Risk factors for benign proliferative breast disease

CM Friedenreicha, HE Bryanta, F Alexanderb,c, J Hughd, J Danyluke and DL Pagef

a Division of Epidemiology, Prevention and Screening, Alberta Cancer Board, 1331–29 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
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Background As part of a nested case-control study of benign proliferative breast disease (BPBD) conducted within the cohort of women participating in the Alberta breast screening programme, an analysis of all women who had a benign breast biopsy between 1990 and 1995 was undertaken to identify the epidemiological risk factors for BPBD.

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 : 1.24–2.94). 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
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Benign breast disease (BBD) has a high prevalence and a noticeable impact on women's quality of life and, for certain histological types, increases breast cancer risk.1 It has been estimated that one out of every two women may develop some form of fibrocystic breast disease during her lifetime and that one out of every five women may develop fibroadenoma.1 Although BBD has been extensively studied, the aetiology of this disease is still poorly understood.2,3 It appears that endocrine factors are associated with BBD, however, the associations found are weak and inconsistent.1 Obesity has been identified as one of the only consistent risk factors for BBD.1 Inconsistent results have been found for most risk factors including exogenous hormone use, smoking, alcohol and caffeine intake.1 No studies have examined whether radiological tissue density is a risk factor for BBD.

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 classification4–7 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 studies9–12 is only 10–20%.

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 50–69. 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
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Study subjects
A nested case-control study was conducted of all women who had a benign breast biopsy within the cohort of women who attended Screen Test between 1 October 1990 and 31 December 1995. Women were eligible if they had a biopsy performed after the baseline screening or during a follow-up visit during this period. In all 43 950 women were screened and 2860 had abnormalities detected. Breast biopsies were performed on 971 women and 604 were benign and potentially eligible for this study. Of the 604 women with benign breast biopsies, 489 could be contacted for an interview. Those that were not contacted included 51 women who were ineligible (language barrier, deceased, non-residents of Alberta, no longer attending the screening programme), 46 women who had moved and 18 who were not available. Of the 489 eligible and available women, 402 completed an in-person interview (82.2% response rate) between January 1995 and October 1996. Of the 402 women, 390 had complete information on their breast histology and radiology and were included in this study.

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.4–7 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 1Go). 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.


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Table 1 Histological classification system for benign proliferative breast disease and number of study subjects within each category
 
It was initially intended that information on breast histology, radiology and epidemiology be combined in this study to identify women at increased risk for BPBD. We were unable to develop a radiological classification system for BPBD that was reproducible, reliable and feasible within the context of this breast screening programme. Rather, we used the assessment of breast tissue density that was made by the radiologists who review all mammograms of women who participate in Screen Test. The per cent fibroglandular tissue density is categorized into quintiles (fatty, >0–<25%, 25–50%, 50–75%, >75%).

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
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
Cases and controls had similar sociodemographic, menstrual, reproductive and anthropometric characteristics but did have slightly different hormone use habits, type of menopause, smoking habits, alcohol intake and physical activity habits (Table 2Go). Overall, there were few large increased or decreased risks for BPBD associated with the risk factors examined (Table 3Go). Slight, non-statistically significant risk increases were found for BPBD and age at menarche, menopausal status, parity, gravidity, age at first full-term birth, ever breastfeeding, and type of menopause. An increase in risk of BPBD was observed in women with fibroglandular breast tissue density that was >=25% as compared to those with <25% tissue density (OR = 1.91, 95% CI : 1.24–2.94).


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Table 2 Sociodemographic, menstrual, reproductive, and anthropometric characteristics, smoking and physical activity habits of women with and without histologically confirmed benign proliferative breast disease (BPBD), Alberta, Canada, 1995–1996, n = 382
 

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Table 3 Age-adjusted risk estimates for menstrual and reproductive factors, anthropometric measures, radiological tissue density, women with and without histologically confirmed benign proliferative breast disease, Alberta, Canada, 1995–1996, n = 382
 
The risks associated with HRT were examined for the postmenopausal women only (Table 4Go). None of the variables on HRT, including type of preparation, duration of use or current use were associated with an elevated risk of BPBD. Likewise, ever use of oral contraceptives was not associated with BPBD risk. No associations between BPBD and tobacco exposure, alcohol or caffeine use was observed in this study (Table 5Go).


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Table 4 Age-adjusted risk estimates for exogenous hormone use for postmenopausal women with and without histologically confirmed benign proliferative breast disease, Alberta, Canada, 1995–1996, n = 353
 

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Table 5 Age-adjusted risk estimates for smoking habits, alcohol and caffeine intake, among women with and without histologically confirmed benign proliferative breast disease, Alberta, Canada, 1995–1996, n = 382
 
There were no clear increases or decreases in risk of BPBD with any measure of physical activity (Table 6Go). Women in the highest quartile of energy expended in exercise had a slightly reduced risk of BPBD (OR = 0.94, 95% CI : 0.51–1.72). All categories of walking pace above the referent category had reduced risks of BPBD, however, the confidence intervals for all of these risk estimates were wide and included the null value. Similarly, there was no indication of decreasing risk of BPBD with increasing number of flights of stairs climbed per day. Total hours per week spent standing/walking and sitting (as a measure of inactivity) were also not associated with BPBD risk (data not shown).


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Table 6 Physical activity among women with and without histologically confirmed benign proliferative breast disease, Alberta, Canada, 1995–1996, n = 382
 

    Discussion
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
These study results suggest that risk of BPBD is increased among women who have more than 25% fibroglandular breast tissue density. This is the first empirical study that has found evidence for an increased risk of proliferative breast lesions with increased fibroglandular breast tissue density. Since increased breast tissue density has also been shown to increase risk of breast cancer,17 this study provides additional information on the aetiology of breast disease and, potentially, of breast cancer.

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.18–20 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 50–69 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 = 4.0–5.0).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 = 8.0–10.0)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 = 1.5–2.0).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;23–28 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 studies31–35 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,12,37–40 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.9,40,42,44–54 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,10,22,44,55–61 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
 
This study was funded by a research grant from the Alberta Cancer Board's Research Initiative Program. CM Friedenreich is supported by a National Health Research Scholar Award from Health Canada. The authors acknowledge the contribution of Dr Len Marx in the review of the breast biopsies, Kathleen Douglas for data management and study co-ordination, and Doreen Mandziuk, Pearl Cooke, Marilyn Dickson, and Tracey Pelsey for interviewing the study subjects.


    References
 Top
 Abstract
 Introduction
 Material and Methods
 Results
 Discussion
 References
 
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