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Selective Estrogen-Receptor Modulators in 2001

Selective Estrogen-Receptor Modulators in 2001

ABSTRACT: Tamoxifen (Nolvadex), a selective estrogen-receptor modulator, or SERM, is currently the endocrine therapy of choice for all stages of hormone-responsive breast cancer. Only tamoxifen has been approved by the US Food and Drug Administration to reduce the incidence of breast cancer in high-risk women. Despite tamoxifen’s antiestrogenic effects in breast tissue, it exhibits paradoxical estrogenic effects in other tissues in the body. These effects result in the maintenance of bone mineral density, but a three- to fourfold increase in endometrial cancer in postmenopausal women. Additionally, tamoxifen can result in troublesome hot flashes and serious thromboembolic events. For this reason, current research is focusing on new agents that may maintain the beneficial effects of tamoxifen while reducing its adverse effects. Raloxifene (Evista) is another SERM, approved for the prevention of osteoporosis in postmenopausal women and now being compared with tamoxifen in an ongoing breast cancer prevention trial. Like tamoxifen, raloxifene is associated with hot flashes and thromboembolic events, but its association with the risk of endometrial cancer is unknown. A number of new SERMs are in preclinical or clinical development in an attempt to improve upon the safety profile of tamoxifen. Additionally, selective aromatase inhibitors are being examined in the early breast cancer setting. [ONCOLOGY 15:1177-1194, 2001]

Breast cancer is the most common cancer seen in women in
the United States, and it is estimated than one in eight women will develop the
disease. Tamoxifen (Nolvadex) is a selective estrogen-receptor modulator (SERM)
that acts as an antiestrogen in certain tissues, including the breast, while
acting like a partial estrogen in other tissues, such as bone and the uterus.
Tamoxifen is currently the hormonal treatment of choice for patients with all
stages of hormone-responsive breast cancer and has been approved by the US Food
and Drug Administration (FDA) for the prevention of breast cancer in high-risk
women.[1] Despite the fact that tamoxifen is generally well tolerated, its use
is associated with hot flashes and more serious toxicities, including an
increased incidence of endometrial cancer and thromboembolic events.[1,2]

Raloxifene (Evista), another SERM, has been approved for the prevention of
osteoporosis in postmenopausal women and is being compared with tamoxifen as a
preventive agent for breast cancer in high-risk women. There is no indication at
present that raloxifene is associated with endometrial cancer,[3] although
patients receiving raloxifene have a comparable incidence of hot flashes.[4] A
number of new agents, including other SERMs, selective estrogen-receptor
downregulators (SERDs), and aromatase inhibitors, are being developed to treat and prevent breast cancer and
prevent osteoporosis.

Tamoxifen in Treatment
and Prevention

Breast Cancer Treatment

Tamoxifen is FDA-approved for the treatment of all stages of
hormone-responsive breast cancer in women of all ages. The overview analysis of
adjuvant breast cancer trials demonstrates conclusively that 5 years of
tamoxifen prolongs disease-free and overall survival in women of all ages (both
pre- and postmenopausal) with node-positive or node-negative, early-stage breast
cancer (Figure 1).[2] Tamoxifen improves outcomes only in patients with
estrogen-receptor-positive and/or progesterone-receptor-positive disease.[2]

The duration of tamoxifen therapy is important, since 5 years of
treatment results in better outcomes, compared with shorter durations.[2,5-7]
What is not clear is whether tamoxifen should be stopped at 5 years or continued
for longer periods. In node-negative patients, tamoxifen results in worse
outcomes when it is continued longer than 5 years,[8,9] and the National Cancer
Institute (NCI) currently recommends stopping tamoxifen at 5 years.

This issue remains controversial, however, especially in patients with
node-positive, early-stage breast cancer. Two large, ongoing trials—the aTTom
(Adjuvant Tamoxifen Treatment-Offer More) and the ATLAS (Adjuvant Tamoxifen-Longer
Against Shorter)—are randomizing patients to adjuvant tamoxifen for 5 years or
longer and hopefully will provide a definitive answer to the question of optimal
duration of therapy.

Women with a diagnosis of breast cancer are at increased risk of cancer in
the opposite breast. The 1998 overview analysis clearly demonstrates that
tamoxifen significantly reduces this risk (Figure
2
).[2] As in early-stage
breast cancer, longer terms of adjuvant tamoxifen, compared with shorter
durations, result in a greater reduction in contralateral breast cancer, with a
50% reduction noted after 5 years. The beneficial effect of tamoxifen persists
even after the drug is stopped.[2]

Tamoxifen has a significant antitumor effect in advanced breast cancer.
Response rates to endocrine agents, including tamoxifen, are dependent on tumor
expression of the estrogen and progesterone receptors.[10] The highest response
rates were observed in tumors expressing both estrogen and progesterone
receptors: Rates approaching 70% were observed in this group, compared with
rates of less than 10% in patients whose tumors express neither receptor.

Effects in Other Tissues

Bone Density—Despite tamoxifen’s antiestrogenic effects on the breast,
it has partial, estrogen-like effects elsewhere in the body. Although tamoxifen
might be expected to result in bone mineral density loss, this was not found to
be the case. Tamoxifen maintains bone density in preclinical models.[11,12]
Likewise, in postmenopausal women, tamoxifen actually increases trabecular bone
density and does not result in significant bone loss compared with controls,
producing a trend toward reduced loss of cortical bone density.[13,14]
Additionally, the National Surgical Adjuvant Breast and Bowel Project prevention
trial (NSABP P-1) demonstrated a nonsignificant (50%) reduction in hip fractures
in women treated with tamoxifen, compared with placebo.[1] Therefore, there is
no evidence to suggest that tamoxifen significantly accelerates bone loss—it
actually appears to prevent bone loss in postmenopausal women. In premenopausal
women, however, tamoxifen results in a slight reduction in bone mineral
density.[15]

Cardiovascular Effects—Another concern about tamoxifen’s preventive
use in patients with early-stage breast cancer and in healthy women was that it
might accelerate the development of coronary heart disease, possibly by a
deleterious effect on the lipid profile. In adjuvant breast cancer trials,
however, tamoxifen significantly reduces total cholesterol levels. Specifically,
tamoxifen reduces low-density lipoprotein[16,17] while causing a slight increase
in high-density lipoprotein,[16,18,19] suggesting that its effects on lipid
profiles are not identical to those of estrogen. Tamoxifen also reduces
fibrinogen,[18,19] lipoprotein(a),[18-20] and homocysteine[21]—all recognized risk factors for the
development of coronary artery disease.

There is no clear indication, however, that tamoxifen’s effects on these
cardiovascular risk factors translate into a reduction in coronary heart
disease. A 25% reduction in cardiovascular mortality was noted in the 1992
overview analysis.[22] A number of other trials demonstrated nonsignificant
trends toward reduced myocardial infarctions[23] or deaths
from coronary heart disease[24] with 5 years of tamoxifen use. However, no
significant reduction in the rates of myocardial infarction, coronary artery
bypass, or angioplasty was found in the NSABP P-1 prevention trial.[1]

These findings can, perhaps, be explained by the recent demonstration that
estrogen replacement therapy does not prevent the progression of coronary
atherosclerosis, as previously thought.[25] In summary, while tamoxifen does not
appear to protect against coronary artery disease, more importantly there is no
evidence to suggest that tamoxifen increases the risk of coronary heart disease.

Endometrial Cancer—One of the most publicized and potentially serious
side effects of tamoxifen is its association with an increased incidence of
endometrial cancer. Overall, tamoxifen is associated with a two- to threefold
increased risk of endometrial cancer.[2,26] Similar findings were noted in the
NSABP P-1 prevention trial, but the increase was seen only in postmenopausal
women, with no significant difference in endometrial cancer incidence among
premenopausal women treated with tamoxifen or placebo (Figure
3
).[1]

A retrospective analysis of tamoxifen-associated endometrial cancer noted an
increased risk only for women with a high body mass index and/or a history of
estrogen replacement therapy use.[27] Additionally, despite one study to the
contrary,[28] tamoxifen is associated with low-grade and early-stage endometrial
tumors and good prognosis.[1,2,26] The majority of endometrial tumors associated
with tamoxifen occur after short durations of therapy, and it seems likely that
tamoxifen stimulates the growth of preexisting cancer cells rather than causing
endometrial cancer.

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