In this population-based study we did not observe any associations between HT and the risk of colorectal cancer mortality or all-cause mortality, regardless of its definition. Among women with proximal colon cancer diagnoses, a modest increased risk of both colorectal cancer and all-cause mortality was observed among long-term users of HT that was attenuated with increasing time since last use of HT. Our confidence in these study results is enhanced by the population based nature of our study, and our ability to adjust for important confounders not available in prior studies, especially screening history.
Our results appear to be in contrast with previous studies of HT use and colon cancer mortality in two previous cohorts of cases; both found inverse relationships between HT use prior to diagnosis and mortality[13
]. Slattery et al
. found that, after a mean 7 years of follow-up after colon cancer diagnosis, women who had ever used HT had a statistically significant 40% lower risk of colorectal cancer mortality than non-users [14
]. Similarly, Mandelson et al
., after 6 years of follow-up, also showed a reduction in mortality associated with HT use, although this reduction appeared to be limited to lesions in the distal colon (hazard ratio=0.33, 95% CI, 0.13-0.83) [13
]. Notably, neither study adjusted for history of endoscopy screening. These effects of screening on colorectal cancer prognosis make this a potentially important confounder in epidemiologic studies of colorectal cancer. In a post-hoc
analysis, although our study did not find differences in risk when screening was removed from our models, we did observe that HT users were more likely to have been screened and been diagnosed with more localized cancers that non-HT users. Women with a history of screening were also more likely to have localized disease (45% and 40% of women diagnosed with localized disease for screened and unscreened, respectively). Additionally, the Mandelson et al.
] relied on linkages of pharmacy records to medical records, and thus it was not possible to adjust for other potential important correlates of HT, such as body mass index. In prior studies examining overall mortality among cohorts of healthy women, the relationship with HT use has been modestly inverse, with the greatest reductions in risk among current HT users [15
]. Such a finding is likely consistent with the strong reductions in incidence associated with current HT use, which is impossible to separate from an association with mortality in this design.
Based upon these limited studies and contradictory results, it is difficult to reach a consensus on the relationship between HT use and colorectal cancer mortality. There is some evidence that the association between HT and colorectal cancer incidence varies by stage of disease. In the Women’s Health Initiative (WHI) trial, women who used estrogen plus progestin were more likely to be diagnosed at an advanced stage of disease (i.e. regional or metastatic) than cases in the placebo arm (76.2% vs. 48.5%, p=0.004, ref.[5
]). After adjustment for stage at diagnosis, no increased or decreased risk of colorectal cancer mortality was observed among our cohort of women. Thus our results appear to be consistent with this randomized controlled trial.
When interpreting the results of this study, several limitations should be considered. We measured HT use 1-2 years prior to diagnosis, and did not evaluate HT use after diagnosis. Thus, there could be some misclassification of the exposure if women who were non-users initiated HT use after their colorectal cancer diagnosis, or selectively continued HT use. Such treatment patterns would be relatively unlikely since, in general as a promoter, HT is often contraindicated after a diagnosis of some cancers because of its growth promoting properties [27
]. We were unable to interview all eligible cases, and 17% of women were deceased before we could enroll them. The loss of subjects due to death is always raises concerns about the possibility of survival bias. However, the results of our case-control study, upon which this study is based, found a strong inverse association with HT that was consistent with the findings of other prospective studies, as well as the Women’s Health Initiative, where losses to death were not an issue [2
]. Women in the study who reported use of HT, however, were actually slightly more likely than non-users to be diagnosed at an earlier stage, so bias towards the null due to advanced stage appears unlikely to explain these results. In addition, our previous study of body mass and colorectal cancer mortality [20
], found no differences in associations with mortality among the different stages of cancer diagnoses. Finally, our sample sizes for several subcategories were quite small, thus limiting our ability to detect some associations of interest, and limiting our ability to assess effect modification; these results may also be due to chance due to the limited power and multiple comparisons.
There is ample biologic plausibility that estrogens may exert an effect on colorectal cancer incidence [1
], possibly through several mechanisms. Indeed, the colon contains hormone receptors that are likely pivotal in its responsiveness to sex hormones[28
]. However, the mechanisms by which HT use might impact survival remain poorly studied. In our study, women who developed incident proximal colon cancer even while using HT prior to diagnosis may have developed tumors resistant to the benefits of HT. If these women develop colon cancer despite exogenous estrogen use, other genetic or environmental factors predisposing women to colorectal cancer may predominate. The presence of differential etiologic pathways predominating in users versus non-users of HT by colon cancer site needs to be explored, in the laboratory, clinic, and population.