that tamoxifen does protect against
Re: Population-Based Study of subsequent development of contralateral
Tamoxifen Therapy and
Subsequent Ovarian,
Endometrial, and Breast Cancers
In a recent issue of the Journal, an ar-
ticle appeared that suggested that short
durations of tamoxifen therapy (<2
years) for women diagnosed with
breast cancer do not carry an increased
risk of endometrial or ovarian cancer,
while on the other hand, such therapy
was found to be associated with a
reduction in contralateral breast cancer
risk (1). This casecontrol study, unlike
a randomized, prospective clinical trial,
has limits on its interpretation, since by
its inherent design, it does not eliminate
selection bias. In this regard, it was most
interesting that the percentage of pa-
tients receiving tamoxifen in the
selected and matched control cohort for
endometrial cancer was found to be
31%, which was quite different from the
other two selected and matched control
cohorts (20% and 18% for ovarian and
contralateral breast cancers, respective-
ly). If, for the sake of argument, we set
the background average percentage of
patients receiving tamoxifen at 18%
(which would account for the vast
majority of the control cohort), then for
those women who subsequently de-
veloped contralateral breast cancer, the
value of 10% of them having used
tamoxifen indicates that tamoxifen pro-
tects against the induction of contra-
lateral breast cancer. For women who
subsequently developed ovarian cancer,
the level of tamoxifen use was the same
as control background, indicating ta-
moxifen use is apparently neutral.
However, for women subsequently de-
veloping endometrial cancer, the value
of 26% that is well above the 18% mark
indicates tamoxifen use promotes en-
dometrial cancer. The latter appears to
be more in keeping with the known in-
creased risk of endometrial cancer as-
sociated with tamoxifen use established
by randomized clinical trials.
Given the limitations of casecontrol
investigations and the relatively small
numbers of case subjects, I would
nevertheless concur with the authors
that this study, while not conclusive,
nevertheless is consistent with the view
210 CORRESPONDENCE
Response
breast cancer. However, it appears to me
that this study also provides some
indication that treatment with antiestro-
gens, such as tamoxifen, even for short
durations, confers an increased risk of
endometrial cancers to the patients and
not the contrary, as was suggested (1).
The question arises as to how tamox-
ifen may ``promote'' cancer in non-
breast, estrogen-responsive tissues like
the endometrium, yet protect against the
initiation of cancer in breast tissues. It is
tempting to speculate that this relates to
the notion that estrogen itself directly
inhibits or antagonizes the growth (DNA
synthesis) of breast cells, while in the
endometrium, estrogen may instead
promote growth (2). If growth antagon-
ism is essential to the oncogenic process,
possibly by inducing an oncogenic
mutator phenotype as has been recently
suggested (3), then in the breast,
tamoxifen would alleviate the oncogenic
mutator phenotype caused by estrogen.
In contrast, in the endometrium, it is
tamoxifen that sets up growth antagon-
ism, promoting an oncogenic mutator
phenotype. Conceptually, this provides a
basis for the prediction that even the
pure antiestrogens currently being de-
veloped in general may carry an
increased risk of endometrial cancer.
Consequently, estrogen-suppression
therapies, other than those that compete
at the transcriptional level, will have to
be considered for breast cancer preven-
tion and therapy.
Marian P. Laderoute, Ph.D.
Laderoute Anticancer
Biotechnologies Inc.
213 Cobourg St.
Ottawa, Ontario K1N 8H9
Canada
References
(1) Cook LS, Weiss NS, Schwartz SM, White E,
McKnight B, Moore DE, et al. Population-
based study of tamoxifen therapy and sub-
sequent ovarian, endometrial, and breast
cancers [see comment citation in Medline]. J
Natl Cancer Inst 1995;87:1359-64.
(2) King RJ. William L. McGuire Memorial
Symposium. Estrogen and progestin effects in
human breast carcinogenesis. Breast Cancer
Res Treat 1993;27:3-15.
(3) Laderoute MP. A new perspective on the
nature of the cancer problem: anti-cellular
senescence. Mol Carcinog 1994;10:125-33.
Journal of the National Cancer Institute, Vol. 88, No. 3/4, February 21, 1996
We appreciate Dr. Laderoute's inter-
est in our recent article in the Journal (1);
however, we believe that it is inap-
propriate to compare the frequency of
tamoxifen use between women with
endometrial cancer and controls who
had been age matched to women with
ovarian and breast cancer. Table 1 of our
article shows that the ages at initial
breast cancer diagnosis among endome-
trial cancer cases were substantially
greater than those of ovarian and
contralateral breast cancer cases, and,
therefore, substantially greater than the
ages of controls matched to those cases.
Age was related to tamoxifen use as
well; older women were more likely to
receive tamoxifen therapy than younger
women. This explains the lower fre-
quency of tamoxifen use among controls
for ovarian and contralateral breast
cancer cases than among controls for
endometrial cancer cases. Thus, any
crude comparison of tamoxifen use
between endometrial cancer cases and
control subjects that were age matched
to ovarian and contralateral breast
cancer cases, such as that suggested by
Dr. Laderoute, is misleading because of
confounding by age.
Linda S. Cook
Noel S. Weiss
Stephen M. Schwartz
Emily White
Janet R. Daling
Department of Epidemiology
University of Washington
Seattle
and
Fred Hutchinson Cancer Research
Center
Seattle
Barbara McKnight
Fred Hutchinson Cancer Research
Center
and
Department of Biostatistics
University of Washington
Donald E. Moore
Departments of Epidemiology and
Obstetrics and Gynecology
University of Washington
References
(1) Cook LS, Weiss NS, Schwartz SM, White E,
McKnight B, Moore DE, et al. Population-
based study of tamoxifen therapy and sub-
 sequent ovarian, endometrial, and breast Cancer Research Center, 1125 Columbia St.,
cancers. J Natl Cancer Inst 1995;87:1359-64. Note MP-381, Seattle, WA 98104.
Correspondence to: Linda S. Cook, Ph.D.,
Department of Epidemiology, Fred Hutchinson

Journal of the National Cancer Institute, Vol. 88, No. 3/4, February 21, 1996 CORRESPONDENCE 211