Tamoxifen, Raloxifene, and the Prevention of Breast Cancer
Tamoxifen, Raloxifene, and the Prevention of Breast Cancer*
V. CRAIG JORDAN 0 1
MONICA MORROW 0 1
0 I. Introduction II. Lacassagne's Prevention Principle: A Target and an Estrogen Antagonist III. Tamoxifen as an Antitumor Agent A. ER status and the duration of tamoxifen B. Contralateral breast cancer C. Endometrial cancer D. Conclusions IV. Selective Estrogen Receptor Modulation A. Antiestrogen activity at the ER B. Coactivators for ER C. Alternate response elements on DNA D. An alternate ER-ERb V. Biological Basis for Tamoxifen as a Breast Cancer Preventive A. Animal models B. Bones C. Lipids D. Uterus VI. Risk Factors for Breast Cancer A. Interactions among risk factors B. Identification of candidates for chemoprevention VII. Prevention of Breast Cancer with Tamoxifen A. Royal Marsden Pilot Study B. NSABP/NCI Study C. Italian study D. Conclusions VIII. Biological Basis for Raloxifene as a Breast Cancer Preventive A. Antitumor actions B. Bones C. Lipids D. Uterus IX. Study of Tamoxifen And Raloxifene (STAR) X. The Future of Prevention
1 Departments of Molecular Pharmacology , Biological Chemistry (V.C.J.), and Surgery (M.M.) , Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School , Chicago, Illinois 60611 , USA
INth1e89o6v,aGrieeosrfgreomBepatrseomnedneompaounssatrlawteodmtehnatwt hitehrmemetoavsataltoicf breast cancer could, in some cases, cause regression of the
-
Address reprint requests to: V. Craig Jordan, Ph.D., D.Sc., Director,
Lynn Sage Breast Cancer Research Program, Robert H. Lurie
Comprehensive Cancer Center, Olson Pavilion 8258, 303 E. Chicago Avenue,
Chicago, Illinois 60611 USA.
* Supported by the generosity of the Lynn Sage Breast Cancer
Research Foundation of Northwestern Memorial Hospital.
disease and improve the prognosis of the patient (
1
).
However, by 1900 Stanley Boyd had established that only one in
three patients would obtain improvement for about 1 yr (
2
).
Despite this disappointment, a link was established between
an ovarian factor and the growth of some breast cancers. This
observation was to become the foundation of modern clinical
practice and the rationale for the use of antiestrogens to treat
breast cancer (
3, 4
). At the turn of the century, studies were
being conducted in the laboratory to complement the clinical
effort. Inbred strains of mice were being established for
medical research, and it was found that certain strains of mice
developed a high incidence of mammary tumors. Lathrop
and Loeb (5) reported that an early ovariectomy could
prevent the spontaneous development of tumors but it was not
until Allen and Doisey (
6
) identified “estrus stimulating
principle” that ovarian hormones could be linked to the
development of breast cancer. By 1936, Professor Antoine
Lacassagne, again working with high-incidence strains of mice,
suggested that if breast cancer was caused by a special
hereditary sensitivity to estrogen, then the disease could be
prevented by developing a therapeutic antagonist to
estrogen action in the breast (
7
). However, there were no
therapeutic antagonists of estrogen at that time, nor was there a
target to design drug molecules. Nevertheless, exciting
developments in the discovery of nonsteroidal estrogens would
establish the structural basis of carrier molecules, which
resulted in the design of the two drugs, tamoxifen and
raloxifene (Fig. 1), both originally described as antiestrogens and
used today in a clinical trial to prevent breast cancer in
high-risk women (see Section IX).
Estrogen action in the 1930s was assayed using
ovariectomized mice as originally described by Allen and Doisy (
6
).
Using this technique, parallel research ventures resulted in
the discovery of the triphenylethylene-based estrogens (
8 –
10
) and the stilbene-based estrogens (Fig. 1). The
triphenylethylenes are long acting and are stored in body fat (
11–14
),
whereas the hydroxystilbene derivatives are short acting (
9,
15, 16
), primarily because of rapid-phase II metabolism after
absorption. However, Dodds and associates (
17, 18
)
described an extremely potent compound, diethylstilbestrol
(Fig. 1), that was widely used in gynecology and also
subsequently used, at high doses, as a treatment for advanced
breast cancer in postmenopausal women (
19, 20
).
In the 1950s and 1960s it became clear that adrenalectomy,
with glucocorticoid support, could also improve the
prognosis of some postmenopausal women with advanced breast
cancer (
21
). In fact, about one third of the women responded,
i.e., about the same proportion as premenopausal women
after oophorectomy. The reason for the apparently arbitrary
responses, however, would not become clear until the
discovery of the estrogen receptor (ER) by Jensen and Jacobson
(
22
) and the subsequent application of this knowledge to
predict the hormone responsiveness of a patient’s tumor to
endocrine ablation (
23
). This was an extremely important
finding because it (...truncated)