There is consensus that tamoxifen is effective in preventing both metastatic
disease and contralateral breast cancer. Because of its effectiveness in
breast cancer treatment, the drug is now the subject of clinical trials
for breast cancer prevention in healthy women at high risk for developing
the disease. However, there has been considerable controversy over the
possibility that tamoxifen either causes or stimulates endometrial cancer,
and this has discouraged enrollment in the prevention trial.
The controversy began with a series of case reports of women diagnosed
with endometrial cancer after tamoxifen treatment. Since those initial
case reports, a variety of epidemiologic studies have been reported, although
the findings of those studies have been far from unanimous.
It is the purpose of this paper to critically examine the epidemiologic
evidence that has accumulated to date. In particular, the issues of confounding
variables and bias will be explored to attempt to reconcile the differing
results of the various studies.
In performing this critical analysis, I have chosen to use only studies
reporting original data, and have omitted from the review most case reports,
review articles, and position papers concerning tamoxifen.
The Common Epidemiology of Breast and Endometrial Cancers
Breast and endometrial cancers share many risk factors. Risk is age
related and increases with early menarche, late menopause, nulliparity,
obesity, and estrogen replacement therapy (ERT), [1-4] although the magnitude
of the risk varies for each disease. Because of their common risk factors
(mostly estrogen-related), it is not surprising that the two diseases occur
more frequently in the same individual than would be expected by chance.[5-8]
The risk factors common to both diseases can all be viewed as potential
confounding variables in any study of the relationship between breast cancer
and endometrial cancer. A confounding variable is a factor related to both
the independent and the outcome variable. Avoiding bias, and recognizing
and controlling potentially confounding variables are issues in every epidemiologic
study of the possible role of tamoxifen and endometrial cancer following
The epidemiologic approach to the question of possible carcinogenic
effects of tamoxifen involves a choice of either cohort or case-control
studies. The most obvious cohorts of tamoxifen-exposed women are the participants
in the many clinical trials of the drug.
In designing a cohort study, the epidemiologist must define not only
the exposed cohort but the reference cohort against which to compare the
exposed group. Naturally, women in the trials who were randomized to not
receive the drug are a likely comparison group, although there may be some
advantage (eg, availability, sample size) to using other cohorts or populations
(such as U.S. SEER data) for comparison.
It must be remembered, however, that even without tamoxifen treatment,
breast cancer patients will be expected to have a higher incidence of endometrial
cancer than will women without breast cancer, thus artificially inflating
relative risk estimates based on the experience of non-breast cancer patients.
If the comparison group or reference population is not under the same
surveillance as women in the clinical trial, there will also be an opportunity
for surveillance bias. Because tamoxifen-treated women are under closer
medical watch than the general population, any second disease (eg, endometrial
cancer) is more likely to be detected. This bias will be especially important
if the second disease is characterized by long duration, low mortality,
and infrequent symptomsall characteristics of endometrial carcinoma.
A high proportion of endometrial carcinoma may be diagnosed only after
an occult phase that has been estimated to average four to six years.
Because of shared risk factors, and also because of surveillance bias,
one can predict that any standardized incidence ratio of a tamoxifen-treated
clinical trial cohort will be elevated if a non-trial population is the
If the comparison group is another arm of a randomized clinical trial,
then surveillance bias should not be operative. However, tamoxifen is known
to induce several gynecologic symptoms. The nonmalignant gynecologic complications
are well described in a review by Assikis and Jordan. A woman undergoing
tamoxifen treatment is about three times as likely to see a gynecologist
because of symptoms such as hot flashes or bleeding due to endometrial
The frequency of gynecologic conditions leads to an increase in doctor
visits, which creates an ascertainment bias. Ascertainment bias will also
be present, as will surveillance bias, in any comparison between a tamoxifen-exposed
cohort and the general population. This bias has been recently discussed.
Because of surveillance and ascertainment biases, clinical trial cohorts
are not ideal groups for the study of any tamoxifen-endometrial cancer
relationship unless the non-tamoxifen group undergoes the same degree of
gynecologic investigation as the tamoxifen group. To date, this has not
been the case. Because they were never designed to ascertain risk of endometrial
cancer, the clinical trials were not planned with the same degree of gynecologic
surveillance for all trial arms. Neither was there appropriate documentation
of possible confounding variables, especially estrogen replacement therapy
(ERT), pre- or post-tamoxifen treatment.
Since many postmenopausal women would have received ERT prior to their
breast cancer diagnosis and some may have received ERT afterward, it is
probably the most potent confounding variable of all, and it has been reported
to increase endometrial cancer risk by as much as ninefold[8,15-17] or
more with prolonged duration of use.
As an alternative to following a cohort, one may use a case-control
study, either population-based or within a cohort (the nested case-control
study). Although cases of endometrial cancer are readily selected from
any population, one must be aware of possible bias. If case selection is
influenced in any way by ascertainment due to tamoxifen treatment, the
study will be biased, since the exposure variable influences identification
Even if a group of endometrial cancer patients is selected without knowledge
of previous exposure to tamoxifen, ascertainment bias may be present but
Tamoxifen-induced gynecologic symptoms may have triggered the investigation
that led to the diagnosis of endometrial cancer. Since the gynecologic
symptoms from tamoxifen do not differ from common symptoms due to other
or unknown causes, there is no easy way to identify the proportion of cases
that may have been ascertained because of the tamoxifen-induced symptoms.
Presumably, controls are selected from a population without an equally
high probability of gynecologic investigation. As a result, there is considerable
chance that any case-control study of this nature will suffer from a bias,
of unknown magnitude, that will elevate relative risk estimates.
It is also possible that because of tamoxifen-associated symptoms, some
women may have been prescribed estrogen therapy, adding yet another possible
confounder to the situation. Although previous breast cancer is generally
considered a contraindication for ERT, I know of several gynecologists
who have chosen to ignore this contraindication and who continue to prescribe
oral estrogens for estrogen- deficiency symptoms. Thus, it can be expected
that the case-control study, like the cohort study, will be somewhat biased
unless extreme care is taken in selection of cases and controls. Specific
case-control studies will be examined in detail later in this article.
Similarly, since it is an important epidemiologic principle that cases
should be selected without regard for exposure, any case-control study
originating with a series of endometrial cancer cases appearing after tamoxifen
treatment will be biased, no matter how subsequent controls are identified.
For that reason, a series of tamoxifen-exposed endometrial cancer patients
should not be converted into a case-control "study" by selecting
a group of controls to complement exposed cases already collected. The
conversion of a set of cases known to be tamoxifen-exposed into a case-control
study indicates that the investigator is testing the hypothesis on the
data which generated it, a clear violation of statistical principles.
Problems of ascertainment of appropriate cases carry over to the selection
of controls, since this group should resemble the cases in as many ways
as possible, except for tamoxifen exposure.
In both cohort and case-control studies, the biases discussed above
all tend to increase the apparent relative risk of endometrial cancer due
to tamoxifen. These biases could thus create either a spurious elevation
of the relative risk or conceal any protective effect that would have been
reflected as reduction in relative risk. Surveillance and ascertainment
biases can be overcome only by using populations in which the comparison
group (for cohort studies) or control group (for case-control studies)
has a frequency and intensity of gynecologic examinations that equal the
tamoxifen-treated cohort or the cases in a case-control study.
A further problem for any epidemiologic study is the issue of latency.
One must be careful to define latency, since to some it may mean time from
exposure to tumor initiation, and to others the time to clinical appearance.
For the epidemiologist, the latter definition is the usual, but it does
allow for several phases of the tumor, including tumor initiation, promotion,
and, finally, sufficient growth to create symptoms. Although the latency
period for induction of endometrial cancer is unknown, experience with
other cancers and other substances suggests that as many as five years
or more may be needed for cancer to develop and be detected.
It is still possible, however, that tamoxifen could either promote tumor
growth or cause symptoms (eg, bleeding) from a pre-existing tumor, thus
shortening latency. This issue will be addressed with reference to specific
Although tamoxifen has undergone many clinical trials, none of its published
studies give mortality rates for endometrial cancer, and few trials report
on incidence of endometrial or other non-breast cancers. This leads one
to suspect publication bias, wherein investigators in trials with an excess
of endometrial cancer publish, while those without do not.
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