a Division of Epidemiology, Prevention and Screening, Alberta Cancer Board, 133129 St NW, Calgary, Alberta, Canada, T2N 4N2. E-mail: chrisf{at}acb-epi.ucalgary.ca
b Tom Baker Cancer Centre, Alberta Cancer Board, Calgary, Alberta, Canada.
c Calgary Regional Health Authority, Calgary, Alberta, Canada.
d Cross Cancer Institute, Alberta Cancer Board, Edmonton, Alberta, Canada.
e Dynacare Kasper Medical Laboratories, Edmonton, Alberta, Canada.
f Vanderbilt University, Nashville, Tennessee, USA.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods The breast biopsies of all eligible women were re-reviewed by a panel of four pathologists using Page's classification for benign breast disease. Cases were 165 women whose biopsies, upon review, showed benign breast tissue changes ranging from sclerosing adenosis to atypical ductal hyperplasia. Controls were 217 women whose biopsies showed no evidence of any proliferative or neoplastic changes. In-person interviews were conducted with all study subjects.
Results Women with 25% fibroglandular breast tissue density, as compared to women with <25% density, experienced nearly a doubling in risk of BPBD (OR = 1.91, 95% CI : 1.242.94). All other possible risk factors examined were not associated with BPBD.
Conclusion This study suggests that fibroglandular tissue density may be a risk factor, or marker, for increased risk of BPBD.
Keywords Benign proliferative breast disease, risk factors, aetiology, screening
Accepted 7 February 2000
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Major difficulties have existed for epidemiological studies of this disease since it includes a wide range of pathological conditions that are associated with varying risks of breast cancer.4 Consequently, considerable outcome misclassification is possible within and across studies since the histological classification of this disease is not completely standardized. Epidemiological studies require histological confirmation of the disease to reduce this misclassification, however, such confirmation is not feasible for a general control population. Attempts have been made to improve the standardization of histological classification47 for BBD. An additional difficulty for epidemiological studies is the high prevalence of unconfirmed BBD. From autopsy studies,8 the prevalence of BBD is estimated to be about 50% whereas the cumulative incidence of biopsy-proven BBD as estimated from epidemiological studies912 is only 1020%.
Many women are now participating appropriately in biennial mammographic screening. Screen Test: Alberta Program for the Early Detection of Breast Cancer, is a screening programme for asymptomatic women aged 5069. The programme routinely collects follow-up information on women who require further diagnostic examinations after screening mammography. Since a proportion of these women will be found to have benign proliferative breast disease (BPBD), the programme provides an ideal setting for examining the predisposing factors among asymptomatic women. One of the known risk factors for breast cancer are specific types of BPBD.12 However, while many of the risk factors for breast cancer are known, the factors that predispose women to BPBD are less well established. Hence, the objective of this study was to examine what risk factors are associated with BPBD with particular attention to the risk associated with radiological tissue density. The study was primarily designed to investigate whether women with histologically confirmed BPBD also had radiologically identifiable increases in breast tissue density.
Limitations in previous research studies related to misclassification of benign breast histology were specifically addressed in this study by developing, testing and using a standardized histological classification system for BPBD. The data from this study are applicable within breast screening programmes that seek to identify women who have breast health problems that need particular attention.
![]() |
Material and Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Cases were defined, for this study, as those women who had histologically confirmed BPBD. Of the 390 women included in this study, 165 had evidence of benign proliferative breast tissue changes ranging from sclerosing adenosis to atypical ductal hyperplasia. Eight cases had neoplastic breast disease (ductal [n = 6] and lobular [n = 1] carcinoma in situ and invasive cancer [n = 1]) and were excluded as the focus was on risk factors for benign disease. The remaining 217 women had no histologically confirmed evidence of any proliferative breast tissue changes and constituted the control group.
Histological and radiological classification
To overcome outcome misclassification problems, a panel of four pathologists was assembled for this study. Our reference pathologist (DLP) assisted in adapting the histological classification system that he has developed for BBD.47 The inter-rater reliability of this classification system was tested in a pilot study using the breast biopsies from 395 women eligible for this study. Each biopsy was examined by at least two pathologists who each reviewed approximately 200 slides with an overlap of 50 slides with each of the other three pathologists. Overall, 80% agreement was found for the classification of these breast biopsies using a 16-level detailed classification system that included eight categories for benign breast histology (normal to usual hyperplasia), five for intermediate histology (atypical lobular hyperplasia to low-grade ductal carcinoma in situ [DCIS]) and three for positive histology (intermediate grade DCIS to invasive cancer). Further discussions and two workshops given by our reference pathologists for community-based pathologists to disseminate information and the use of this histological classification system within Alberta resulted in simplification of the classification system to 14 levels for use in this study (Table 1). Two categories were eliminated that were for other histological types. The resulting agreement in the classification system increased to over 90%. Any discrepancies found in classifications were reviewed by the panel of pathologists and a final diagnosis was made for each case. The pathologists did not have any knowledge of the study subjects' personal characteristics when they reviewed their breast tissue histology.
|
Epidemiological risk factors
Data on epidemiological risk factors for BPBD were obtained through in-person interviews conducted with all study subjects between January 1995 and September 1996. Information gathered on these questionnaires included: demographic characteristics, personal rating of health and wellbeing, current and past anthropometric measurements, health care visits, breast self-examination behaviour, personal and family history of BPBD and breast biopsies, medical, menstrual and reproductive history, hormone use history, smoking habits, physical activity, caffeine and alcohol consumption.
Pre-existing, standardized questions were used for this questionnaire where applicable. The questions on physical activity were developed for the Nurses' Health Study II (NHS) and had been tested for reliability and validity.13 The NHS II activity questionnaire is a self-reported measure of weekly recreational physical activity estimated for the past year. The questionnaire assesses eight moderate and vigorous activities, usual walking pace and number of flights of stairs climbed daily. Inactivity is also assessed by measuring the time spent at home and at work standing and sitting. Total recreational activities were estimated as the sum of all the reported recreational activities. The duration and frequency of these activities assessed in the questionnaire were multiplied by the intensity value for each activity (defined in metabolic equivalents [MET]) according to the Compendium of Physical Activities14 as previously tested by Wolf et al.13 Thus, the energy expended (in MET*hours/week) for recreational activities was estimated.
Variables that were estimated for this study included total pack-years of smoking, total alcohol and caffeine intake. Pack-years of smoking were estimated for current and ex-smokers separately and then combined into total pack-years of smoking. The duration of smoking, in years, was multiplied by the packs of cigarettes consumed daily. Respondents were asked to report the frequency and serving size for their intake of caffeine-containing beverages and alcohol. The average portion size for regular coffee, tea, hot chocolate/cocoa was 8 oz/230 ml cup or mug and for regular and diet colas was a 12 oz/360 ml can. The daily intake of caffeine from each of these beverages was estimated by multiplying the quantity consumed (frequency x usual serving size). The caffeine content for a standard serving of coffee was estimated to be 0.137 g; for tea, 0.036 g; for cocoa, 0.005 g; for regular colas, 0.042 g; for diet colas, 0.046 g.15 The reported daily intakes of beer (1 can or bottle), of wine (5 oz/ 140 ml glass), sherry, port or dessert wine (3 oz/85 ml glass) and spirits (1.5 oz/45 ml drink) were multiplied by the alcohol content of each type of beverage. The alcohol content for a standard serving of beer was estimated to be 13.2 g; for wine, 13.7 g; for sweet wines 13.5 g; and for spirits 15.6 g.16
These data were first analysed by estimating the means and frequencies for all variables and examining the case-control differences. Odds ratios (OR) for the risk of BPBD associated with the main possible risk factors were then estimated using unconditional logistic regression. These variables included: demographic characteristics (age, educational level), menstrual and reproductive history (age at menarche, parity, gravidity, age at first full-term birth, lactation history, menopausal status, age at menopause and type of menopause), maternal history of breast cancer, anthropometric factors (body mass index [BMI] weight gain, weight, height), radiological fibroglandular tissue density, exogenous hormone use (hormone replacement therapy [HRT] including type and duration of use and oral contraceptive use), smoking history, caffeine and alcohol intake, recreational activity, walking pace and stairs climbed. None of these variables were confounders for any of the main effects estimated, hence only age-adjusted results are presented. The analysis was restricted to postmenopausal women (n = 154 cases and 199 controls) for the variables pertaining to HRT use.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There were some slight risk increases and decreases for other possible risk factors, however, no clear associations with BPBD were observed for the other factors considered. This study used a standardized histological classification system for BPBD that was reliable and that reduced the possibility of outcome misclassification.
Before discussing these results, some aspects of the study design and methods should be considered. To begin, the sample for this study was taken from a screening programme rather than from the general population. A number of advantages existed with this sampling scheme. These women were all known to be asymptomatic at the time of screening, they were identified and recruited by population-based recruitment letters. The mammography was performed under quality-controlled circumstances with abnormality and cancer detection rates in the ranges acceptable to international standards.1820 At the time that this study sample was taken, about 20% of women eligible for breast screening in Alberta were participating in this programme. Women were ineligible for screening if they had previously been diagnosed with breast cancer, had breast implants or been screened in the previous year. The screening programme had not been fully expanded to saturate the population of women aged 5069 years of age in Alberta.
The radiological assessment of breast tissue density appeared to be associated with breast histology and may be a predictor of risk of BPBD. Despite the fact that a subjective assessment of breast tissue density was used, there was still some discrimination possible between women with and without proliferative breast tissue changes. Additional quantification of breast density21 with some standardized approach for assessing microcalcifications of the breast may provide additional risk predictive powers. At this time, however, the value of increased quantification of breast tissue density for risk prediction purposes cannot be assessed.
A clear strength of this study was the standardized histological classification of all the benign breast biopsies that had been performed within the context of this screening programme for this time period. The analysis of risks for different types of BPBD was, however, not possible with this sample size. Although there were nearly 400 women eligible for the study, only 19 women had atypical breast diseases (i.e. atypical lobular and ductal hyperplasias) that would place them in a category of moderately increased risk for breast cancer (RR = 4.05.0).7 Likewise there was only one case with lobular carcinoma in situ and six cases with ductal carcinoma in situ. These cases would have a markedly increased risk of breast cancer (RR = 8.010.0)7 but were excluded from this analysis since the focus was on non-neoplastic disease. Inclusion or exclusion of the atypical hyperplasias from the proliferative BPBD category did not alter the risk estimates noticeably, hence, they were included in this category for the final analyses.
A fundamental feature of this study was that biopsies were performed on all study subjects. This feature provides study strength since the exact type of breast tissue histology could be ascertained and women could be clearly classified as having, or not having, benign proliferative breast tissue changes. However, it is also a potential limitation for this study as all women were identified as having an abnormality on their screening mammogram that required a biopsy. Hence, the case-control differences with respect to the exposures of interest may have been diminished which would have power implications for this study. Thus, the lack of association between the risk factors and BPBD examined in this study may be attributable to the limited power of the study.
We were also unable, with this study design, time frame and types of BBD to determine which of these women eventually developed breast cancer. Numerous studies have already examined the risks of breast cancer associated with different histological types of BBD and these associations are now fairly well established and accepted.7,22 The majority of the women in our study (n = 146) were within the category that confers a slightly increased risk of breast cancer (RR = 1.52.0).7 This category includes all those women with complex fibroadenoma, moderate or florid hyperplasia, sclerosing adenosis, and papilloma.7 Since there were so few women with atypical hyperplasia within this study sample who would be at a moderately increased risk of breast cancer, no follow-up of this cohort of women was undertaken.
Previous research1 has suggested that there are no known modifiable risk factors for BPBD which is supported by this study. Most previous studies have shown no substantial effect of ever, former or current smoking;2328 however one study29 found decreased risks and another30 increased risks for BPBD associated with smoking. In this study, cigarette smoking as assessed as current, past, or passive smoking was not associated with an increased risk of BPBD. Likewise, caffeine and alcohol intake were not associated with risk of BPBD. Several studies3135 have examined caffeine consumption and the potential deleterious effect on BPBD, however, no strong or consistent association have been delineated. One study has examined in detail the effect of alcohol consumption on BPBD, however, no association was found even after stratification by degree of atypia.36
Endocrine factors appear to be involved in the aetiology of BPBD but their exact roles remain unclear.1 Estrogen replacement therapy (ERT) has been identified as a risk factor for BPBD in some studies,12,3740 while other studies have shown no effect29,41,42 or a protective effect.43 This study found only a slight risk elevation for ERT use that was not, however, statistically significant. Oral contraceptive use may decrease the risk of BPBD but the evidence is inconsistent.9,40,42,4454 In this study, no association was found between any measure of oral contraceptive use and risk of BPBD.
Obesity has been consistently shown to decrease risk of BPBD,10,22,44,5561 a result that was not supported in this study for any of the anthropometric variables examined including weight gain since age 18, BMI, current weight, and height and weight at ages 30, 40, and 50. The associations with obesity in these studies may be related to cysts and increased fibroglandular tissue density rather than with specific histological findings.
Radiological tissue density may be an important predictor of risk that should be considered more fully. Improved methods of quantifying radiological tissue density and classifying mammographic tissue characteristics would permit more detailed examination of these characteristics and their association with histological characteristics as well as epidemiological risk factors for BBD. In this study, radiological tissue density appears to be somewhat associated with breast histology and to predict risk of BPBD. The association between breast tissue density and histology was not, however, strong since there may have been misclassification of the breast tissue density as it was based on a subjective assessment made by the radiologists as opposed to some more objective quantification of breast tissue density.
As women continue to participate in mammography screening programmes, the number of cases of BPBD detected among asymptomatic women as a result of screening is expected to increase. Since the pathophysiology of BPBD development is poorly understood, any improved understanding of the risk factors for this disease would be helpful. Further work that examines the risks of different types of BPBD would permit further elucidation of aetiological pathways.
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Ernster VL. The epidemiology of benign breast disease. Epidemiol Rev 1981;3:184202.[ISI][Medline]
3 Bodian CA. Benign breast diseases, carcinoma in situ, and breast cancer risk. Epidemiol Rev 1993;15:17787.[ISI][Medline]
4 Page DL, Vander Zwaag R, Rogers LW, Williams LT, Walker WE, Hartman WH. Relation between component parts of fibrocystic disease complex and breast cancer. J Natl Cancer Inst 1978;61: 105563.[ISI][Medline]
5 Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 1985;312:14651.[Abstract]
6 Page DL, Dupont WD, Rogers LW, Rados MS. Atypical hyperplastic lesions of the female breast: a long-term follow-up study. Cancer 1985;55:2698708.[ISI][Medline]
7 Fitzgibbons PL, Henson DE, Hutter RVP. Benign breast changes and the risk for subsequent breast cancer. An update of the 1985 consensus statement. Arch Pathol Med 1998;122:105355.[ISI]
8 Bartow SA, Pathak DR, Black WC, Key CR, Teaf SR. Prevalence of benign, atypical, and malignant breast lesions in populations at different risk for breast cancer: a forensic autopsy study. Cancer 1987;60: 275160.[ISI][Medline]
9 Ory H, Cole P, MacMahon B, Hoover R. Oral contraceptives and reduced risk of benign breast diseases. N Engl J Med 1976;294: 41922.[Abstract]
10 Cole P, Elwood JM, Kaplan SD. Incidence rates and risk factors of benign breast neoplasms. Am J Epidemiol 1978;108:11220.[Abstract]
11 Fleming NT, Armstrong BK, Sheiner HJ. The comparative epidemiology of benign breast lumps and breast cancer in Western Australia. Int J Cancer 1982;30:14752.[ISI][Medline]
12 Jick SS, Walker AM, Jick H. Conjugated estrogens and fibrocystic breast disease. Am J Epidemiol 1986;124:74651.[Abstract]
13 Wolf AM, Hunter DJ, Colditz GA et al. Reproducibility and validity of a self-administered physical activity questionnaire. Int J Epidemiol 1994;23:99199.[Abstract]
14 Ainsworth BE, Haskell WL, Leon AS et al. Compendium of physical activities: classification of energy costs of human physical activities. Med Sci Sports Exerc 1993;25:7180.[ISI][Medline]
15 Pennington JAT. Supplementary Tables: Caffeine. In: Bowes and Church's Food Values of Portions Commonly Used. Philadelphia, PA: JB Lippincott Co., 1994, pp.38183.
16 Pennington JAT. Supplementary tables: alcohol (ethanol) content of alcoholic beverages. In: Bowes and Church's Food Values of Portions Commonly Used. Philadelphia, PA: JB Lippincott Co., 1994, p.378.
17 Byng JW, Yaffe MJ, Jong RA et al. Analysis of mammographic density and breast cancer risk. Radiographics 1998;18:158798.[Abstract]
18 Tabar L, Fagerberg G, Duffy SW, Day NE, Gad A, Grontoft O. Update of the Swedish Two-County program of mammographic screening for breast cancer. Radiol Clin N Am 1992;30:187209.[ISI][Medline]
19 Europe Against Cancer. European Guidelines for Quality Assurance in Mammographic Screening. European Commission, June 1996.
20 Standards for the NHS Breast Screening Programme. NHSBSP, 1993.
21 Byng J, Boyd NF, Yaffe M. Quantitative assessment of mammographic densities. Phys Med Biol 1994;39:162938.[ISI]
22 Bianchi S, Palli D, Galli M, Zampi G. Benign breast disease and cancer risk. Crit Rev Oncol/Hematol 1993;15:22142.[ISI][Medline]
23 Yu H, Rohan TE, Cook MG, Howe GR, Miller AB. Risk factors for fibroadenoma: a case-control study in Australia. Am J Epidemiol 1992; 135:24758.[Abstract]
24 Parazzini F, Ferraroni M, La Vecchia C et al. Smoking habits and risk of benign breast disease. Int J Epidemiol 1991;20:43034.[Abstract]
25 Rohan TE, Cook MG, Baron JA. Cigarette smoking and benign proliferative epithelial disorders of the breast in women: a case-control study. J Epidemiol Community Health 1989;43:36268.[Abstract]
26 Rohan TE, Baron JA. Cigarette smoking and benign breast disease. In: Wald N, Baron JA, (eds). Smoking and Hormone-related Disorders. New York, NY: Oxford University Press, 1990, pp.7280.
27 Mant D, Vessey MP, Smith MA, Yeates D. Cigarette smoking and benign breast disease (Letter). J Epidemiol Community Health 1986;40: 27778.[ISI][Medline]
28 Berkowitz GS, Canny PF, Livolsi VA, Merino MJ, O'Connor TZ, Kelsey JL. Cigarette smoking and benign breast disease. J Epidemiol Community Health 1985;39:30813.[Abstract]
29 Pastides H, Najjar MA, Kelsey JL. Estrogen replacement therapy and fibrocystic breast disease. Am J Prev Med 1987;3:28286.[ISI][Medline]
30 Nomura A, Comstock GW, Tonascia JA. Epidemiologic characteristics of benign breast disease. Am J Epidemiol 1977;105:50512.[Abstract]
31 Boyle CA, Berkowitz GS, LiVolsi VA et al. Caffeine consumption and fibrocystic breast disease: a case-control epidemiologic study. J Natl Cancer Inst 1984;72:101519.[ISI][Medline]
32 La Vecchia C, Franceschi S, Parazzini F et al. Benign breast disease and consumption of beverages containing methylxanthines. J Natl Cancer Inst 1985;74:9951000.[ISI][Medline]
33 Schairer C, Brinton LA, Hoover RN. Methylxanthines and benign breast disease. Am J Epidemiol 1986;124:60311.[Abstract]
34 Lubin F, Ron E, Wax Y, Black M, Funaro M, Shitrit A. A case-control study of caffeine and methylxanthines in benign breast disease. JAMA 1985;253:238892.[Abstract]
35 Rohan TE, Cook MG, McMichael AJ. Methylxanthines and proliferative epithelial disorders of the breast in women. Int J Epidemiol 1989; 18:62633.[Abstract]
36 Rohan TE, Cook MG. Alcohol consumption and risk of benign proliferative epithelial disorders of the breast in women. Int J Cancer 1989;43:63136.[ISI][Medline]
37 Trapido EJ, Brinton LA, Schairer C, Hoover R. Estrogen replacement therapy and benign breast disease. J Natl Cancer Inst 1984;73:110105.[ISI][Medline]
38 Berkowitz GS, Kelsey JL, LiVolsi VA et al. Exogenous hormone use and fibrocystic breast disease by histopathologic component. Int J Cancer 1984;34:44349.[ISI][Medline]
39 Berkowitz GS, Kelsey JL, Holford TR et al. Estrogen replacement therapy and fibrocystic breast disease in postmenopausal women. Am J Epidemiol 1985;121:23845.[Abstract]
40 Sartwell PE, Arthes FG, Tonascia JA. Epidemiology of benign breast lesions: lack of association with oral contraceptive use. N Engl J Med 1973;288:55154.[ISI][Medline]
41 Parazzini F, La Vecchia C, Franceschi S et al. Risk factors for pathologically confirmed benign breast disease. Am J Epidemiol 1984;120: 11522.[Abstract]
42 Ravnihar B, Seigel DG, Lindtner J. An epidemiologic study of breast cancer and benign breast neoplasias in relation to oral contraceptive and estrogen use. Eur J Cancer 1979;15:395405.[ISI][Medline]
43 Bright RA, Morrison AS, Brisson J et al. Histologic and mammographic specificity of risk factors for benign breast disease. Cancer 1989; 64:65357.[ISI][Medline]
44 Brinton LA, Vessey MP, Flavel R, Yeates D. Risk factors for benign breast disease. Am J Epidemiol 1981;113:20314.[Abstract]
45 Canny PF, Berkowitz GS, Kelsey JL, LiVolsi VA. Fibroadenoma and the use of exogenous hormones: a case-control study. Am J Epidemiol 1988;127:45461.[Abstract]
46 Kelsey JL, Lindfors KK, White C. A case-control study of the epidemiology of benign breast diseases with reference to oral contraceptive use. Int J Epidemiol 1974;3:33340.[ISI][Medline]
47 Kelsey JL, Holford TR, White C, Mayer ES, Kilty SE, Acheson RM. Oral contraceptives and breast disease: an epidemiological study. Am J Epidemiol 1978;107:23644.[Abstract]
48 Franceschi S, La Vecchia C, Parazzini F et al. Oral contraceptives and benign breast disease: a case-control study. Am J Obstet Gynecol 1984;149:60206.[ISI][Medline]
49 Vessey MP, Doll R, Sutton PM. Investigation of the possible relationship between oral contraceptives and benign and malignant breast disease. Cancer 1971;28:139599.[ISI][Medline]
50 Pastides H, Kelsey JL, LiVolsi VA, Holford TR, Fischer DB, Goldenberg IS. Oral contraceptive use and fibrocystic breast disease with special reference to its histopathology. J Natl Cancer Inst 1983;71:59.[ISI][Medline]
51 Lees AW, Burns PE, Grace M. Oral contraceptives and breast disease in premenopausal northern Alberta women. Int J Cancer 1978;22: 70007.[ISI][Medline]
52 Hsieh CC, Crosson AW, Walker AM, Trapido EJ, MacMahon B. Oral contraceptive use and fibrocystic breast disease of different histologic classifications. J Natl Cancer Inst 1984;72:28590.[ISI][Medline]
53 LiVolsi VA, Stadel BV, Kelsey JL, Holford TR, White C. Fibrocystic breast disease in oral-contraceptive users: a histopathological evaluation of epithelial atypia. N Engl J Med 1978;299:38185.[Abstract]
54 Berkowitz GS, Kelsey JL, LiVolsi VA et al. Oral contraceptive use and fibrocystic breast disease among pre- and postmenopausal women. Am J Epidemiol 1984;120:8796.[Abstract]
55 Soini I, Aine R, Lauslahti K, Hakama M. Independent risk factors of benign and malignant breast lesions. Am J Epidemiol 1981;114: 50714.[Abstract]
56 Hislop TG, Elwood JM. Risk factors for benign breast disease: a 30-year cohort study. Can Med Assoc J 1981;124:28391.[Abstract]
57 Pastides H, Kelsey JL, Holford TR, LiVolsi VA. An epidemiologic study of fibrocystic breast disease with reference to ductal epithelial atypia. Am J Epidemiol 1985;121:44047.[Abstract]
58 London SJ, Stein EA, Henderson IC et al. Carotenoids, retinol, and vitamin E and risk of proliferative benign breast disease and breast cancer. Cancer Causes Control 1992;3:50312.[ISI][Medline]
59 Simard A, Vobecky J, Vobecky JS. Nutrition and lifestyle factors in fibrocystic disease and cancer of the breast. Cancer Detect Prev 1990;14:56772.[ISI][Medline]
60 Ingram D, Nottage E, Ng S, Sparrow L, Roberts A, Willcox D. Obesity and breast disease: the role of female sex hormones. Cancer 1989;64:104953.[ISI][Medline]
61 Hislop TG, Band PR, Deschamps M et al. Diet and histologic types of benign breast disease defined by subsequent risk of breast cancer. Am J Epidemiol 1990;131:26370.[Abstract]