DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 63–1
Clinical Uses for Anti-Estrogen Therapy in ER+ Breast Cancer
DISEASE SETTING
ADJUVANT ADJUVANT METASTATIC METASTATIC
DRUG (premen) (postmen) (premen) (postmen)
Tamoxifen Yes (5 yr) Yes (before AI Yes Yes
for 2-5 yr)
Fulvestrant No No No Yes (PD on TAM
or AI)
Anastrozole No Yes (upfront or No Yes
after TAM)
Letrozole No Yes (upfront or No Yes
after TAM)
Exemestane No Yes (upfront or No Yes
after TAM)
Toremifene No Yes No Yes
Premen, premenopausal; Postmen, postmenopausal; AI, aromatase inhibitor; PD, progressive disease; TAM, tamoxifen; ER, estrogen receptor.
for use in various stages of breast cancer. It has become
a standard agent as a result of its anticancer activity and
good tolerability profile. Tamoxifen is prescribed for the
prevention of breast cancer in high-risk patients, for the
adjuvant therapy of early-stage breast cancer, and for
the therapy of advanced breast cancer. It also prevents
the development of breast cancer in women at high risk
based on a strong family history, prior nonmalignant
breast pathology, or inheritance of the BRCA1 or
BRCA2 genes.
Mechanism of Action. Tamoxifen is a competitive inhibitor
of estradiol binding to the ER.
There are two subtypes of estrogen receptors: ERα and ERβ,
which have different tissue distributions and can either homo- or
heterodimerize. Binding of estradiol and SERMs to the estrogenbinding
sites of the ERs initiates a change in conformation of the ER,
dissociation of the ER from heat-shock proteins, and inhibition of ER
dimerization. Dimerization facilitates the binding of the ER to specific
DNA estrogen-response elements (EREs) in the vicinity of estrogen-regulated
genes. Co-regulator proteins interact with the receptor
to act as co-repressors or co-activators of gene expression. At least 50
transcriptional activating factors transduce and modulate the effects
of estrogen on target genes. Differences in tissue distribution of ER
subtypes, the function of co-regulator proteins, and the various transcriptional
activating factors likely explain the variability of response
to tamoxifen in hormone receptor–positive (ER + ) breast cancer and
its agonist and antagonist activities in noncancerous tissues. Other
organs displaying agonist effects of tamoxifen include the uterine
endometrium (endometrial hypertrophy, vaginal bleeding, and
endometrial cancer), the coagulation system (thromboembolism),
bone metabolism (increase in bone mineral density [BMD]), and
liver (alterations of blood lipid profile).
Absorption, Fate, and Excretion. The usual oral dose of
tamoxifen in the U.S. is 20 mg once a day. Doses as
high as 200 mg/day have been used in the therapy of
breast cancer, but high doses are associated with retinal
degeneration.
Tamoxifen is readily absorbed following oral administration,
with peak concentrations measurable after 3-7 hours and steady-state
levels being reached at 4-6 weeks. Metabolism of tamoxifen is complex
and principally involves CYPs 3A4/5, and 2D6 in the formation of
N-desmethyl tamoxifen, and CYP2D6 to form 4-hydroxytamoxifen, a
more potent metabolite (Figure 63–1). Both metabolites can be further
converted to 4-hydroxy-N-desmethyltamoxifen, which retains high
affinity for the ER. The parent drug has a terminal t 1/2
of 7 days; the t 1/2
of N-desmethyltamoxifen and 4-hydroxytamoxifen are significantly
longer (14 days). After enterohepatic circulation, glucuronides and other
metabolites are excreted in the stool; excretion in the urine is minimal.
Therapeutic Uses. The usual oral dose of tamoxifen in the
U.S. is 20 mg once a day.
Tamoxifen is used for the endocrine treatment of women with
ER + metastatic breast cancer or following primary tumor excision
as adjuvant therapy. For the adjuvant treatment of premenopausal
women, tamoxifen is given for 5 years, or in postmenopausal women,
for 2 years, followed by an AI. In patients with high risk of recurrence,
it may be sequenced after adjuvant chemotherapy. Tamoxifen
is used in premenopausal women with ER + tumors. Disease response
rates are similar to those seen in postmenopausal patients. Alternative
or additional anti-estrogen strategies in premenopausal women
include oophorectomy or gonadotropin-releasing hormone analogs.