Benign Proliferative Epithelial Disorders Research Articles

P4-10-09: Hormone Replacement Therapy: A Benign Breast Disease's Risk?

Abstract Background Use of hormone replacement therapy (HRT) has been associated with increased risk of breast cancer. However relations between use of HRT and benign breast lesions remain contradictory (1-3). Our goal was to investigate whether HRT and its duration use are associated with benign breast lesions. Materials & Methods From 2001 to 2007, 2708 patients with a non palpable breast lesion were referred to our breast care center. Radiological abnormalities were screened either by breast ultrasound mammography, or MRI. Of those, 1 329 patients had a biopsy in our Radiology Unit. We focus on the postmenopausal women (n=739). Clinical data including HRT use extent were reported. Patients with previous history of benign breast disease or malignancy were excluded. Results The analysis was performed on 739 patients. Biopsies yielded a benign result in 414 (56%) of them (fibroadenoma n=71, blunt duct adenosis n=94, fibrocystic disease n=92, epithelial hyperplasia n=56, others n=101), high risk lesions in 57 (8%) (atypical ductal hyperplasia n=28, atypical lobular hyperplasia n=19, lobular carcinoma in situ n=10) and malignancy in 268 (36%) (not studied here). For the 471 patients with benign or high risk breast lesion, the median age was 59 years, 80% had at least one pregnancy and 27% had a family history of breast cancer. Among these 471 patients, 47% of them had used an oral contraceptive and 53% of them a HRT, with a mean duration of use of 2 years. The HRT use was not significantly associated with the type of benign or high risk breast disease. No association was observed either between breast disease and duration of HRT (less or more than 7 years respectively).Older age was significantly correlated to atypia or carcinoma (median age at diagnosis 59 y.o in benign lesions, 60 y.o in high risk lesions and 62 y.o in malign lesions, with significant difference) (p<0,0001). Conclusion In this study of postmenopausal women, HRT and its duration use were not associated with the type of benign or high risk breast lesion. Although a lack of statistical power may be invoked to explain the results, we are called to believe that the magnitude of an effect of HRT use is small, if ever it exists. 1. Finkelde DT, Kitchen PR, Hayes PR, McKinlay MR, Henderson MA 2001 Symptomatic benign breast disease and hormone replacement therapy. Breast 10:127–130 2. Gayet A, Esteve J, Seradour B, Piana L, Jacquemier J 2003 Does hormone replacement therapy increase the frequency of breast atypical hyperplasia in postmenopausal women? Results from the Bouches du Rhone district screening campaign. Eur J Cancer 39:1738–1745 3. Rohan TE, Miller AB 1999 Hormone replacement therapy and risk of benign proliferative epithelial disorders of the breast. Eur J Cancer Prev 8:123–130 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-10-09.

Menstrual and reproductive history, postmenopausal hormone use, and risk of benign proliferative epithelial disorders of the breast: a cohort study

Menstrual and reproductive history and postmenopausal hormone use are well-established risk factors for breast cancer. However, previous studies that have assessed these factors in association with risk of benign proliferative epithelial disorders (BPED) of the breast, putative precursors of breast cancer, have yielded inconsistent findings. To investigate these associations, we conducted a cohort study among 68,132 postmenopausal women enrolled in the Women's Health Initiative randomized clinical trials. Women were prospectively followed and those reporting an open surgical biopsy or a core needle biopsy had histological sections obtained for centralized pathology review. Over an average of 7.8 years of follow-up, we identified 1,792 women with BPED of the breast. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence limits (CLs) for the associations of interest. Menstrual and reproductive histories were not associated with risk of BPED of the breast, overall or by histological subtype. Women who had used postmenopausal hormones for 15 years or more had a two-fold increase in risk of BPED of the breast compared to women who had never used postmenopausal hormones (HR = 2.03 95% CL = 1.73, 2.38) and the increase in risk was observed for both BPED of the breast without atypia and for atypical hyperplasia. Furthermore, the risk of BPED of the breast decreased with time since cessation of use so that there was essentially no increase in risk 5 or more years after ending use (HR for stopping >or=5 years earlier = 0.96, 95%CL = 0.79, 1.16; HR for stopping <5 years earlier = 1.32, 95% CL = 1.08,1.61).

Benign proliferative epithelial disorders of the breast: a review of the epidemiologic evidence

Benign breast disease (BBD) is a heterogeneous condition consisting of many histological entities [1], including ductal epithelial proliferations, adenomas and papillomas, and fibroadenomas [2]. Some of these lesions are thought to represent progressive changes in the stepwise sequence of histological changes leading to the development of breast cancer. Specifically, it has been hypothesized that non-atypical proliferative forms of BBD, proliferative disease with atypia, and in situ cancer represent successive steps preceding the development of invasive breast carcinoma [3]. This hypothesis is supported by experimental and epidemiologic evidence. Experimentally, xenografts of MCF10AneoT cells have been shown to progress from intraductal proliferative changes to lesions resembling atypical hyperplasia of the human breast and ultimately to lesions resembling carcinoma in situ [4]; this step-wise development of breast cancer has also been demonstrated using transgenic rat [5] andmouse [6] models. Epidemiologic studies have shown that women with proliferative epithelial disorders affecting the small ducts and the terminal ductal lobular units of the breast are at increased risk of subsequent breast cancer, particularly when the epithelial proliferation is accompanied by evidence of atypia [1, 7–9]. Risk is increased approximately 1.5–2 fold for those with epithelial proliferation without atypia [7–9] and 4–5 fold for those with proliferative disease with atypia [8, 10]. The higher risk associatedwith atypia is consistent with the notion that it ismore proximal to carcinoma thanproliferative disease without atypia. Given these findings, benign proliferative epithelial disorders (BPED) of the breast are considered to have malignant potential [11]. Our focus in the remainder of this review is on BPED of the breast.

Alcohol and folate consumption and risk of benign proliferative epithelial disorders of the breast

Alcohol consumption has been associated with increased breast cancer risk and the increase in risk may be attenuated by adequate folate intake. However, their associations with the risk of benign proliferative epithelial disorders (BPEDs) of the breast, possible precursors of breast cancer, are not well understood. To investigate these associations, we conducted a cohort study among 68,132 postmenopausal women participating in the Women's Health Initiative randomized clinical trials. Women were prospectively followed and those reporting a breast procedure (open surgical biopsy or core needle biopsy) had histological sections obtained for central pathology review. A total of 1,792 women with BPED of the breast were identified over an average of 7.8 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence limits (CLs) for the associations of interest. Compared to nondrinkers, total current alcohol intake of 30 g/day or more was not associated with BPED risk (HR = 0.98, 95% CL = 0.70, 1.38). The risk of BPED was not associated with folate intake from diet (highest vs. lowest quartile: HR = 1.10, 95% CL = 0.96, 1.26), from supplements (yes vs. no: HR = 1.05, 95% CL = 0.96, 1.16) or from all sources combined (highest vs. lowest quartile: HR = 1.11, 95% CL = 0.96, 1.27). Furthermore, there was no effect modification between alcohol and folate in relation to the risk of BPED. In conclusion, we observed that alcohol consumption and folate intake were not associated with altered risk of BPED, and that there was no effect modification between them in relation to the risk of BPED.

Cigarette smoking and risk of benign proliferative epithelial disorders of the breast in the Women’s Health Initiative

To investigate the association between cigarette smoking and risk of benign proliferative epithelial disorders (BPED) of the breast. We used data from an ancillary study of benign breast disease that is being conducted in the Women's Health Initiative randomized clinical trials among 68,132 postmenopausal women aged 50-79 at recruitment. After following the trial participants for an average of 7.8 years, we had ascertained 294 incident cases with atypical hyperplasia and 1,498 incident cases with non-atypical BPED of the breast. We used Cox proportional hazards models to estimate hazard ratios for the association between cigarette smoking and risk of BPED. Smoking measures, including duration of smoking, intensity of smoking, pack-years of smoking, age at which smoking commenced, and years since quitting smoking, were not associated with risk of BPED overall or by histological subtypes. The null association between cigarette smoking and risk of BPED of the breast suggests that the carcinogenic and antiestrogenic effects of cigarette smoking on the breast might counterbalance each other and that cigarette smoking might have no overall effects on BPED of the breast among postmenopausal women.

Hormone replacement therapy and risk of benign proliferative epithelial disorders of the breast.

Use of hormone replacement therapy (HRT) has been associated with increased risk of breast cancer, and it is possible that this reflects a positive association between HRT use and risk of proliferative forms of benign breast disease (BBD), conditions which are thought to have pre-malignant potential. The purpose of the present investigation was to study the association between HRT use and risk of benign proliferative epithelial disorders of the breast (BPED). The study was undertaken using the 56,837 women within the Canadian National Breast Screening Study (NBSS) who completed self-administered lifestyle and dietary questionnaires. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 at recruitment.) During the course of the follow-up period, a total of 691 women in the dietary cohort were diagnosed with biopsy-confirmed incident BPED. For comparative purposes, a sub-cohort consisting of a random sample of 5681 women (including 65 of the subjects with BPED) was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 691 cases and 5443 non-cases. In post-menopausal women, in whom most of the reported use occurred, there was a positive association between duration of HRT use and risk of BPED, the adjusted incidence rate ratio (95% confidence interval) in those who had used HRT for more than 8 years being 1.70 (1.06-2.72). There were too few cases of atypical BPED for meaningful analysis, but results for those whose BPED showed no atypia were similar to the overall results. Further analyses conducted separately in the screened and control arms of the NBSS were similar to those observed overall, as were those conducted separately for screen-detected and interval-detected BPED.

Cigarette smoking and risk of benign proliferative epithelial disorders of the breast.

Benign proliferative epithelial disorders (BPED) of the breast are conditions which are thought to have premalignant potential. The purpose of the present investigation was to study the association between cigarette smoking and risk of BPED. The study was undertaken within the 56,837 women within Canadian National Breast Screening Study (NBSS) who completed self-administered lifestyle and dietary questionnaires. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 at recruitment.) During the course of the follow-up period, a total of 691 women in the dietary cohort were diagnosed with biopsy-confirmed incident BPED. For comparative purposes, a subcohort consisting of a random sample of 5681 women (including 65 of the subjects with BPED) was selected from the full cohort. After exclusions for various reasons, the analyses were based on 691 cases and 5443 non-cases. Overall, the results of the present study are almost uniformly null, and provide little support for an association between cigarette smoking and risk of BPED. Analyses conducted separately in the screened and control arms of the NBSS also failed to provide strong support for associations, and there was little difference between the results for screen-detected and interval-detected BPED. There was some suggestion of an increase in risk in post-menopausal ex-smokers, but the trend in risk with cigarette-years of exposure in this group was not statistically significant. Risk in ex-smokers varied little by years since smoking cessation. There was little evidence for associations with either atypical or non-atypical forms of BPED.

Alcohol consumption and risk of benign proliferative epithelial disorders of the breast: a case-cohort study.

To study the association between alcohol consumption and risk of benign proliferative epithelial disorders (BPED) of the breast (conditions which are thought to have premalignant potential). Case-cohort study. The study was undertaken within the 56,537 women in the Canadian National Breast Screening Study (NBSS) who completed self-administered dietary questionnaires. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40-59 years at recruitment.) The study subjects were the 657 women in the dietary cohort who were diagnosed with biopsy-confirmed incident BPED. For comparative purposes, a subcohort consisting of a random sample of 5681 women was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 557 cases and 5028 non-cases. When compared to non-drinkers, rate ratios (95% CI) for those consuming > 0 and < or =10 g of ethanol day(-1), >10 and < or =20 g day(-1), >20 and < or =30 g day(-1) and >30 g day(-1) were 0.35 (0.27-0.45), 0.26 (0.18-0.39), 0.29 (0.18-0.48), and 0.23 (0.13-0.40), respectively (the associated P value for the trend was 0.089). Similar findings were obtained from analyses conducted separately in the screened and control arms of the NBSS, in premenopausal and postmenopausal women, and for non-atypical and atypical forms of BPED, and there was little difference between the results for screen-detected and interval-detected BPED. Alcohol consumption was associated with a non-dose-dependent reduction in risk of BPED.

A case-cohort study of diet and risk of benign proliferative epithelial disorders of the breast (Canada).

A case-cohort analysis of the association between diet and risk of benign proliferative epithelial disorders (BPED) of the breast was undertaken within a cohort of 56,537 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40 to 59 years.) BPED are thought to have premalignant potential. Specific hypotheses were that risk of BPED would increase with increasing energy-adjusted fat intake and decrease with increasing energy-adjusted vitamin A and fiber intake. Additionally, we explored the association between calcium intake and risk of BPED. During the active follow-up phase of the NBSS, 657 women in the dietary cohort were diagnosed with biopsy-confirmed incident BPED. For comparative purposes, a subcohort consisting of a random sample of 5,581 women was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 545 cases and 4,921 non-cases. Overall, the results were almost uniformly null, and provided little support for the study hypotheses. Rate ratios (95 percent confidence intervals [CI]) for the highest cf the lowest quintile levels for total fat, retinol, beta-carotene, fiber, and calcium were 0.88 (CI = 0.65-1.20), 0.97 (CI = 0.71-1.31), 0.94 (CI = 0.70-1.27), 1.11 (CI = 0.82-1.50), and 0.81 (CI = 0.60-1.07), respectively. There were too few cases of atypical BPED for meaningful analysis, but results for those whose BPED showed no atypia were similar to the overall results. Further analyses conducted separately in the screened and control arms of the NBSS also failed to provide strong support for dietary associations, as did those conducted separately for screen-detected and interval-detected BPED.

Dietary fiber and risk of benign proliferative epithelial disorders of the breast

Following a recent finding, from a case-control study in Adelaide, South Australia, of a reduced risk of breast cancer among women consuming diets rich in fiber, the fiber densities in the diets of 354 women with incident benign proliferative epithelial disorders of the breast (BPED) were compared with the fiber densities of the diets of 354 matched community controls and with those of 189 unmatched controls having breast conditions for which there was no evidence of BPED at biopsy. Fiber intakes were estimated by means of a self-administered quantitative food-frequency questionnaire, and the risk of BPED was estimated for each quintile of fiber density (grams of fiber/megaJoule of total energy intake) relative to an arbitrarily assigned risk of one for the lowest quintile. For women with the highest dietary fiber densities the estimated risk was 0.64 (95% CI 0.34, 1.19) when cases were compared with community controls, and 0.45 (95% CI 0.24, 0.82) when cases were compared with biopsy-negative controls. Similar trends in risk were observed for the intakes of other major fiber components, the association being stronger when the comparison was made with biopsy-negative as opposed to community controls. If these findings can be substantiated, they may open the way to dietary intervention strategies for reducing the incidence of breast cancer.

Recreational physical activity and risk of benign proliferative epithelial disorders of the breast in women

The association between recreational physical activity and the risk of benign proliferative epithelial disorders (BPED) of the breast was examined in a case-control study conducted in Adelaide, Australia, between 1983 and 1985. The study included 383 incident, histologically confirmed cases of BPED identified through the major private pathology laboratory, 383 unbiopsied community controls matched to the cases for age and area of residence, and 192 controls whose biopsies did not show any signs of epithelial proliferation. Subjects reported their level of usual weekly physical activity in a self-administered questionnaire. When cases were compared with community controls, there was some evidence for a negative association between risk of BPED and total recreational physical activity. However, the reverse was observed when the cases were compared with biopsy controls. These patterns were essentially the same when examined by intensity of activity and by menopausal status. Despite the lack of an association between physical activity and risk BPED in this study, further investigation is warranted because of the potential benefits for the primary prevention of breast disease.

Cigarette smoking and benign proliferative epithelial disorders of the breast in women: a case-control study.

The purpose of the study was to investigate the possible association between cigarette smoking and benign proliferative epithelial disorders of the breast. This was a case-control study with two different control groups. The study was community based and took place in metropolitan Adelaide, South Australia. 506 biopsy proven cases between 18 and 75 years were identified, of whom 39 could not be approached because of surgeon refusal, 66 would not be interviewed and 18 were untraceable, leaving 383 for inclusion in the study. Controls were 192 women who had had a negative breast biopsy, out of a possible 259 (17 surgeon refusals, 39 interview refusals, 11 untraceable); and a randomly selected group of women matched to the index group for age and area of residence (582 subjects were approached to enrol 383 controls). All breast biopsies were examined by one pathologist and classified using a standard system. Sociodemographic and medical information was collected by trained interviewers using structured questionnaires. Overall, and within menopausal strata, risk of benign proliferative epithelial disease for women who had ever smoked and for current and ex-smokers was similar to that for women who had never smoked. In premenopausal women, using community controls as the comparison group, risk decreased with cigarette-years of exposure, but the trend was not statistically significant. Risk appeared to increase when biopsy controls were used. There was no trend in the association when examined by degree of cytological atypia. The data suggest that cigarette smoking is not related to the risk of benign proliferative epithelial breast disease.

Methylxanthines and benign proliferative epithelial disorders of the breast in women.

The relationship between methylxanthine intake (caffeine, theobromine and theophylline) and risk of benign proliferative epithelial disorders (BPED) of the breast was examined in a case-control study conducted in Adelaide, South Australia. The study involved 383 cases with biopsy-confirmed BPED, 192 controls whose biopsy did not show epithelial proliferation, and 383 unbiopsied community controls individually matched to cases on age and area of residence. Overall, there was relatively little variation in risk of BPED with total methylxanthine intake, or with intake of caffeine or theophylline, while there was a positive association between theobromine intake and risk of BPED, but only when cases were compared with biopsy controls. Total methylxanthine intake was positively associated with risk of BPED showing severe atypia, but the trend in risk was statistically significant only when community controls formed the comparison group. These data do not provide strong support for an association between methylxanthine intake and risk of BPED.

The patho‐epidemiology of benign proliferative epithelial disorders of the female breast

Benign breast disease is associated with increased risk of subsequent breast cancer, especially when there is evidence of epithelial proliferation. There is no standard terminology for benign proliferative epithelial disorders (BPED), and this hinders direct comparisons between the various studies which have examined their pathology and their relationship to breast cancer. The present paper reviews previous classification schemes for BPED, and proposes an alternative system in which epitheliosis and blunt duct adenosis are the major features, the degree and pattern of the hyperplasias being graded separately. Adoption of this or a similar system as a standard should facilitate future comparative studies of these conditions. As BPED are apparently pre-malignant conditions, an understanding of their aetiology is important because it may help to elucidate the aetiology of breast carcinoma, and to open up avenues for its prevention. If BPED are precursors to breast carcinoma, then risk factors for BPED should also be risk factors for breast carcinoma. To date, in epidemiological studies of BPED, such concordance has not been demonstrated, as consistent risk factors for the BPED have not yet emerged. This may have resulted, at least in part, from differences in the histological categories included in the various studies. Therefore, collaboration between epidemiologists and pathologists may facilitate progress towards an understanding of BPED.