 years of age or a current smoker under 46 years of age. Between these ages, we considered women with hysterectomy without bilateral oophorectomy to be of uncertain menopausal status (56,189 personyears; 108 cases) and did not include them in analyses done by menopausal status. Likewise, women with missing information on menopause (20,011 person-years; 19 cases) were excluded from the separate analyses of premenopausal and postmenopausal women.
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LACTATION AND BREAST CANCER RISK TABLE 1
Relative risk of breast cancer in relation to total duration of lactation, by menopausal status, among 89,413 parous US registered nurses aged 30-55 years in 1976 and followed through 1986 Total duration of lactation (months) Never lactated 12-23
£24
z (trend)* (p value)
All woment No. of cases Person-years of observation RRt (ageadjusted)! (95% CI$) RR (age- and parityadjusted) (95% CI) RR, multivariate|| (95% CI)
500
293,201
459
283,716
104
74,220
132
90,002
67
44,819
1.00
0.93 (0.82-1.06)
0.85 (0.69-1.05)
0.89 (0.74-1.08)
0.89 (0.69-1.15)
-1.70 (0.09)
1.00
0.95 (0.84-1.08) 0.94 (0.82-1.06)
0.87 (0.71-1.08) 0.83 (0.67-1.03)
0.94 (0.77-1.14) 0.90 (0.74-1.09)
0.98 (0.76-1.28) 0.95 (0.73-1.23)
-0.80 (0.42) -1.29 (0.20)
1.00
Premenopausal women No. of cases Person-years of observation RR (ageadjusted) (95% CI) RR (age- and parityadjusted) (95% CI) RR, multivariateH (95% CI)
232
152,514
225
56
72
39
146,438
43,920
54,601
26,598
1.00
0.99 (0.82-1.19)
0.86 (0.64-1.15)
0.88 (0.68-1.15)
0.94 (0.67-1.32)
-1.03 (0.30)
1.00
1.01 (0.84-1.22) 1.00 (0.83-1.20)
0.88 (0.65-1.17) 0.85 (0.63-1.14)
0.94 (0.72-1.22) 0.90 (0.69-1.18)
1.07 (0.76-1.52) 1.06 (0.75-1.50)
-0.30 (0.76) -0.54 (0.59)
1.00
Postmenopausal women No. of cases Person-years of observation RR (ageadjusted) (95% CI) RR (age- and parityadjusted) (95% CI) RR, multivariate*' (95% CI)
203
111,200
199
41
47
21
109,823
23,728
27,314
13,622
1.00
0.97 (0.80-1.18)
0.93 (0.67-1.30)
0.93 (0.67-1.27)
0.81 (0.52-1.28)
-0.91 (0.36)
1.00
0.99 (0.82-1.21) 0.99 (0.82-1.21)
0.96 (0.68-1.34) 0.93 (0.66-1.31)
0.97 (0.70-1.34) 0.96 (0.70-1.33)
0.90 (0.57-1.43) 0.87 (0.55-1.39)
-0.43 (0.67) -0.59 (0.55)
1.00
* The test for trend is the regression coefficient for lactation (coded as an ordinal variable) from the proportional hazards model specified divided by its standard error. t Includes 108 cases occurring during 56,189 person-years of observation among women with hysterectomy without bilateral oophorectomy who were smokers aged 46-54 years or nonsmokers aged 48-56 years. Also includes women with missing menopausal status (19 cases; 20,011 person-years). These 127 cases and 76,200 person-years were excluded from separate analyses of premenopausal and postmenopausal women. X RR, relative risk; CI, confidence interval. § Never lactation is used as the reference category. || Multivariate model includes age, parity, age at first birth, age at menarche, family history of breast cancer, history of benign breast disease, oral contraceptive use, and menopausal status. 1 Multivariate model includes all terms above, with the exception of menopausal status. ** Multivariate model includes all terms above, with the exception of menopausal status and the addition of years since menopause.
or other known or suspected risk factors for breast cancer (age at menarche, age at first birth, family history of breast cancer, history of benign breast disease, and oral contraceptive use).
For the time period 1980-1986, when data on alcohol intake were available prospectively, adjustment for this variable did not alter the association between lactation and risk of breast cancer (data not shown).
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7-11
4 births No. of cases Person-years of observation RR 95% CI
X ^trena; (p value)
363
-0.29 (0.77)
-1.49 (0.14)
0.35 (0.73)
0.05 (0.96)
* The test for trend is the Mantel extension test (36), xt RR, age-adjusted relative risk; CI, confidence interval. \ Never lactation is used as the reference category.
cer, either overall or within subgroups of age or menopausal status. Our data have several limitations. First, we assessed lactation retrospectively. A tendency for women with breast cancer to systematically under- or overreport their lactation history might have introduced recall bias. If serious recall bias had occurred, we might expect the bias to change with time since diagnosis, producing a drift in the observed association. However, we did not find a systematic variation in the relative risk with successive follow-up intervals. Another limitation arises from the exclusion of nonrespondents to the 1986 questionnaire for lack of information on lactation. Nonetheless, for loss to follow-
up to have masked a true protective association between lactation and breast cancer, longer durations of lactation would have had to increase the likelihood of loss to follow-up or death. Although we have no data to address this issue directly, an independent association between lactation and loss to follow-up or death seems unlikely. We note that our data include no women over age 66 and therefore do not address the association between lactation and breast cancer in older women. The registered nurses in our study were slightly more likely to have breast-fed than US women of comparable birth cohorts; however, mean durations of lactation were similar (16). The duration of lactation was
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Parity
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LONDON ET AL.
Two studies recently reported an inverse association between breast cancer and lactation of relatively short duration among younger women: Byers et al. (4) observed a relative risk of 0.60 for 12 or more months of lactation among premenopausal women, and Layde et al. (6) found a relative risk of 0.67 for 25 or more months or lactation among women under age 56. McTiernan and Thomas (5) observed a protective effect for 12 or more months of lactation, but the data were a subset of those subsequently reported by Layde et al. (6). Although Anderson (19) reported a decreased risk with 24 months of lactation among premenopausal South African women, he did not adjust for parity. Among women of all ages, Lubin et al. (3) found an independent protective effect of lactation for ever versus never lactation, but no dose response. In one of the earliest studies, Levin et al. (20) reported a protective effect of lactation. In contrast, most authors have not observed an important independent association between lactation and breast cancer among westernized women with relatively short durations of exposure (21-30). Several authors reported
no relation among younger women in particular (2, 23, 25, 26). The reason for the discrepancy between the studies by Byers et al. (4), Layde et al. (6), and Lubin et al. (3), in which an inverse association was found, and most other studies of westernized women is not obvious. One notable distinction emerges: These three groups used community controls— Layde et al. used random digit dialing (5, 6), and Byers et al. (4) and Lubin et al. (3) used population rosters. Authors of the other studies enlisted controls from hospitals (21, 22, 25, 27, 29) or screening programs (23, 24, 26). Community controls should be preferable to hospital or screening program controls if the exposure of interest determines risk of hospitalization or screening, but they may be subject to selection bias if the exposure of interest affects participation (31). For example, because women who delay return to full-time work after delivery have longer durations of lactation than women who return to fulltime work sooner (32), a spurious association could arise if they are also more likely to be contacted as community controls or to agree to participate. Thus, in the Cancer and Steroid Hormone Study (5, 6), the use of random digit dialing may have oversampled women with longer durations of breast feeding. In the study by Lubin et al. (3), participation rates were disparate between cases (89 percent) and controls (73 percent). In the study reported by Byers et al. (4) and Graham and Schotz (33), a common control group was used for both cervical and breast cancers. Although cancer of the cervix is generally associated with lower socioeconomic status, no association was found in that study (33), which suggests that socioeconomic factors may have influenced control selection. Although lactation is related to socioeconomic factors (34) that in turn influence participation in population surveys (35), we know of no data on whether lactation per se influences hospitalization, screening, or response rates. However, given the lack of other obvious
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relatively short, as in other North American studies (4, 5); only 6 percent of the cohort lactated for at least 24 months. Therefore, we could not address the possibility that longer durations of lactation, such as those experienced by women in non-Western societies, decrease the risk of breast cancer. Yuan et al. (7), studying women in China, observed a protective effect only for more than 72 months of lactation. However, data from non-Western populations with relatively long durations of lactation are inconsistent. MacMahon et al. (2) observed no independent association in seven international case-control studies despite long average durations of lactation among subjects in Brazil, Japan, and Taiwan. Likewise, case-control data from Costa Rica (17) and Burma (18) do not support a relation between breast cancer and lactation independent of parity.
LACTATION AND BREAST CANCER RISK
REFERENCES
1. Kelsey JL, Berkowitz GS. Breast cancer epidemiology. Cancer Res 1988;48:5615-23. 2. MacMahon B, Lin TM, Lowe CR, et al. Lactation and cancer of the breast: a summary of an international study. Bull WHO 1970;42:185-94. 3. Lubin JH, Burns PE, Blot WJ, et al. Risk factors for breast cancer in women in Northern Alberta, Canada, as related to age at diagnosis. JNCI1982; 68:211-17. 4. Byers T, Graham S, Rzepka T, et al. Lactation and breast cancer: evidence for a negative association in premenopausal women. Am J Epidemiol 1985;121:664-74. 5. McTiernan A, Thomas DB. Evidence for a protective effect of lactation on risk of breast cancer in young women: results from a case-control study. Am J Epidemiol 1986;124:353-8. 6. Layde PM, Webster LA, Baughman L, et al. The independent associations of parity, age at first full term pregnancy, and duration of breastfeeding with the risk of breast cancer. J Clin Epidemiol 1989;42:963-73. 7. Yuan J, Yu MC, Ross RK, et al. Risk factors for breast cancer in Chinese women in Shanghai. Cancer Res 1988;48:1949-53. 8. Kvale G, Heuch I. Lactation and cancer risk: Is there a relation specific to breast cancer? J Epidemiol Community Health 1987;42:30-7. 9. Willett WC, Stampfer MJ, Colditz GA, et al. Dietary fat and the risk of breast cancer. N Engl J Med 1987;316:22-8.
10. Stampfer MJ, Willett WC, Colditz GA, et al. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med 1985;313:1044-9. 11. Willett WC, Stampfer MJ, Colditz GA, et al. Moderate alcohol consumption and the risk of breast cancer. N Engl J Med 1987;316:1174-80. 12. Willett WC, Sampson L, Stampfer MJ, et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am J Epidemiol 1985;122:51-65. 13. Stampfer MJ, Willett WC, Speizer FE, et al. Test of the National Death Index. Am J Epidemiol 1984;119:837-9. 14. Kleinbaum DG, Kupper LL, Morgenstern H. Epidemiologic research: principles and quantitative methods. Belmont, CA: Lifelong Learning Publications, 1982:345. 15. Cox DR. Regression models and life tables (with discussion). J R Stat Soc (B) 1972;34:187-220. 16. Hendershot GE. Trends in breast-feeding. Pediatrics 1984;74:591-602. 17. Rosero-Bixby L, Oberle MW, Lee NC. Reproductive history and breast cancer in a population of high fertility, Costa Rica, 1984-85. Int J Cancer 1987;40:747-54. 18. Thein-Hlaing, Thein-Maung-Myint. Risk factors of breast cancer in Burma. Int J Cancer 1978;21: 432-7. 19. Anderson JD. Breast feeding and breast cancer. S Afr Med J 1975;49:479-82. 20. Levin ML, Sheehe PR, Graham S, et al. Lactation and menstrual function as related to cancer of the breast. Am J Public Health 1964;54:580-7. 21. Salber EJ, Trichopoulos D, MacMahon B. Lactation and reproductive histories of breast cancer patients in Boston, 1965-66. JNCI 1969;43:101324. 22. MacMahon B, Feinleib M. Breast cancer in relation to nursing and menopausal history. JNCI 1960;24:733-53. 23. Abramson JH. Breast-feeding and breast cancer: a study of cases and matched controls in Jerusalem. Isr J Med Sci 1966;2:457-64. 24. Brignone G, Cusimano R, Dardanoni G, et al. A case-control study on breast cancer risk factors in a Southern European population. Int J Epidemiol 1987;16:356-61. 25. Brinton LA, Hoover R, Fraumeni JF. Reproductive factors in the aetiology of breast cancer. Br J Cancer 1983;47:757-62. 26. Kalache A, Vessey MP, McPherson K. Lactation and breast cancer. Br Med J 1980;280:223-4. 27. Duffy SW, Roberts MM, Elton RA. Risk factors for breast cancer: relevance to screening. J Epidemiol Community Health 1983;37:127-31. 28. Wynder EL, MacCormack FA, Stellman SD. The epidemiology of breast cancer in 785 US Caucasian women. Cancer 1978;41:2341-54. 29. MacMahon B, Purde M, Cramer D, et al. Association of breast cancer risk with age at first and subsequent births: a study in the population of the Estonian Republic. JNCI 1982;69:1035-8. 30. Siskind V, Schofield F, Rice D, et al. Breast cancer and breastfeeding: results from an Australian
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differences between the studies by Layde et al. (6), Byers et al. (4), and Lubin et al. (3) and most case-control studies, the possibility that lactation history might have been related to the enrollment of community controls merits consideration. In the only prospective study of lactation and risk of breast cancer, Kvale and Heuch (8) observed no independent association among either premenopausal or postmenopausal Norwegian women. Of note is the fact that this analysis included a high percentage of women with long durations of lactation relative to case-control studies of other westernized populations. Furthermore, the high follow-up rate in this Norwegian cohort precludes selection bias. Our results, consistent with those from most case-control studies and the sole prospective study, suggest that breast feeding does not decrease the risk of breast cancer, at least among Western populations.
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26
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case-control study. Am J Epidemiol 1989;130:22936. 31. Hennekens CH, Buring JE. Epidemiology in medicine. 1st ed. Boston: Little, Brown and Company, 1987:273-4. 32. Kurinij N, Shiono PH, Erzine SF, et al. Does maternal employment affect breast-feeding? Am J Public Health 1989;79:1247-50. 33. Graham S, Schotz W. Epidemiology of cancer of
Vol. 132, No. 1
Copyright © 1990 by The Johns Hopkins University School of Hygiene and Public Health All rights reserved
Printed in U.S.A.
Original Contributions
STEPHANIE J. LONDON,12 GRAHAM A. COLDITZ,3 MEIR J. STAMPFER,1-3 WALTER C. WILLETT, 134 BERNARD A. ROSNER,36 KAREN CORSANO,3 AND FRANK E. SPEIZER3 London, S. J. (U. of Southern California Medical School, Los Angeles, CA 90033), G. A. Colditz, M. J. Stampfer, W. C. Willett, B. Rosner, K. Corsano, and F. E. Speizer. Lactation and risk of breast cancer in a cohort of US women. Am J Epidemiol 1990;132:17-26. The relation between lactation and risk of breast cancer was examined in a cohort of 89,413 parous female US registered nurses aged 30-55 years and free from cancer in 1976 who provided information on total duration of lactation in 1986. Between 1976 and 1986, 1,262 cases of breast cancer occurred during 785,958 person-years of follow-up. There was no independent association between lactation and the risk of breast cancer. After adjustment for age and parity, compared with women who had never lactated, the relative risks (and 95% confidence intervals (Cl)) were 0.95 (95% Cl 0.84-1.08) for women with 24 months (test for trend: z = -0.80, p = 0.42). The association did not differ by age or menopausal status. These results do not confirm reports that relatively short durations of lactation reduce the risk of breast cancer among younger women. breast feeding; breast neoplasms; lactation; risk
Reproductive factors, including age at first birth, parity, and age at menarche, influence the risk of breast cancer; an association with lactation has long been postulated, but uncertainty remains (1). In 1970, MacMahon et al. (2) found no important association between lactation and the risk of breast cancer after adjusting for
parity in data from a series of international case-control studies. Subsequently, lactation was generally not regarded as an independent risk factor in studies of breast cancer. Recently, however, several authors have reported that lactation, even of relatively short duration, is associated with reduced risk of breast cancer (3), particularly
Received for publication June 23,1989, and in final form January 22, 1990. Abbreviation: Cl, confidence interval. 1 Department of Epidemiology, Harvard School of Public Health, Boston, MA. 2 Current address: University of Southern California Medical School, Los Angeles, CA. 3 Channing Laboratory, Departments of Medicine and Preventive Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. 4 Department of Nutrition, Harvard School of Publie Health, Boston, MA. 6 Departments of Medicine and Preventive Medi-
cine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. Reprint requests to Dr. Stephanie J. London, University of Southern California Medical School, Parkview Medical Building, B-306, 1420 Pablo Street, Los Angeles, CA 90033. This work was supported by research grants CA 40356 and CA 40935 and an Institutional National Research Service Award (CA 09001) from the National Institutes of Health. The authors acknowledge the expert help of Gail Cammarata, Suewei Chiang, Barbara Egan, Doreen Hurd, Marion McPhee, and Donna Vincent.
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LACTATION AND RISK OF BREAST CANCER IN A COHORT OF US WOMEN
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LONDON ET AL.
MATERIALS AND METHODS
The Nurses' Health Study cohort The Nurses' Health Study was established in 1976 when 121,700 female nurses aged 30-55 years and residing in one of 11 larger US states returned a mailed questionnaire (9, 10). On biennial follow-up questionnaires, participants provided information on risk factors for breast cancer and reported the occurrence of breast cancer and other major illnesses. Ascertainment of exposures The initial questionnaire in 1976 included information on parity, age at first birth, age at menarche, personal and family history of breast cancer, history of benign breast disease, weight, height, oral contraceptive use, and menopausal status. Follow-up questionnaires were mailed to cohort members in 1978, 1980, 1982, 1984, and 1986 to update information on parity, menopausal status, weight, and benign breast disease. In 1980, alcohol intake was assessed using a semiquantitative food frequency questionnaire (11, 12). In 1986, we inquired about the total number of months of breast feeding for all births combined using the following categories: never, 48 months, and unknown. Thus, we obtained data on lactation retrospectively and data on other
potential breast cancer risk factors prospectively. Ascertainment of cases On each follow-up questionnaire, we inquired as to whether breast cancer had been diagnosed during the previous 2 years. We telephoned nonrespondents to the 1982 and 1986 questionnaires to ask about the diagnosis of breast cancer and other medical events since 1976. Most deaths were identified by the next of kin or by postal authorities in response to follow-up questionnaires. We used the National Death Index to identify deaths among nonrespondents to each follow-up questionnaire, and we estimate the mortality follow-up to be 98 percent complete (13). For each case of breast cancer identified (for decedents, from the next of kin), we sought permission to obtain hospital records and pathology reports. Pathology reports were obtained for 93 percent of women reporting breast cancer between 1976 and 1986. We excluded the 0.4 percent of records that failed to confirm the diagnosis. Because the accuracy of self-report was extremely high (99.6 percent), we included the 7 percent of reported cases for whom we did not obtain pathology reports. Population for analysis From the baseline population in 1976, we excluded women with a prior history of cancer (other than nonmelanoma skin cancer) on the 1976 questionnaire (n = 3,427). We also excluded women who did not report lactation history on the 1986 questionnaire (n = 16,936, including 1,588 known to have died prior to June 1, 1986). Because the exposure of interest was lactation, we limited the analysis to parous women, thus eliminating nulliparous women (n = 8,928) and those with missing parity information (n = 1,254). Breast cancer might affect a woman's likelihood of breast-feeding children born after the diagnosis. However, we did not know when, prior to 1986, women had
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among younger women (4-6). Yuan et al. (7) observed a protective effect only for long-term lactation among women in China. However, in the only prospective study, Kvale and Heuch (8) found no relation between breast cancer and lactation. Given the continuing controversy on the relation between lactation—a potentially modifiable factor—and the risk of breast cancer, we undertook an analysis within the Nurses' Health Study, a large cohort of US women.
LACTATION AND BREAST CANCER RISK
and the return of the 1978 questionnaire was allocated to each participant without a diagnosis of breast cancer. Lactation status was ascertained only in 1986; other covariates were ascertained on multiple questionnaires beginning in 1976. For the initial follow-up interval, person-time was allocated according to each participant's lactation status (reported in 1986) and to levels of other covariates reported in 1976. For subsequent 2-year intervals, person-time was similarly assigned according to the covariates, other than lactation, updated at the beginning of each 2-year interval by follow-up questionnaires. If a given questionnaire was not returned, we used the most recently updated covariate status to assign person-time for the subsequent follow-up interval. For the intervals from 1980 to 1986, person-time also was classified according to intake of alcohol recorded in 1980. Subjects who developed breast cancer accrued person-time time only up to the reported date of that diagnosis. These subjects, as well as those who developed other cancers (exclusive of nonmelanoma skin cancer), were excluded from subsequent follow-up intervals. Thus, the base population for any 2-year interval was always Because data on pregnancies were up- free of cancer. dated every 2 years, varying numbers of We calculated an incidence rate for each women met the inclusion criteria (no chil- category of exposure status by dividing the dren under age 4 and no subsequent births) number of incident breast cancers by the at the beginning of each 2-year follow-up person-time of follow-up. The relative risk cycle. Between the return of the 1978 and was used as a measure of association; 1986 questionnaires, an additional 17,931 women who had never breast-fed served as women met the eligibility criteria and en- the reference group. Relative risks were tered into the analysis during at least one adjusted for age in 5-year intervals, and 95 follow-up interval. Added to the 71,482 percent confidence intervals were calcuwomen in the baseline population, this gave lated (14). us a total of 89,413 women included beTo control simultaneously for age and tween 1976 and 1986. other potential confounders, we used a proportional hazards model (15). The coData analysis variates included parity, age at first birth, We first performed stratified analyses age at menarche, family history of breast using person-time denominators. During cancer, history of benign breast disease, the first time interval (1976-1978), person- menopausal status, years since menopause, time equal to the number of months be- oral contraceptive use, and body mass actween the return of the 1976 questionnaire cording to Quetelet's index (weight (kg)/
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breast-fed. We thought that any woman with a child under 4 years of age at the time of the return of the 1976 questionnaire, as well as any woman with a later birth, might have breast-fed after 1976, and therefore we excluded these women from the baseline population (n = 11,735). If we did not know whether a woman had a child under age 4 or subsequently gave birth, we excluded her unless she met one of the following criteria: age 45 or older, history of tubal ligation, or menopause; this resulted in the exclusion of 7,938 women. (In the cohort as a whole, less than 0.1 percent of pregnancies of more than 6 months' duration occurred among women 45 or over at the beginning of a follow-up interval.) Because we applied the exclusion criteria equally to all women regardless of whether they developed breast cancer, we ensured that cases and noncases were included only if their total duration of lactation reported in 1986 was already completed and eliminated the possibility of a bias due to reduced breast feeding after a diagnosis of breast cancer. After the exclusion of a total of 50,218 women (many of whom were excluded for more than one reason) at baseline, 71,482 parous women met the eligibility criteria for inclusion in the study population.
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LONDON ET AL. 2
RESULTS
In 1986, 37 percent of the cohort had never lactated, 35 percent had lactated for up to 7 months, 10 percent had lactated for 7-11 months, 12 percent had lactated for 12-23 months, and 6 percent had lactated for 24 months or more. Between 1976 and 1986, 1,262 incident cases of breast cancer occurred during 785,958 person-years of follow-up.
When adjusting for age alone, we observed a weak, nonsignificant inverse association between lactation and the risk of breast cancer in all women, regardless of menopausal status (the relative risk for >24 months of lactation, relative to never lactation, was 0.89 (95 percent confidence interval (CI) 0.69-1.15); test for trend: z = -1.70, p = 0.09) (table 1). However, adjustment for parity using categories of one, two, three, and four or more births essentially eliminated this association (the relative risk for >24 months of lactation, relative to never lactation, was 0.98 (95 percent CI 0.76-1.28); test for trend: z = -0.80, p = 0.42) (table 1). Adjustment for age at first birth, singly or in combination with family history of breast cancer, history of benign breast disease, age at menarche, oral contraceptive use, and menopausal status, did not materially alter the age- and parityadjusted relative risks (table 1). We examined the association between duration of lactation and breast cancer by menopausal status and observed no important association among either premenopausal or postmenopausal women (table 1). We examined further the parity-adjusted association between lactation and breast cancer among all women regardless of menopausal status within each of five age categories: 30-39, 40-44, 45-49, 50-54, and >55 years (table 2). Although we did not find an important association within any age group, there was a slight and nonsignificant decrease in risk with increasing lactation only among the 50-54 age group (table 2). Terms for the interaction of age and lactation both as ordinal and categorical terms were not significant. We found no material association among all women under age 55 considered together (the relative risk, adjusted for age and parity, for 24 or more months of lactation compared with never lactation was 0.92 (95 percent CI 0.68-1.25); test for trend: z = -0.83, p = 0.41) (data not shown). The association between breast cancer and duration of lactation did not vary substantially within levels of parity (table 3)
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height (m) ). To test for linear trend, we divided the regression coefficient for lactation (coded as an ordinal variable) by its standard error and compared the resulting test statistic with a standard normal distribution. We prospectively evaluated possible confounding by alcohol intake among women otherwise eligible for the analysis who provided detailed dietary information in 1980 (415,172 person-years; 769 cases). We performed the analysis within the entire cohort and separately among premenopausal and postmenopausal women. We classified a woman as postmenopausal as of the return of a questionnaire with a report of natural menopause or hysterectomy with bilateral oophorectomy. In addition, we classified women reporting hysterectomy without bilateral oophorectomy as postmenopausal at the age when natural menopause had occurred in 90 percent of the cohort—54 years for current cigarette smokers and 56 years for nonsmokers. We classified a woman reporting hysterectomy without bilateral oophorectomy as premenopausal if she was a nonsmoker under 48 years of age or a current smoker under 46 years of age. Between these ages, we considered women with hysterectomy without bilateral oophorectomy to be of uncertain menopausal status (56,189 personyears; 108 cases) and did not include them in analyses done by menopausal status. Likewise, women with missing information on menopause (20,011 person-years; 19 cases) were excluded from the separate analyses of premenopausal and postmenopausal women.
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LACTATION AND BREAST CANCER RISK TABLE 1
Relative risk of breast cancer in relation to total duration of lactation, by menopausal status, among 89,413 parous US registered nurses aged 30-55 years in 1976 and followed through 1986 Total duration of lactation (months) Never lactated 12-23
£24
z (trend)* (p value)
All woment No. of cases Person-years of observation RRt (ageadjusted)! (95% CI$) RR (age- and parityadjusted) (95% CI) RR, multivariate|| (95% CI)
500
293,201
459
283,716
104
74,220
132
90,002
67
44,819
1.00
0.93 (0.82-1.06)
0.85 (0.69-1.05)
0.89 (0.74-1.08)
0.89 (0.69-1.15)
-1.70 (0.09)
1.00
0.95 (0.84-1.08) 0.94 (0.82-1.06)
0.87 (0.71-1.08) 0.83 (0.67-1.03)
0.94 (0.77-1.14) 0.90 (0.74-1.09)
0.98 (0.76-1.28) 0.95 (0.73-1.23)
-0.80 (0.42) -1.29 (0.20)
1.00
Premenopausal women No. of cases Person-years of observation RR (ageadjusted) (95% CI) RR (age- and parityadjusted) (95% CI) RR, multivariateH (95% CI)
232
152,514
225
56
72
39
146,438
43,920
54,601
26,598
1.00
0.99 (0.82-1.19)
0.86 (0.64-1.15)
0.88 (0.68-1.15)
0.94 (0.67-1.32)
-1.03 (0.30)
1.00
1.01 (0.84-1.22) 1.00 (0.83-1.20)
0.88 (0.65-1.17) 0.85 (0.63-1.14)
0.94 (0.72-1.22) 0.90 (0.69-1.18)
1.07 (0.76-1.52) 1.06 (0.75-1.50)
-0.30 (0.76) -0.54 (0.59)
1.00
Postmenopausal women No. of cases Person-years of observation RR (ageadjusted) (95% CI) RR (age- and parityadjusted) (95% CI) RR, multivariate*' (95% CI)
203
111,200
199
41
47
21
109,823
23,728
27,314
13,622
1.00
0.97 (0.80-1.18)
0.93 (0.67-1.30)
0.93 (0.67-1.27)
0.81 (0.52-1.28)
-0.91 (0.36)
1.00
0.99 (0.82-1.21) 0.99 (0.82-1.21)
0.96 (0.68-1.34) 0.93 (0.66-1.31)
0.97 (0.70-1.34) 0.96 (0.70-1.33)
0.90 (0.57-1.43) 0.87 (0.55-1.39)
-0.43 (0.67) -0.59 (0.55)
1.00
* The test for trend is the regression coefficient for lactation (coded as an ordinal variable) from the proportional hazards model specified divided by its standard error. t Includes 108 cases occurring during 56,189 person-years of observation among women with hysterectomy without bilateral oophorectomy who were smokers aged 46-54 years or nonsmokers aged 48-56 years. Also includes women with missing menopausal status (19 cases; 20,011 person-years). These 127 cases and 76,200 person-years were excluded from separate analyses of premenopausal and postmenopausal women. X RR, relative risk; CI, confidence interval. § Never lactation is used as the reference category. || Multivariate model includes age, parity, age at first birth, age at menarche, family history of breast cancer, history of benign breast disease, oral contraceptive use, and menopausal status. 1 Multivariate model includes all terms above, with the exception of menopausal status. ** Multivariate model includes all terms above, with the exception of menopausal status and the addition of years since menopause.
or other known or suspected risk factors for breast cancer (age at menarche, age at first birth, family history of breast cancer, history of benign breast disease, and oral contraceptive use).
For the time period 1980-1986, when data on alcohol intake were available prospectively, adjustment for this variable did not alter the association between lactation and risk of breast cancer (data not shown).
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7-11
4 births No. of cases Person-years of observation RR 95% CI
X ^trena; (p value)
363
-0.29 (0.77)
-1.49 (0.14)
0.35 (0.73)
0.05 (0.96)
* The test for trend is the Mantel extension test (36), xt RR, age-adjusted relative risk; CI, confidence interval. \ Never lactation is used as the reference category.
cer, either overall or within subgroups of age or menopausal status. Our data have several limitations. First, we assessed lactation retrospectively. A tendency for women with breast cancer to systematically under- or overreport their lactation history might have introduced recall bias. If serious recall bias had occurred, we might expect the bias to change with time since diagnosis, producing a drift in the observed association. However, we did not find a systematic variation in the relative risk with successive follow-up intervals. Another limitation arises from the exclusion of nonrespondents to the 1986 questionnaire for lack of information on lactation. Nonetheless, for loss to follow-
up to have masked a true protective association between lactation and breast cancer, longer durations of lactation would have had to increase the likelihood of loss to follow-up or death. Although we have no data to address this issue directly, an independent association between lactation and loss to follow-up or death seems unlikely. We note that our data include no women over age 66 and therefore do not address the association between lactation and breast cancer in older women. The registered nurses in our study were slightly more likely to have breast-fed than US women of comparable birth cohorts; however, mean durations of lactation were similar (16). The duration of lactation was
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Parity
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LONDON ET AL.
Two studies recently reported an inverse association between breast cancer and lactation of relatively short duration among younger women: Byers et al. (4) observed a relative risk of 0.60 for 12 or more months of lactation among premenopausal women, and Layde et al. (6) found a relative risk of 0.67 for 25 or more months or lactation among women under age 56. McTiernan and Thomas (5) observed a protective effect for 12 or more months of lactation, but the data were a subset of those subsequently reported by Layde et al. (6). Although Anderson (19) reported a decreased risk with 24 months of lactation among premenopausal South African women, he did not adjust for parity. Among women of all ages, Lubin et al. (3) found an independent protective effect of lactation for ever versus never lactation, but no dose response. In one of the earliest studies, Levin et al. (20) reported a protective effect of lactation. In contrast, most authors have not observed an important independent association between lactation and breast cancer among westernized women with relatively short durations of exposure (21-30). Several authors reported
no relation among younger women in particular (2, 23, 25, 26). The reason for the discrepancy between the studies by Byers et al. (4), Layde et al. (6), and Lubin et al. (3), in which an inverse association was found, and most other studies of westernized women is not obvious. One notable distinction emerges: These three groups used community controls— Layde et al. used random digit dialing (5, 6), and Byers et al. (4) and Lubin et al. (3) used population rosters. Authors of the other studies enlisted controls from hospitals (21, 22, 25, 27, 29) or screening programs (23, 24, 26). Community controls should be preferable to hospital or screening program controls if the exposure of interest determines risk of hospitalization or screening, but they may be subject to selection bias if the exposure of interest affects participation (31). For example, because women who delay return to full-time work after delivery have longer durations of lactation than women who return to fulltime work sooner (32), a spurious association could arise if they are also more likely to be contacted as community controls or to agree to participate. Thus, in the Cancer and Steroid Hormone Study (5, 6), the use of random digit dialing may have oversampled women with longer durations of breast feeding. In the study by Lubin et al. (3), participation rates were disparate between cases (89 percent) and controls (73 percent). In the study reported by Byers et al. (4) and Graham and Schotz (33), a common control group was used for both cervical and breast cancers. Although cancer of the cervix is generally associated with lower socioeconomic status, no association was found in that study (33), which suggests that socioeconomic factors may have influenced control selection. Although lactation is related to socioeconomic factors (34) that in turn influence participation in population surveys (35), we know of no data on whether lactation per se influences hospitalization, screening, or response rates. However, given the lack of other obvious
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relatively short, as in other North American studies (4, 5); only 6 percent of the cohort lactated for at least 24 months. Therefore, we could not address the possibility that longer durations of lactation, such as those experienced by women in non-Western societies, decrease the risk of breast cancer. Yuan et al. (7), studying women in China, observed a protective effect only for more than 72 months of lactation. However, data from non-Western populations with relatively long durations of lactation are inconsistent. MacMahon et al. (2) observed no independent association in seven international case-control studies despite long average durations of lactation among subjects in Brazil, Japan, and Taiwan. Likewise, case-control data from Costa Rica (17) and Burma (18) do not support a relation between breast cancer and lactation independent of parity.
LACTATION AND BREAST CANCER RISK
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differences between the studies by Layde et al. (6), Byers et al. (4), and Lubin et al. (3) and most case-control studies, the possibility that lactation history might have been related to the enrollment of community controls merits consideration. In the only prospective study of lactation and risk of breast cancer, Kvale and Heuch (8) observed no independent association among either premenopausal or postmenopausal Norwegian women. Of note is the fact that this analysis included a high percentage of women with long durations of lactation relative to case-control studies of other westernized populations. Furthermore, the high follow-up rate in this Norwegian cohort precludes selection bias. Our results, consistent with those from most case-control studies and the sole prospective study, suggest that breast feeding does not decrease the risk of breast cancer, at least among Western populations.
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case-control study. Am J Epidemiol 1989;130:22936. 31. Hennekens CH, Buring JE. Epidemiology in medicine. 1st ed. Boston: Little, Brown and Company, 1987:273-4. 32. Kurinij N, Shiono PH, Erzine SF, et al. Does maternal employment affect breast-feeding? Am J Public Health 1989;79:1247-50. 33. Graham S, Schotz W. Epidemiology of cancer of
