Download Pharmacogenetics of tamoxifen

TAMOXIFEN IN HORMONE
DEPENDENT BREAST
CANCER
Cecilia Gallego
Irene Gallego
Ignacio Gallego
Beatriz Galván
Yanira García
Rafael García
Rubén García
Alberto García
PHARMACOGENETICS
OF
TAMOXIFEN
BREAST CANCER


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-
Is the most common cancer in women.
RISK FACTORS:
- Family history
- Nulliparity
- Early menarche
- Elderly
- Personal history of breast cancer
IMPACT IN SPAIN:
36 new cases per 100.000 inhabitants/year.
12% of women will suffer from breast cancer.
3.5% will die from cancer.
TAMOXIFEN



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Selective estrogen receptor
It acts as anti-estrogens in breast tissue
and partial agonist in some organs.
Dose: 20 mg/day for 5 years.
Beneficial effects on lipid metabolism and
bone.
TREATMENT OF HORMONO-DEPENDENT
BREAST CANCER
PHARMACOGENETIC AND
METABOLISM
PHARMACOGENETIC
MODULATION OF THERAPY

ESR1, ESR2
Genes estrogen receptor
Loos of exon 5
ERd5


Mutated receptor
no recognized by
tamoxifen
CYCLIN D1
Activation of the
expression of estrogen receptors
CYP17A1
Increase the levels of
circulating estrogens
CYP2D6
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Cr. 22, CYP 450,family 2, subfamily D
No related to the metabolism of precarcinogenesis
Polymorphism do no show interindividual differences in
the probability of developing cancer
Mutant alleles
Gene polymorphisms
Enzyme
activity increased, decreased or void
PHARMACOGENETIC TEST
 Amplichip CYP450-Roche: PCR amplification
Reports to genotype and metabolizer phenotype of the patient
Technique of Single Base Extension: specific
oligonucleotides and amplified PCR
Detected a small
number of mutations in each region
NORMAL ALLELES
CYP2D6*1
Enzyme with catalytic activity
MUTANT ALLELES
CYP2D6*2, *33,*35
CYP2D6*4, *5
CYP2D6*3, *4, *5, *6
activity (white people)
CYP2D6 amplified
Enzyme with catalytic activity
Reduced metabolic activity
Nonfunctional enzyme
Enzyme activity increased
TAMOXIFEN AND GENETIC
STUDY?????

A gene test could predict the efectiveness of Tamoxifen
searching changes in CYP2D6 genes
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The study be held because the metabolism of Tamoxifen
shows a great variability:
- FAST METABOLICERS: 60%
- INTERMEDIATE METABOLICERS: 33%
- SLOW METABOLICERS: 7%
The utility could prevent:
- Therapeutic failure
- Toxicity
- Impredecible interactions

Inheritance of genetic variants
Increased risk of recurrence:
- FAST METABOLICERS: 14,9%
- INTERMEDIATE METABOLICERS: 20,9%
- SLOW METABOLICERS: 29%
 ONLY RECOMMENDED IN PATIENTS WITH A
RELEVANT PHARMACOLOGICAL HISTORY
 Treatment failure is also due to the influence of
enviromental factors not detected in the genetic
test.
 Genetic mutations in the 2 alleles
(homozygous)
Recurrence time and
Survival
affecting only 7% of the population
CURRENT USES OF TAMOXIFEN

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Adjuvant treatment after surgery.
Neoadjuvant treatment before surgery.
Advanced stages of the disease
palliative.
Prevention of breast cancer in women at
high risk.
 In pre- and postmenopausal women.
OTHER ALTERNATIVE DRUGS
(I)
Anti-estrogenic of SECOND GENERATION
A. Nonsteroidal: Raloxifen.

Similar to tamoxifen.
B. Steroidal: Pure antiestrogen (ICI).


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Reduce side effects of tamoxifen and improve
efficiency.
Experience shorter.
Second choice.
OTHER ALTERNATIVE DRUGS
(II)
o
o
o
o
AROMATASE INHIBITORS
The most used: anastrozole, letrozole,
formestane.
Action: adrenal suppression chemical.
Block the synthesis of androgens
estrogens.
Postmenopausal.
(-)
OTHER ALTERNATIVE DRUGS (III)
PROGESTOGENS


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More used: megestrol
acetate.
Action:
- Cell cytotoxic effect.
- Anti-estrogenic effect
and
gonadotropins.
Adjuvant effect.
LHRH ANALOGS
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More used: goserelin.
Action: chemical
suppression.
Adjuvant tamoxifen.
Premenopausal.
BREAST CANCER TREATMENT
PREMENOPAUSAL
WOMEN
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TREATMENT OF FIRST
CHOICE: TAMOXIFEN
- Adjuvants: LHRH
analogs or progestogens.
TREATMENT OF SECOND
ELECTION: RALOXIFEN,
FULVESTRANT.
TREATMENT OF THIRD
ELECTION: AROMATASE
INHIBITORS.
POSTMENOPAUSAL
WOMEN
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TREATMENT OF FIRST
CHOICE: TAMOXIFEN.
Adjuvants:Progestogens.
TREATMENT OF SECOND
ELECTION: AROMATASE
INHIBITORS.
BREAST CANCER TREATMENT
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ADJUVANT TREATMENT:
Chemotherapy + Tamoxifen.
NEOADJUVANT TREATMENT:
Chemotherapy + Surgery +
Chemotherapy/Radiotherapy + Tamoxifen.
ADVANCED STAGES:
Tamoxifen/Aromatase inhibitors +
Polichemotherapy.
PREVENTION: Tamoxifen.
DRUG
INTERACTIONS OF
TAMOXIFEN
CYP3A4 INDUCERS
CYP3A4 inducers act by activating the nuclear
receptor PXR and stimulate the metabolism of
tamoxifen.
The association of tamoxifen with these drugs
reduces the effectiveness of tamoxifen.
CYP3A4 inducers are:
• Several anticancer drugs: cyclophosphamide,
docetaxel, erlotinib, flutamide, ifosfamide and
paclitaxel.
• Rifampicin is the most powerful inducer.
• Tamoxifen is a weak PXR activator.
MITOMYCIN C + TAMOXIFEN
This association can provoke an haemolytic
uraemic syndrome:
- Mitomycin C causes subclinical endotelial
damage.
- Tamoxifen has got thrombotic effect.
AROMATASE INHIBITORS
FIRST GENERATION
Does the association with aminoglutethimide
improve the response at treatment?
- Yes. Plasmatic levels of estrogen decrease.
- No. Sensibility of estrogenic receptors of tumor
cells increases.
- No. Toxicity increases due to administration of two
drugs.
AROMATASE INHIBITORS THIRD
GENERATION

There are relevant pharmacokinetic interactions resulting in
decreased plasma concentrations of third generation aromatase
inhibitors when combined with tamoxifen.
LETROZOLE
ANASTRAZOLE
Combination of tamoxifen and
letrozole:
The letrozole concentrations
approximately 35-40% lower
than when letrozole is used
alone.
Single agent anastrozole is
superior to tamoxifen or the
combination of both.
In recent clinical studies, anastrozole, letrozole and exemestane have
shown advantages over tamoxifen as treatment for advanced disease.
MEDROXYPROGESTERONE

What do we use them for?
- Inducing normal menstruation.
- Decreasing the risk of developing cancer
of the uterus in patients taking estrogens.
Medroxyprogesterone treatment in postmenopausal women
increases the incidence of breast cancer.
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Concomitant use of tamoxifen and medroxyprogesterone increases the liver
enzymes.
Tamoxifen induces signs of autophagy, which was enhanced when it was combined
with MPA.
HORMONE REPLACEMENT
THERAPY (HRT)
When we use tamoxifen with HRT may occur:
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SIDE EFFECT: The beneficial effects of tamoxifen on cardiovascular risk
factors (because tamoxifen reduces the cholesterol level in blood) are
unchanged in current HRT users, whereas they may be attenuated in women
who start HRT while on tamoxifen.
POSITIVE EFFECT: Increases bone density in bones, mainly in the femur.
Drug Interactions in the
Treatment of Breast Cancer
and Depression
Depression in Breast Cancer
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The estimated point prevalence of major depressive disorder in all
women is in the range of 3.5%–7%
In comparison, the rate of depression in women with breast
cancer is estimated to be in the range of 10%–25%
Endocrine Therapy for Breast
Cancer
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Analyses of thousands of women treated with 5 years of tamoxifen
versus no endocrine therapy for invasive breast cancer
demonstrate a 31% decrease in annual breast cancer death rate
with tamoxifen.
Tamoxifen is antiestrogenic in the breast, resulting in decreased
breast cancer development and recurrence, as well as in the
brain, leading to hot flashes as side effect
Treatments for Concurrent Hot
Flashes and Depression
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Prospective randomized clinical trials have demonstrated
that selective serotonin reuptake inhibitors (SSRIs)
decrease vasomotor symptoms in healthy menopausal
women and women with breast cancer.
In general, these studies have shown that most of these
medications decrease hot flash frequency by about 60%,
compared with a decrease of 25%–35% with placebo.
Tamoxifen Metabolism
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Tamoxifen is converted to endoxifen principally by a
noninducible P450 enzyme that is coded for by the most
polymorphic, and most studied, gene in the cytochrome
P450 system: CYP2D6.
In one study, breast cancer patients treated with
tamoxifen who were homozygous for a poor metabolizer
genotype (*4/*4) had significantly lower serum
concentrations of endoxifen than those with the active.
Coadministration of Tamoxifen
and an SSRI or SNRI
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In addition to genetic inactivation of CYP2D6, CYP2D6
activity can be decreased by medications that inhibit the
enzyme.
Use of CYP2D6 inhibitors in patients who are being treated
with tamoxifen, even if they have the homozygous active
genotype, could potentially affect breast cancer
outcomes, in a manner similar to the poor metabolizer
genotype.
Inhibition of tamoxifen conversion to endoxifen may
decrease the efficacy of tamoxifen therapy and increase the
risk of breast cancer development or recurrence. Several
SSRIs and SNRIs are potent, moderate, or mild inhibitors of
CYP2D6.
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An observational study of women treated with tamoxifen
demonstrated low serum concentrations of endoxifen in
those concomitantly treated with strong inhibitors of
CYP2D6, such as paroxetine and fluoxetine, and
intermediate levels of endoxifen in those concomitantly
treated with weak inhibitors, such as sertraline and
citalopram.
It is noteworthy that venlafaxine, which does not inhibit
CYP2D6, had little effect on endoxifen concentration.
Women with decreased CYP2D6 metabolism had
increased rates of breast cancer recurrence
and decreased relapse-free survival time.
Possible recommendations

Routine CYP2D6 genotyping for patients being treated with
tamoxifen.
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Alternative treatment options (such as citalopram,
gabapentin, and venlafaxine)
Other therapies. For example, ovarian suppression can be
used for treatment of premenopausal women, and
aromatase inhibitor therapy can be an excellent option for
postmenopausal women.
QUESTIONS

What is the main metabolite of the
tamoxifen?
Endoxifen
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What is the main citochrome implicated?
CYP2D6

When would we do a genetic test?
In patients with a relevant
pharmacological history

What is the use of tamoxifen?
- Adjuvant treatment after surgery.
- Neoadjuvant treatment before
surgery.
- Advanced stages of the disease
palliative.
- Prevention of breast cancer in
women at high risk.

What SSRI would you use in a
woman in treatment with tamoxifen?
Venlafaxine
BIBLIOGRAPHY
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Stockley’s Drug Interactions. Sixth edition.
www.ncbi.nlm.nih.gov/pubmed
ajp.psychiatryonline.org
jama.ama-assn.org
www.thelancet.com