With the advent of aromatase
inhibitor use in the adjuvant
setting, and the inception
of trials examining their use
for breast cancer prevention, it seems
prudent to evaluate what we know to
date about the long-term effects of these agents. Unfortunately, unlike selective
(SERMs)-in particular tamoxifen,
which has been used for over 15 years
in patients with early-stage breast cancer-
long-term data on the use of aromatase
inhibitors are minimal.
As outlined by Mortimer and Urban,
the largest data set concerning
the toxicities of aromatase inhibitors
comes from the Arimidex, Tamoxifen
Alone or in Combination (ATAC)
trial, the results of which were recently
updated at 4 years. By comparison,
tamoxifen was approved in
the late 1980s for the treatment of
early-stage breast cancer in both preand
postmenopausal women, resulting
in almost 15 years of follow-up.
In addition, as outlined by the authors,
we have data from the experience of well women using tamoxifen as a chemopreventive.
In general, tamoxifen has a good
toxicity profile and was described in
1996 by the World Health Organization
as an essential treatment for breast
cancer. However, most likely because
of its estrogen-like effects,
tamoxifen increases the incidence of
endometrial cancer and thromboembolic
events. Aromatase inhibitors do
not produce these estrogen-like effects,
and the long-term toxicities associated
with these agents will likely relate to
profound estrogen suppression.
Endometrial Cancer Risk
Tamoxifen increases the incidence
of endometrial cancer approximately
fourfold in postmenopausal women.
To date, raloxifene (Evista)
has not been associated with an increase
in the incidence of endometrial
cancer. However, the association
between tamoxifen and endometrial
cancer was not noted until the drug
had been in use for almost 15 years.
Despite the fact that raloxifene does
not exhibit estrogen-like effects on
the endometrium in clinical studies,
it promotes the growth of endometrial
cancers in athymic mice.
Longer follow-up of osteoporosis
trials and the Study of Tamoxifen
and Raloxifene (STAR) will be necessary
before we can definitively state
that raloxifene is not associated with
an increase in endometrial cancer.
Results of the ATAC trial to date
demonstrate a significant increase in
endometrial cancers among tamoxifen-
treated patients compared to
Bones and Bisphosphonates
Prolonged estrogen suppression is
likely to result in a loss in bone mineral
density and a possible increase in fractures.
At a relatively short follow-up of
the ATAC trial, the incidence of fractures
in the anastrozole-treated group
was increased compared to the tamoxifen-
treated group. How important
is this bone loss, and can it be prevented?
The Austrian Breast Cancer Study
Group treated 1,200 premenopausal
women with early-stage breast cancer
with goserelin (Zoladex), and then
randomized them to tamoxifen or
anastrozole, with or without zoledronate
(Zabel, Zometa) given every
6 months. At 18 months, both
tamoxifen and anastrozole reduced
bone density, based on T-scores in
the lumbar spine (Figure 1).
Zoledronate completely prevented
the bone loss associated with both
agents, resulting in no change in
T-score at 18 months.
This question will be addressed
directly by the Zometa/Femara Adjuvant
Synergy Trial (Z-FAST), in
which postmenopausal women with
early-stage breast cancer are treated with letrozole (Femara) and randomized
to receive zoledronate at the
start of letrozole therapy or when
their T-score drops to -2 standard
deviations. Preclinical data on exemestane
(Aromasin) suggest that it
can prevent ovariectomy-induced
bone loss in rats, possibly via its
androgenic effects. Limited clinical
data to date confirm this finding
Lipids and the Heart
Despite the fact that tamoxifen has
a beneficial effect on the lipid profile
by reducing low-density lipoprotein
(LDL) cholesterol levels, it has never
been demonstrated to reduce the risk
of coronary artery disease.[2,4] This
may be explained by the lack of benefit
of hormone-replacement therapy on
coronary heart disease. Raloxifene
has effects on the lipid profile similar
to those of tamoxifen, and its effect
on the risk of coronary artery disease
is being addressed by the Raloxifene
Use for The Heart (RUTH) trial, as
pointed out by the authors.
Data on the effects of the aromatase
inhibitors on the lipid profile
are sparse, although this issue will be
addressed in a subprotocol of the
ATAC trial. Data from patients with
metastatic breast cancer demonstrate
no adverse effects of anastrozole on
the lipid profile. Letrozole may
increase LDL cholesterol levels,
whereas exemestane produces no such
effect in preclinical models.
One of the primary reasons that
tamoxifen was chosen as a possible
chemopreventive was the finding that
it reduces contralateral breast cancer
by 50% in patients whose first primary
is estrogen-receptor positive.
Based on the finding that raloxifene
reduced the incidence of breast cancer
threefold compared to placebotreated
patients in the osteoporosis
trials, the STAR trial, which now
requires 19,000 patients and is 50%
accrued, is comparing raloxifene to
tamoxifen as a chemopreventive.
At the initial presentation of the
ATAC data at 33 months' follow-up, the incidence of contralateral breast cancer was significantly lower in
anastrozole-treated patients than in
tamoxifen-treated patients (Table 1).
At the more recent follow-up of 47
months, this difference no longer
achieved statistical significance, although
there continues to be significantly
less invasive contralateral
breast cancer among anastrozoletreated
patients. Longer followup
will determine whether there is a
difference in contralateral events between
tamoxifen and anastrozole.
Meanwhile, a number of preventive
trials comparing the aromatase inhibitors
to placebo are planned.
Estrogen and the Brain
One of the biggest concerns associated
with the use of aromatase inhibitors
as adjuvant and preventive agents
relates to the effects of profound, prolonged
estrogen suppression on cognitive
function. As outlined by Mortimer
and Urban, raloxifene may have a beneficial
effect on memory and attention
in women over age 70, and no effect in
other women. No data are available
on the effects of aromatase inhibitors
on cognitive function. This is an
important concern and one of the factors
that led the American Society of
Clinical Oncology expert committee
to recommend that tamoxifen remain
the gold standard adjuvant treatment
for postmenopausal women.
In summary, we have many years
of data concerning the "good and
bad" effect of tamoxifen. Based on
the similarities between the two
SERMs, raloxifene, perhaps apart
from the issue of endometrial cancer,
is likely to have a similar risk/benefit
profile to tamoxifen. In contrast, we
know nothing about the long-term
effects of aromatase inhibitors, and
patients should be monitored closely
for long-term toxicities.
1. Anastrozole alone or in combination with
tamoxifen versus tamoxifen alone for adjuvant
treatment of postmenopausal women with early
breast cancer: First results of the ATAC randomised
trial. Lancet 359:2131-2139, 2002.
2. Early Breast Cancer Trialists’ Collaborative
Group: Tamoxifen for early breast cancer.
Lancet 351:1451-1467, 1998.
3. Group T.A.T.: The ATAC (‘Arimidex’,
Tamoxifen, Alone or in Combination) trial in
postmenopausal women with early breast cancer—
updated efficacy results based on a median
follow-up of 47 months. Breast Cancer Res
Treat 76(suppl 1):12, 2002.
4. Fisher B, Costantino JP, Wickerham DL,
et al: Tamoxifen for prevention of breast cancer:
Report of the National Surgical Adjuvant
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5. International Agency for Research in Cancer
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8. Duffy SRG, Jackson TL, on behalf of the
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al: Changes in bone mineral density caused by
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receptor-positive premenopausal breast
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10. Goss P, Grynpas M, Qi S, et al: The
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11. Goss P, Thomsen T, Banke-Bochita J, et al:
A randomized, placebo-controlled, explorative study
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women during the 12-week treatment
with exemestane or letrozole (abstract 267).
Breast Cancer Res Treat 76:S76, 2002.
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14. Yaffe K, Krueger K, Sarkar S, et al:
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treated with raloxifene. N Engl J Med 344:1207-