We used a population-based observational design to estimate relative rates of fatal breast cancer, i.e. developing and dying from breast cancer, in HT users compared to non-users. Point estimates of the association between CHT or ET and fatal breast cancer were generally below 1.0, although, given fairly wide CIs, increases in risk of up to 50% or more could not be excluded for some CHT exposures.
The few previous studies of HT use and incidence of fatal breast cancer in healthy users have had mixed results and did not publish results by type of HT. The prospective Million Women Study reported that current users of HT at the beginning of follow-up were at 22% increased risk for breast cancer death after 4.1 years (RR 1.22, 95% CI: 1.05, 1.41).21
The prospective Kuopio Osteoporosis Risk Factor and Prevention Study found an elevated risk of breast cancer death after 7 years of follow-up among women who used HT more than 5 years compared to non-users (HR 2.62, 95% CI 0.98, 7.00).32
Most of the 10 studies reviewed by Nanda and colleagues 20
found a reduced risk of death from breast cancer in users. In four of these studies, the reduced risk decreased with duration of use, duration of follow-up, and years since last use. The two studies showing an increased risk of death with HT use had wide confidence intervals. Adjustment for confounding varied across the studies; only two studies reported data on mammography screening, which, in our study, was a strong confounder whose control attenuated observed protection for HT use against death, especially for CHT.
CHT use has been more often linked to an increased risk of breast cancer incidence in postmenopausal women than ET.22,23,30
Observational studies of HT use and prognostic factors at breast cancer diagnosis suggest that HT users present with tumors that are smaller with less lymph node involvement compared to non-users, and that HT use is associated with less aggressive histology.33
However, results have not been consistent,34
and few studies have provided data by HT regimen, duration and recency of use. Tumors in the CHT arm of the WHI were larger than those in the placebo group and were diagnosed at a later stage.35
In our Women’s CARE dataset, among all breast cancer cases HT users appeared to have more favorable tumor characteristics than non-users, with a greater likelihood of lobular as opposed to ductal histology,23
a higher proportion of ER and PR positive tumors, and a lower proportion of late-stage disease36
but adjustment for recent screening attenuated some of these effects.
Among the study’s strengths is the efficient population-based case-control design which allows timely collection of information on HT use and potential confounders directly from the study subject. Our data included start and stop dates of use, type of regimen and reasons for starting and stopping use. Unlike the women studied in the WHI, about 90% of our study participants began HT use at or within 5 years of menopause, and around 90% of use was for relief of menopausal symptoms, exposures of primary interest. HT use was assessed between 1994 and 1998, before the results of the WHI were publicized, and over a narrow period in which prescribing patterns were relatively constant.
Our study has several limitations. First, with a case-control design, our outcome was limited to death from breast cancer, in contrast to prospective studies, which can examine the entire range of disease outcomes, such as venous thromboembolism, stroke and coronary heart disease, that can be affected by HT use. Second, with 278 cases an up to 50% increase in risk of fatal breast cancer with CHT use for menopausal symptoms could not be excluded. Third, although our case group captured fatal breast cancers occurring within 6 years after breast cancer diagnosis, longer follow-up may have been needed to reveal an association between HT and fatal breast cancer, especially since HT use has been associated with less aggressive histology in some studies. Finally, potential limitations of any case-control study include selection bias, recall bias and confounding. Interview response rates for the Women’s CARE Study were similar for case and control subjects and were within the ranges reported by other recent studies.25
Bias could result if study participants differed from non-participants. However, we have no reason to believe that decisions to participate were based on hormone history, or that there was differential participation of cases and controls in the CARE Study related to hormone use. Exposures to HT and other potential confounders were obtained from face-to-face interviews,22
and most HT users were current users at the reference date (), aiding HT recall. Agreement between self-reported HT use and prescription data in the Million Women Study was high overall and for the hormonal constituents of the preparations, for both current and former users.37
We lacked information on exposures after diagnosis that could affect survival, including possible continued HT use as well as cancer treatment and access to care. Estimates of HT use after breast cancer diagnosis suggest that it is low.38,39
We adjusted for education, income, and screening mammography, all related to access to care. While unmeasured confounding remains possible, we explored a wide variety of potential confounders, and we deemed, conservatively, a 5% or greater change in the ratio of adjusted to crude ORs minimally important in this particular setting with ORs often close to the null.