The extent to which specific HT use influences the risk of mortality among breast cancer cases had been largely unknown, and no prior research has investigated whether or not this risk varies by either patient or tumor characteristics. In this large population-based cohort of women with breast cancer, current use of HT was associated with a moderately lower breast cancer specific mortality when compared to never use of these preparations. Mortality was lowest among current and long-term users of combined EP therapy. The present results provide the strongest evidence to date that HT use is associated with the subsequent development of less aggressive breast cancers through mechanisms that are not yet fully clear.
Evidence is limited on the relationship between HT use before breast cancer diagnosis and mortality from this disease. This and other studies evaluated self-reported HT use before the diagnosis of invasive breast cancer (3
). Only one showed a statistically significant lower risk of the association of pre-diagnostic HT use with case fatality in a cohort (n= 2,614 women) with breast cancers assembled in a large breast cancer screening program (5
). After adjustment for age, race, BMI, tumor size, and number of positive lymph nodes, women using HT at the time of diagnosis experienced approximately half the risk of dying of breast cancer in both node-negative and node-positive disease, although this effect waned with increasing time since diagnosis. These authors reported that the inverse association was no longer apparent after 4 years for node-positive disease and 12 years for node-negative disease, and thus this association may reflect residual confounding due to screening for node-positive disease, but this is less likely for node-negative disease, given the prolonged protection conferred. Limitations of the study are that the results were not stratified by type of HT, and other relevant personal and tumor characteristics.
In an earlier study, Bergkvist et al compared a group of 261 cases of breast cancer that had taken E-alone prior to diagnosis with 6627 breast cancer cases identified through a population cancer registry whose estrogen exposure status was unknown (3
). After consideration of mortality attributable to competing risks of death, the relative survival rate among previous users of HT was suggestively higher when compared with the general cancer registry cases with a greater reduction in breast cancer mortality in users of EP. Other investigators have reported decreased all-cause mortality among women with breast cancer who had used HT, though these studies made no adjustment for competing risks of death, potentially leading to bias (4
Studies have also generally shown lower breast cancer mortality with HT use in women initially without cancer, although in one study the mortality effects observed with HT use appear to wane over time, with increased
breast cancer mortality observed among women using HT for 10 years of more (29
). Because studies have consistently indicated a modestly increased risk of developing breast cancer in HT users (30
), these results suggest that breast cancers that develop in HT users may be associated with a less aggressive course than breast cancers that develop in nonusers (9
). A further reason for lower case-fatality may be that the cancers developing in women using HT are selected to be more hormonally responsive. Thus, with termination of the promoting factor at diagnosis (HT use) and the use of anti-estrogen treatment, now standard of care, these tumors would be expected to be associated with improved prognosis.
It has been suggested that the reduction in breast cancer mortality associated with HT use is attributable to an earlier stage at diagnosis (3
), which may be due to a higher likelihood of screening among HT users (surveillance bias) (5
) or the tendency for women who develop a serious illness to stop taking HT (healthy estrogen-user effect) (43
), rather than a modifying effect of hormone use on tumor biology. We observed that the inverse association between HT use and breast cancer mortality was limited to women originally diagnosed with regional, but not localized, disease. It has been well-documented that HT users are likely to be screened more aggressively than non-users (44
) and have cancers that are diagnosed at an earlier stage (45
), despite evidence that use of postmenopausal hormones reduces both sensitivity and specificity of screening mammograms (46
). However, even in analyses that adjust for screening, cancers that develop in HT users tend to be smaller (11
), of lower grade (47
), have fewer positive axillary lymph nodes (11
), lower tumor cell proliferation rate (49
), and have other clinically more favorable features (14
). Yet, in the Women's Health Initiative (WHI) randomized trial of the combined EP regimen, the rate of incident metastatic breast cancer was similar regardless of HT assignment (2
It may also be relevant to consider an effect of HT's on tumor growth after diagnosis. Although rare, HT use initiated after
diagnosis of breast cancer has been shown to have a beneficial (5
) or neutral (18
) association with survival, and there has been no observed improvement in survival associated with duration of use or route of administration (oral or vaginal cream) (51
In our study, we found better breast cancer survival among women who used combined EP therapy before diagnosis. Widespread use of combined EP preparations began in the 1980's (52
) and most earlier mortality studies evaluated the use of E-alone formulations. Two previous studies have reported more favorable prognostic profiles associated with combined estrogen-progestin therapy relative to other types of HT. Magnusson et al. found that women receiving a combined EP regimen were less likely to have tumors >20mm in diameter, but to have axillary lymph node dissemination, and poorly differentiated, or aneuploid tumors at diagnosis (19
). Daling et al. observed that the tumors of users of continuous EP therapy (relative to E-alone therapy or sequential EP therapy) were more likely to be estrogen receptor and progesterone receptor positive (53
), features that are associated with better prognosis. (14
) Thus, our observation of reduced mortality among users of combined HT might be expected, based upon the generally favorable profiles of the tumors occurring among women using HT compared to the tumors developing in non-users, or users of other regimens.
Our confidence in these study results is enhanced by the large sample size, mature follow-up, and availability of comprehensive information on tumor stage and other covariates associated with breast cancer mortality. Arising from a population-based study with high response rates, the cohort reflected the spectrum of breast cancer as it occurs in the population. However, some limitations should be considered when interpreting our results. This evaluation was based upon HT use before diagnosis, approximately two years prior to interview. Participants were not followed-up for changes in HT practices after breast cancer diagnosis, except on a subset of the population that participated in a study of post-diagnosis diet and other factors, including HT, in relation to breast cancer survival. In this actively followed sub-group, few women (4.5%) reported use of HT—which has generally not been recommended after breast cancer diagnosis (54
). Thus, the uncommon use of post diagnostic HT is unlikely to have biased our results. However, other exposures sustained or initiated after diagnosis may affect survival. Unmeasured post-diagnosis characteristics of HT users, such as changes in weight and physical activity, could influence the observed differences in survival according to HT use. To reduce this possibility we excluded from the analysis women whose breast cancer was diagnosed at a late stage and the results were unchanged.
Screening is a particularly important covariate affecting breast cancer survival. In our population, HT was associated with mammography; only 10% of HT users had never been screened compared with 30% of never HT users. Surprisingly, stratification by mammography screening suggested stronger inverse relations with HT, particularly with respect to EP use, among women who were not screened compared to women who reported regular screening. Limited sample sizes made it impossible to rule out chance in these associations, but the results are generally reassuring in that characteristics as measured by screening use are unlikely to have introduced bias. The examination of cause specific mortality may suggest some artifact of unmeasured confounders, since HT users did have statistically significantly reduced cardiovascular disease. Follow-up of cases randomized to receive HT prior to diagnosis, such as in the WHI or HERS studies, will help address this limitation of observational studies.
We were unable to consider the ER/PR status of tumors in our analysis. As a common phenotype of breast cancer tumors, the inability to control for receptor status is unlikely to overestimate our estimates of survival by HT use; rather, the combination of all tumor types increases the heterogeneity of our sample and may attenuate our results if HT use is related to survival only among those with tumors expressing ER/PR. However, since ER/PR positivity increases with increasing age (55
), and our sample was postmenopausal, most women's tumors would have been hormone receptor positive.
In summary, we found that use of HT prior to diagnosis in a large population-based cohort of women with breast cancer was associated with improved breast cancer survival. Survival was best among current and long-term users among women using combination regimens of EP, and appeared limited to women with regional disease. The better breast cancer survival in users of HT prior to diagnosis persisted after adjustment for screening, stage, and measured risk factors.