Does estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) increase the risk of breast cancer? This question is still being asked today, even though more than 5 decades of experience with this therapy and scores of epidemiological studies addressing the issue are available. This important question refuses to go away, despite a lack of direct evidence supporting a causal association. It is a question that remains timely because of societal concerns about breast cancer and the large numbers of women who currently use HRT. And, it is a question that continues to be addressed in the medical literature and lay media because of the commonly held belief that estrogens in some way must cause breast cancer.
Based on information in the article by Gapstur and colleagues1 in this issue of THE JOURNAL, one new answer to this old question is yes, but only for invasive tumors with a favorable histology. Are the results reported in the article biologically plausible? How do they compare with findings from other studies? Most important, what does this finding mean for the millions of American women using HRT?
The study by Gapstur and colleagues reports data from the Iowa Women's Health Study, a large, well-designed, well-conducted, population-based cohort study. In their analysis, 37,105 healthy postmenopausal women aged 55 to 69 years were followed up for cancer and/or mortality outcomes for up to 11 years. During the interval, 1520 women (4%) were diagnosed as having breast cancer. Of those diagnosed as having breast tumors, 1164 (77%) had invasive lobular or ductal tumors, 175 (12%) had ductal carcinoma in situ, and 82 (5%) had invasive carcinoma with favorable histology. The remaining 99 women (7%) with lobular carcinoma in situ, nonepithelial tumors, or tumors that were rare or poorly defined were excluded from the analysis.
The major finding reported is that HRT "was associated most strongly with an increased risk of invasive breast cancer with a favorable prognosis." But what determined whether a tumor had a favorable prognosis? The tumor groupings can be challenged, for while there is consistent agreement in the literature that mucinous and tubular carcinomas are associated with a good prognosis, there is no consensus regarding medullary tumors (included in the group with a favorable histology).2 -Â 4 This lack of consensus regarding the definition of a favorable histologic type raises the possibility that the present finding occurred as a result of the choice of tumor groupings and not as a result of a real association between HRT and tumor occurrence.
Are the results reported biologically plausible? Perhaps, but at this time, there is no apparent reason (and the authors offer no reason) why ERT or HRT would increase the occurrence of invasive mucinous and tubular carcinomas but not invasive ductal or lobular carcinomas.
The authors chose to focus almost exclusively on the increased risk of "good prognosis" breast tumors occurring in women using HRT, and thus did not emphasize their observation that HRT use did not increase the risk of ductal carcinoma in situ or invasive ductal and lobular carcinomas. This is puzzling, since 95% of women diagnosed as having breast tumors in their analysis had either invasive lobular or ductal tumors, or ductal carcinoma in situ. In other words, the major result reported here, that ERT is associated with an increased risk of breast cancers with a favorable prognosis, was seen in only 5% of the study population. Further, when all tumor types were combined and stratified by duration of use, ERT was not associated with an increased risk either in the short- (≤5 years) or long- (>5 years) term users (relative risk, 1.07 [95% confidence interval, 0.94-1.22]; and relative risk, 1.11 [95% confidence interval, 0.92-1.35], respectively).
This overall null result of the study by Gapstur et al is consistent with most (but not all) studies published in the 1990s.5 -Â 10 Nonetheless, the belief that estrogens cause breast cancer persists, in part because some studies do show such an increased risk of cancer with ERT and these studies appear to generate more attention than those showing no association with ERT. Such a pervasive belief can lead investigators to focus their energies on demonstrating an elusive ERT-breast cancer association. Such a narrow focus, however, ultimately may be detrimental to identifying modifiable risk factors for breast cancers.
Finally, and most important, does ERT increase the risk of breast cancer? After more than 5 decades of ERT use in the United States and scores of epidemiological studies, this question still cannot be answered definitively. In contrast, the association between ERT and endometrial cancer was clearly established nearly 25 years ago by epidemiological studies. At this time the absence of convincing evidence of an association between ERT and breast cancer risk should be reassuring. Any real increase in risk, if it exists at all, must be too small or must occur in too limited a population, otherwise it would have been observed more consistently in most of the well-designed, well-conducted, epidemiological studies, including this one.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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