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Selective Estrogen-Receptor Modulators in 2001

Selective Estrogen-Receptor Modulators in 2001

A number of issues remain to
be clarified concerning the use of selective estrogen-receptor modulators (SERMs) in the treatment and
prevention of breast cancer. These considerations include identification of the
ideal agent; the appropriate target population, particularly for chemoprevention
with SERMs; the duration of use; the age at which to begin therapy; and a proper
risk/benefit calculation.

The prototype SERM, tamoxifen (Nolvadex), has been a landmark in the history
of breast cancer treatment. The ability of this drug to reduce both recurrences
and deaths when used in the adjuvant setting are well known,[1] and the
demonstration that it could reduce primary breast malignancies was a milestone
in 20th-century medical oncology.[2] Tamoxifen, however, is associated with an
increased risk of endometrial carcinoma, cataracts, menopausal symptoms, and
thrombotic events. Drs. O’Regan and Gradishar did not specifically address the
issue of thrombosis, but this concern becomes particularly important after
menopause, especially in women aged 60 years and over.

Risk/Benefit Calculations

Gail and colleagues have shown that it is possible to calculate the risk vs
benefit of tamoxifen use in a way that considers reduction in breast cancer
incidence and osteoporotic fractures along with increased risk of thrombotic
events, endometrial cancer, and cataracts.[3] Clinicians who are considering
prescribing tamoxifen for risk reduction should be cognizant of this strategy.
They should also be aware that the calculation of net benefit or risk is
conditioned by the weights assigned by either the patient or her clinician to
the individual benefits and risks.

Using this strategy, it is relatively easy to show that all premenopausal
women with a 5-year risk of invasive breast cancer of 1.66% or greater derive a
positive net benefit from the use of tamoxifen for risk reduction. It is also
clear that net benefit is more difficult to demonstrate in postmenopausal women,
particularly among those with an intact uterus, and especially in light of the
rising baseline risks of thromboembolic events associated with increasing age.
Nevertheless, women at a moderate to high risk of invasive breast cancer who are
older than 50 years still derive net benefit from using tamoxifen for risk
reduction. Additional research is needed to identify the best strategy for
communicating the relative risks/benefits and a net benefit calculation for the
entire at-risk population.

Large Studies of Tamoxifen
Risk/Benefit

The largest, and perhaps most informative, review of the association between
exposure to tamoxifen and development of endometrial carcinoma appears in the
National Surgical Adjuvant Breast and Bowel Project (NSABP) report on study
B-14.[4] This evaluation suggests that tamoxifen-associated endometrial
carcinomas can occur over prolonged periods after the administration of
tamoxifen. Unlike the information cited by Drs. O’Regan and Gradishar, these
data suggest that endometrial tumors associated with tamoxifen may not merely
occur after short durations of therapy. Importantly, however, the Breast Cancer
Prevention Trial showed that endometrial cancer incidence was not increased
among menstruating, premenopausal women; the increase in risk was confined only
to nonmenstruating, postmenopausal women.

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