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Wednesday, 13 February 2002 00:00
"Context - Studies of long-term hormone replacement therapy (HRT) suggest an associated increased risk of breast cancer, but whether this association differs according to histologic type of cancer has not been extensively studied."

"Objective - To determine whether the association between HRT and risk of breast cancer varies by HRT formulation and differs across histologic cancer types."

"Design, Setting, and Participants - Nested case-control study among 705 postmenopausal women enrolled in the Group Health Cooperative of Puget Sound (GHC) who were aged 50 to 74 years and had primary invasive breast cancer diagnosed between July 1, 1990, and December 31, 1995 (cases), and 692 randomly selected aged-matched female members of GHC (controls)."

"Main Outcome Measure - Incidence and type of breast cancer by duration of HRT use in the 5-year period ending 1 year before diagnosis, which was ascertained from computerized pharmacy records."

"Results - The incidence of breast cancer, all histologic types combined, was increased by 60% to 85% in recent long-term users of HRT, whether estrogen alone or estrogen plus progestin. Longer use of HRT (odds ratio [OR], 3.07 for 57 months or more; 95% confidence interval [CI], 1.55-6.06) and current use of combination therapy (OR, 3.91; 95% CI, 2.05-7.44) were associated with increased risk of lobular breast cancer. Long-term HRT use was associated with a 50% increase in nonlobular cancer (OR, 1.52 for 57 months or more; 95% CI, 1.01-2.29)."

"Conclusion - Our data add to the growing body of evidence that recent long-term use of HRT is associated with an increased risk of breast cancer and that such use may be related particularly to lobular tumors."

"In this nested case-control study, we found an elevated risk of invasive breast cancer among postmenopausal women who were long-term, recent users of oral estrogen, either alone or in combination with progestin. These results are generally consistent with the results from other case-control and cohort studies and the recent collaborative analysis."

"When we divided breast cancer cases into lobular and nonlobular (primarily ductal) cancers, we found somewhat divergent patterns associated with HRT. The association with HRT was considerably stronger for lobular breast cancer, with an approximately 3-fold increased risk associated with longer duration of HRT and a 4-fold risk for current use of combination therapy. Two prior studies, one a population-based case-control study conducted from 1988 to 1990 in Seattle, Wash, and the other a multicenter case-control study conducted from 1989 to 1991, also found a positive association between current use of combination therapy and lobular breast cancer (Seattle study: for current use of at least 6 months' duration, OR, 2.6; 95% CI, 1.1-5.8; multicenter study: for current use defined as within 2 years of diagnosis, OR, 3.1; 95% CI, 1.8-5.3). These findings are consistent with the results of our study, although the number of cases of lobular breast cancer in this study was small (n = 91) and the follow-up time since combination therapy has become popular in the United States (late 1980s) is limited. Nevertheless, the magnitude of risk, the fact that an association is biologically plausible, and a similar finding in other studies all argue in support of the causal nature of association."

"Our finding that recent, longer HRT use is associated with a 50% increase in risk of nonlobular (primarily ductal) cancer also deserves mention, because ductal breast cancers are much more common than lobular. If our results are correct, then nonusers of HRT would have an incidence rate of ductal cancer of about 230 per 100 000 women per year, whereas women with 5 years of recent HRT use would have a rate of 349 per 100 000 women per year (using the 1993-1995 rates of US breast cancer by histologic type for women aged 60 to 69 years to represent the incidence of postmenopausal breast cancer and the distribution and ORs for oral HRT groups as in Table 4). Similarly, a 3-fold risk of lobular cancer associated with HRT use would translate into an incidence of lobular cancer among non-HRT users of 23 per 100 000 women per year and 70 per 100 000 women per year among women with 5 years of recent HRT use. Thus, a woman with long-term HRT use would still be 5 times more likely to develop ductal rather than lobular breast cancer."

"In summary, 2 prior studies have observed a 2- to 3-fold increased risk of lobular breast cancer associated with current combination therapy, and we found similarly large risks of lobular cancer associated with current combination therapy and longer duration of all formulations of HRT. A true increase in the risk of lobular breast cancer could have implications for screening, because lobular carcinomas are relatively more difficult to palpate and more difficult to diagnose by mammography. However, until more is known about the costs and benefits of different screening modalities for women using HRT, it would be premature to use our results as a basis for modifying early detection activity in them."


Chen Chi-Ling, PhD; Weiss Noel S., MD, DrPH; Newcomb Polly, PhD; Barlow William, PhD; and White Emily, PhD, "Hormone Replacement Therapy in Relation to Breast Cancer", JAMA, February 13, 2002, Vol. 287, Num. 6, pp. 734-741

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