1 Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA.
2 Station for Prevention and Treatment of Cancer, Shanghai Textile Industry Bureau, Shanghai, China.
Received for publication November 12, 2001; accepted for publication May 24, 2002.
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ABSTRACT |
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breast diseases; estrogens; fibroadenoma; risk factors
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INTRODUCTION |
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Several studies of risk factors for benign breast lesions have been conducted, many of which have included women with fibroadenoma along with other categories of "benign breast disease" (1114). However, because the pathogenesis and epidemiology of fibroadenoma may be distinct from those of other benign breast conditions (15, 16), these studies provide limited information on the risk factors for fibroadenoma. Studies specifically of fibroadenoma consistently provide evidence that exposure to endogenous and exogenous estrogens enhances risk: An inverse association with age after the mid twenties and a reduction in rates at menopause have been observed (10, 17); premenstrual mastalgia, which is related to enhanced estrogen activity, has been associated with fibroadenoma (7); and estrogen replacement therapy has been associated with an increase in risk (15, 16, 18). In addition, cigarette smoking has been inversely related to risk of fibroadenoma (9, 15, 19) and benign breast conditions in general, and it has been shown to have antiestrogenic effects (2023).
The use of combined oral contraceptives has been associated with a reduced risk of fibroadenoma (7, 1517, 24, 25) and of benign breast conditions in the aggregate (12, 14), suggesting that progestins may protect against fibroadenoma (24, 26). Parity has not consistently been associated with altered risk of fibroadenoma (4, 7, 10, 15, 24, 27). Several studies have examined the relation between family history of breast disease and fibroadenoma (4, 7, 15), but the results were not consistent across age groups, and adjusted relative risk estimates were not statistically significant.
This study was conducted to estimate incidence rates of fibroadenoma in a Chinese population and to identify risk factors for this condition. To our knowledge, it is the largest prospective study of fibroadenoma to date.
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MATERIALS AND METHODS |
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Data collection
Thirty-four nurses or former factory medical workers (subsequently referred to as study workers) were recruited and trained for the breast self-examination study. After receiving training from the study workers, approximately 5,000 factory medical clinic workers orally administered a four-page optically scanned baseline questionnaire between October 1989 and October 1991 to all women who were eligible for the study. Information was elicited on demographic characteristics, smoking and alcohol habits, reproductive and gynecologic history, and family history of breast cancer.
All women were followed for vital status and continued residence in Shanghai through July 31, 2000. This information was collected by study workers during frequent visits to the factories and by periodic surveys of the cohort, as well as from a Tumor and Death Registry operated by the Shanghai Textile Industry Bureau, which receives annual reports from each factory on all deaths and incident cancers.
When a current or retired factory worker developed a breast problem or detected a breast lump, she would report to the medical clinic in her factory, where she would be evaluated by a medical worker. If a breast abnormality was confirmed, the woman was usually referred to one of three hospitals operated by the Shanghai Textile Industry Bureau, where clinics had been established to evaluate and treat breast diseases in women in the breast self-examination trial. In some instances, women were referred to other hospitals that had contractual agreements with individual factories.
Study personnel reviewed the pathology reports and other medical records of all women found to have a histologically confirmed benign or malignant breast lesion. The tumor size, location within the breast, and its histologic classification were abstracted onto a standardized form, and slides of all tumors were sent to Seattle, Washington, for storage and future review. Subjects with fibroadenoma were identified for this study from these forms.
Validation of the diagnoses of fibroadenoma
A reference pathologist reviewed slides from selected cases with and without an initial diagnosis of fibroadenoma. Of 483 fibroadenomas diagnosed by a local pathologist in Shanghai, 442 (92 percent) were also identified by the reference pathologist as fibroadenoma. The remaining 41 were classified as "other benign" conditions. Of 705 benign breast disease cases not considered fibroadenoma by a local pathologist, 634 (90 percent) were confirmed as a nonfibroadenoma by a reference pathologist. Because of the high concordance between the diagnoses made by local and reference pathologists, no further slide review was undertaken for this study, and the diagnoses made by the local pathologists in Shanghai were used for this investigation.
Validation of the baseline questionnaire
A subset of 2,637 women with benign and malignant breast disease and controls that were enrolled in a nested case-control study by October 1999 was reinterviewed. The questionnaire for that study, the Reproductive Health Survey, was designed to collect data on contraceptive and reproductive history, as well as on family history of malignant breast disease, more comprehensively than was possible using the baseline questionnaire and by more rigorously trained interviewers. By assuming that the Reproductive Health Survey is the more reliable of the two survey instruments, evaluation of response concordance between similar questions on the two questionnaires provided an opportunity to validate the quality of information from the baseline questionnaire.
The variables on the baseline questionnaire that were least reliable were stillbirths, contraceptive injection use, and sisters with breast cancer; less than 50 percent of those who answered positively on the baseline questionnaire also answered positively on the Reproductive Health Survey. However, agreement of over 80 percent was observed for most variables, indicating that the baseline questionnaire is a fairly reliable study tool, and concordance of over 90 percent was observed for induced abortion, use of intrauterine device, reason for menstrual cessation, hysterectomy, and tubal ligation. The level of concordance for most variables was similar in cases and controls (unpublished data).
Data analysis
Age-specific rates of fibroadenoma were calculated as follows. The number of person-years that each woman in the cohort contributed to each age interval was calculated, and all person-years were summed to provide the denominator for that interval. The number of women diagnosed with fibroadenoma in that age interval was then divided by the total person-years in the interval to yield the incidence rate for that age group.
Using Cox regression (29) with time since baseline interview as the survival time variable, we estimated the relative risk associated with each variable of interest, adjusted for age at baseline (categorized into 5-year intervals). The significance of trends in risk with level of exposure was calculated by assigning scores to the categorized levels of exposure and treating the scores as a continuous variable in the regression model. All factors determined to be significant on a univariate basis using a likelihood ratio test were considered in further multivariate analyses.
Adjusted relative risks were estimated after grouping variables of interest into several categories: endogenous hormonal factors, exogenous hormonal factors, personal history of breast disease, and breast examination. Potential confounders that caused a greater than 10 percent change in the relative risk of interest were retained in the models. Variables that did not add significant information after adjusting for other variables in the same group were eliminated from the model. All significant factors from each group, as well as risk factors that did not fit logically into any of the groups, were included in a final predictive model. Interaction was evaluated within each group of exposures by stratification to determine the patterns of relative risks for exposures in different subgroups of the study population. To assess multiplicative interactions, the likelihood ratio test was used to measure the difference in the deviance between a model with and without an interaction term (29).
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RESULTS |
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Exogenous hormonal factors
Risk was reduced in women who ever used pill number 1 (0.625 mg of norethisterone and 0.035 mg of ethinyl estradiol until 1974; 0.3 mg of norethisterone and 0.03 mg of ethinyl estradiol 1974 and after) (relative risk = 0.8, 95 percent confidence interval: 0.7, 1.0), and a decreasing trend in risk with duration of its use was observed. Too few users of other types of oral contraceptives precluded meaningful analyses. Age at first oral contraceptive use and age at last oral contraceptive use were not significantly associated with risk of fibroadenoma. Use of monthly injectable contraceptives (250 mg of 17-hydroxyprogesterone and 5 mg of estradiol-zalerate) was not significantly associated with risk, but the point estimate of the relative risk associated with greater than 1 year of use (relative risk = 0.7, 95 percent confidence interval: 0.4, 1.2) was similar to that for 14 years of oral contraceptive use.
History of benign breast disease
Ever having had a breast lump was strongly associated with an increased risk of fibroadenoma (relative risk = 6.5, 95 percent confidence interval: 5.8, 7.3), regardless of whether the lump was biopsied (not shown). Significant increasing linear trends in risk with increasing number of breast lumps and with decreasing age at first breast lump were observed. When the number of breast lumps and the age at first breast lump were adjusted for each other, both factors remained significantly associated with risk. After adjustment, compared with women with no breast lumps (relative risk = 1.51, 95 percent confidence interval: 1.0, 2.2), those with three or more previous lumps (relative risk = 0.17, 95 percent confidence interval: 0.1, 0.2) had almost a ninefold increased risk of fibroadenoma. Results for the number of breast lumps were similar, regardless of the age at first breast lump, and the risk associated with age at first breast lump was the same across the strata of number of breast lumps (not shown).
Breast examination
A history of breast self-examination at baseline and being in the instruction arm of the breast self-examination trial were associated with an increased risk of fibroadenoma (table 3). The risk of fibroadenoma was not associated with history of clinical breast examination at baseline after adjustment for these two factors (not shown). Among those who had had a clinical breast examination, no trend in risk with time since last examination was observed.
Other risk factors
Based on 52 subjects with a first degree relative with breast cancer and 52,238 person-years contributed by women with such a family history, the relative risk of fibroadenoma in relation to family history of breast cancer was estimated to be 1.6 (95 percent confidence interval: 1.2, 2.1). After adjustment for all of the variables shown in table 3, the estimate was reduced to 1.3 (95 percent confidence interval: 0.9, 1.7). In the instruction group, the relative risk remained marginally significant after adjustment for compliance with breast self-examination trial procedures (relative risk = 1.5, 95 percent confidence interval: 1.0, 2.1).
No significant association with risk was observed with marital status, alcohol consumption, ever having smoked regularly, or smoking duration, although the numbers of unmarried women and users of alcohol and tobacco were too small to provide stable relative risk estimates. No significant association was observed with use of an intrauterine device or a tubal ligation.
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DISCUSSION |
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A history of benign breast lesions was associated with a substantially increased risk of a subsequent fibroadenoma. It was not possible to distinguish whether the prior lumps were fibroadenoma or other benign breast conditions, so risks in relation to specific types of benign breast conditions could not be estimated. Multiple occurrence (3) and recurrence (4, 30) of fibroadenoma have been well established, and if the observed associations are a reflection of this phenomenon, then the relative risk estimates in relation to prior fibroadenoma are undoubtedly higher than the relative risks of over 8.0 observed in relation to all types of benign breast conditions. Early age at first breast lump was determined to be an independent predictor of risk. One possible explanation for this is that the benign lesions in young women more likely were fibroadenoma than those in older women. The presence of significant associations with prior breast lumps and age at first breast lump after adjustment for each other and breast examination variables indicates that they are strong risk factors for fibroadenoma beyond a possible effect of increasing awareness of breast disease in women who have already had a benign breast condition.
Prior studies of risk of fibroadenoma in relation to parity have yielded inconsistent results (4, 7, 10, 15, 24, 27). This study identified a decreasing risk of fibroadenoma associated with an increasing number of livebirths but an absence of associations with other outcomes of pregnancy or breastfeeding. During early pregnancy, estrogens and other circulating hormones cause the rapid proliferation of epithelial breast tissue (31), followed by hormonally driven differentiation of the mammary epithelium, as the breast prepares for lactation. It is possible that this latter effect might protect against the development of fibroadenoma, which is likely a result of hyperplastic processes that are estrogen dependent (32, 33).
This study confirmed results of previous investigations that the use of oral contraceptives is associated with decreased risk of fibroadenoma (7, 1517, 24). Although use of injectable contraceptives was not significantly associated with fibroadenoma, the relative risk associated with greater than 1 year of use suggests a possible protective effect also of these preparations. Both the oral contraceptive pill number 1 and the standard injectable contraceptive used in Shanghai contain an estrogen plus a progestogen. These exogenous hormones suppress ovarian hormone production and may act differently from endogenous hormones on breast tissue (34). Studies suggest that progestins may act to counter the stimulating effects of endogenous or exogenous estrogens on breast tissue (26) and thus protect against fibroadenomas or retard their growth (24).
The increased relative risks associated with the study arm of the breast self-examination trial and history of breast self-examination at baseline clearly represent increased awareness and detection of fibroadenoma, rather than risk factors for development of the disease.
Previous studies have found a positive family history of breast cancer or breast disease (including breast cancer) to be related to fibroadenoma (4, 7, 15). In this study, after adjustment for multiple variables, family history of breast cancer was not a strong or significant predictor of fibroadenoma. Among women in the instruction group, the association with family history of breast cancer was not confounded by compliance with breast self-examination trial procedures, suggesting that preferential screening is not an explanation for the small increase in risk that was observed.
After adjustment for history of breast self-examination and study arm of the breast self-examination trial, the significant associations observed with the number of births, duration of oral contraceptive use, number of prior breast lumps, age at first breast lump, and menopause support the conclusion that these are true risk factors for the development of fibroadenoma and are not explained by increased breast awareness and examination in women with these factors.
No association between cigarette smoking and risk of fibroadenoma was observed in this study, despite previous reports of a reduced risk associated with this exposure (9, 15, 19). This may be due to the small numbers of subjects who were cigarette smokers, which is consistent with the smoking habits of the female Chinese population at the time of this study. It is also possible that the choice of hospital controls in several of the prior case-control studies of cigarette smoking could have led to selection bias for smokers in the control group. However, because cigarette smoking has been found to alter the risk of several estrogen-related conditions including endometrial cancer, uterine fibroids, and osteoporosis (20), because smokers tend to have lower levels of endogenous estrogen than do nonsmokers (35), and because fibroadenoma is believed to be stimulated by estrogen (32, 33), an association between smoking and fibroadenoma is biologically plausible. Further investigation of the effect of this exposure on the risk of fibroadenoma seems warranted.
Although the results of this study might have been subject to misclassification of exposure due to inaccurate self-reporting on the baseline questionnaire, this would bias the results toward the null. Because many fibroadenomas are never clinically detected, some women with fibroadenoma were undoubtedly classified as nondiseased in this study, thereby also introducing conservative bias into the estimates of relative risks. Among the subjects identified with fibroadenoma, the histologic diagnoses have been shown to be of high validity, and they were made without knowledge of the exposures of interest. Chance and confounding seem unlikely to account for the present findings, because the study was large and the estimates of association with fibroadenoma were adjusted for potential confounding factors.
In summary, we conclude the following: The development and persistence of fibroadenomas are dependent on the presence of ovarian hormones; differentiation of breast tissue during full-term pregnancies reduces the risk of fibroadenoma; exposure to exogenous estrogen-progesterone combinations before menopause reduces the risk of fibroadenoma; women with a history of a benign breast lesion are at a high risk of fibroadenoma; and women who practice breast self-examination detect fibroadenomas that may otherwise go undetected.
Fibroadenoma presents more than a trivial public health problem; approximately one of 350 women in Shanghai may be diagnosed with this lesion before the age of 60 years. In addition, the rates of fibroadenoma may increase in the future in response to Chinas nearly universal one child per family policy. This effect of reduced parity on the occurrence of fibroadenoma will outweigh the apparent protective effect of steroid contraceptives, which are currently used by a relatively small proportion of the population. One benefit of an increase in use of steroid contraceptives in Chinas family planning programs would be a decline in the magnitude of fibroadenoma as a public health problem.
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ACKNOWLEDGMENTS |
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The authors thank the following persons for their valuable contributions to this study: Dr. Helge Stalsberg, pathologist; Dr. William Barlow, statistician; and Wen Wan Wang, data collection manager.
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REFERENCES |
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NOTES |
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