2. Introduction
Tamoxifen is come under a class of Selective
Estrogen Receptor Modulator (SERM)
•The most important drug worldwide for hormone
receptor positive breast cancer
3. Cont.
•Approved by the FDA for treatment of
•High-risk patients
•DCIS
•Pre and Postmenopausal breast
cancer
•Metastatic disease
7. Tamoxifen itself is a prodrug, having relatively little
affinity for its target protein, the oestrogen receptor.
8. It is metabolized in the liver by the cytochrome P450
isoform CYP2D6 and CYP3A4 into active metabolites
such as 4-hydroxytamoxifen (afimoxifene) and N-
desmethyl-4-hydroxytamoxifen (endoxifen) which
have 30-100 times more affinity with the estrogen
receptor than tamoxifen itself
9. • These active metabolites compete with estrogen in the
body for binding to the estrogen receptor. In breast
tissue, 4-hydroxytamoxifen acts as an estrogen
receptor antagonist so that transcription of estrogen-
responsive genes is inhibited.
• 4-hydroxytamoxifen binds to estrogen receptors (ER),
the ER/tamoxifen complex recruits other proteins
known as co-repressors and then binds to DNA to
modulate gene expression
10. 4-Hydroxytamoxifen binds to estrogen receptors
competitively (with respect to the endogenous agonist
estrogen) in tumor cells and other tissue targets,
producing a nuclear complex that decreases DNA
synthesis and inhibits estrogen effects
11. It is a nonsteroidal agent with potent antiestrogenic
properties which compete with estrogen for binding
sites in breast and other tissues.
Tamoxifen causes cells to remain in the G0 and G1
phases of the cell cycle. Because it prevents
(pre)cancerous cells from dividing but does not cause
cell death, tamoxifen is cytostatic rather than
cytocidal.
12. Pharmacokinetic
Long t1/2 : 7 -14 days.
OD dose can be used
Reduced bioavailability is not a cause for resistance.
False negative receptor assays for several months after
stopping Rx in tumor tissue.
Metabolism in liver and excretion in feces ► Renal
dysfunction not a contraindication.
Metabolized by CYP 450 3A4 enzyme:
Can reduce warfarin metabolism.
Careful INR monitoring needed in patients receiving warfarin
with tamoxifen.
13. Pharmaco-genetics and
drug interactions
• Patients with variant forms of the gene CYP2D6 (also
called simply 2D6) may not receive full benefit from
tamoxifen because of too slow metabolism of the
tamoxifen prodrug into its active metabolite 4-
hydroxytamoxifen.
14. Certain CYP2D6 variations in breast cancer patients
leads to a worse clinical outcome for tamoxifen
treatment
Genotyping therefore has the potential for
identification of women who have these CYP2D6
phenotypes and for whom the use of tamoxifen is
associated with poor outcomes.
15. Recent studies suggest that taking the selective
serotonin reuptake inhibitors (SSRIs) antidepressants
paroxetine (Paxil), fluoxetine (Prozac), and sertraline
(Zoloft) can decrease the effectiveness of tamoxifen,
as these drugs compete for the CYP2D6 enzyme which
is needed to metabolize tamoxifen into the active
form, endoxifen.
16. A U.S. study presented at the American Society of
Clinical Oncology's annual meeting in 2009 found that
after two years, 7.5 percent of women who took only
tamoxifen had a recurrence, compared with 16 percent
who took either paroxetine, fluoxetine or sertraline,
drugs considered to be the most potent CYP2D6
inhibitors
17. . That difference translates to a 120 percent increase in
the risk of breast cancer recurrence. Patients taking
the SSRIs; Celexa (citalopram), Lexapro
(escitalopram), and Luvox (fluvoxamine), did not have
an increased risk of recurrence, due to their lack of
competitive metabolism for the CYP2D6 enzyme.
18. A newer study demonstrated a clearer and stronger
effect from paroxetine in causing the worst outcomes.
Patients treated with both paroxetine and tamoxifen
have a 67% increased risk of death from breast cancer,
from 24% to 91%, depending on the duration of
coadministration
19. Recent research has shown that 7-10% of women with
breast cancer may not receive the full medical benefit
from taking tamoxifen due to their unique genetic
make-up
20. . DNA Drug Safety Testing can examine DNA variations
in the CYP2D6 and other important drug processing
pathways. More than 20% of all clinically used
medications are metabolized by CYP2D6 and knowing
the CYP2D6 status of a person can help the doctor with
the future selection of medications
21. Other molecular biomarkers may also be used to select
appropriate patients likely to benefit from tamoxifen
26. Tamoxifen use along
with GnRH analog ??
Improved overall survival than either alone [ Klinj et
al.]
27. Aromatase Inhibitors
Include a class of drugs which prevent peripheral conversion of
androgens to estrogen.
Also cause selective impairment of gonadal steroidogenesis.
Thus are capable of selective estrogen deprivation without
impairment of adrenal androgen synthesis.
Two types exist:
Type I : Enzyme inactivators (Steroidal)
Type II : Competitive antagonists ( Non steroidal)
3 generations exist:
1st generation: Aminoglutethemide
2nd generation: Formestane (Type I) , Fadrazole
3rd generation: Exemestane (Type I) , Anastrazole , Letrozole, Vorozole
28. 3rd generation AI
These drugs inhibit the Aromatase enzyme selectively by
blocking the heme moiety of the enzyme.
Active sites of other steroidogenic enzymes remain free.
3rd generation AIs are 3 times more potent than
aminoglutethemide.
Dose:
Letrozole (Femara) – 2.5 mg OD
Anastrazole (Arimidex) – 1 mg OD
Exemestane (Aromasin) – 25 mg OD
29. Special Properties
Anastrazole:
Less than 10% of the drug is cleared as unchanged drug because
of its extensive metabolism.
Letrozole:
Only 5% is excreted in the urine, letrozole can be safely used in
patients with renal insufficiency.
Used with caution when patients have severe liver impairment.
Produces the greatest suppression of estrogen synthesis
Exemestane:
Weakly androgenic metabolite (17-hydroexemestane) that may
ameliorate bone loss associated with estrogen deprivation
