TAMOXIFEN IN TAMOXIFEN IN HORMONE HORMONE

DEPENDENT BREAST DEPENDENT BREAST CANCERCANCER

Cecilia GallegoIrene GallegoIgnacio GallegoBeatriz Galván Yanira GarcíaRafael García Rubén GarcíaAlberto García

PHARMACOGENETIPHARMACOGENETICSCS

OF OF

TAMOXIFEN TAMOXIFEN

BREAST CANCERBREAST CANCER Is the most common cancer in women.Is the most common cancer in women. RISK FACTORS:RISK FACTORS:

- Family history - Family history - Nulliparity- Nulliparity- Early menarche- Early menarche- Elderly- Elderly- Personal history of breast cancer- Personal history of breast cancer

IMPACT IN SPAIN: IMPACT IN SPAIN: - 36 new cases per 100.000 inhabitants/year.36 new cases per 100.000 inhabitants/year.- 12% of women will suffer from breast cancer.12% of women will suffer from breast cancer.- 3.5% will die from cancer.3.5% will die from cancer.

TAMOXIFEN Selective estrogen receptor Selective estrogen receptor It acts as anti-estrogens in breast tissue It acts as anti-estrogens in breast tissue

and partial agonist in some organs. and partial agonist in some organs. Dose: 20 mg/day for 5 years.Dose: 20 mg/day for 5 years. Beneficial effects on lipid metabolism Beneficial effects on lipid metabolism

and bone.and bone.

TREATMENT OF HORMONO-DEPENDENT TREATMENT OF HORMONO-DEPENDENT BREAST CANCER BREAST CANCER

PHARMACOGENETIC AND PHARMACOGENETIC AND METABOLISMMETABOLISM

PHARMACOGENETICPHARMACOGENETIC

MODULATION OF THERAPYMODULATION OF THERAPY ESR1, ESR2ESR1, ESR2 Genes estrogen Genes estrogen

receptorreceptor

Loos of exon 5Loos of exon 5

ERd5ERd5 Mutated receptor Mutated receptor no recognized by no recognized by tamoxifentamoxifen

CYCLIN D1CYCLIN D1 Activation of the Activation of the expression of estrogen receptorsexpression of estrogen receptors

CYP17A1CYP17A1 Increase the levels of Increase the levels of circulating estrogenscirculating estrogens

CYP2D6CYP2D6

Cr. 22, CYP 450,family 2, subfamily DCr. 22, CYP 450,family 2, subfamily D No related to the metabolism of precarcinogenesisNo related to the metabolism of precarcinogenesis Polymorphism do no show interindividual Polymorphism do no show interindividual

differences in the probability of developing cancerdifferences in the probability of developing cancer Mutant alleles Mutant alleles Gene polymorphismsGene polymorphisms

Enzyme activity increased, decreased or voidEnzyme 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 ALLELESNORMAL ALLELES

CYP2D6*1CYP2D6*1 Enzyme with catalytic activityEnzyme with catalytic activity

MUTANT ALLELESMUTANT ALLELES

CYP2D6*2, *33,*35CYP2D6*2, *33,*35 Enzyme with catalytic Enzyme with catalytic activityactivity

CYP2D6*4, *5CYP2D6*4, *5 Reduced metabolic activity Reduced metabolic activity CYP2D6*3, *4, *5, *6CYP2D6*3, *4, *5, *6 Nonfunctional Nonfunctional

enzyme activityenzyme activity (white people)(white people)

CYP2D6 amplifiedCYP2D6 amplified Enzyme activity Enzyme activity

increasedincreased

TAMOXIFEN AND GENETIC TAMOXIFEN AND GENETIC STUDY?????STUDY?????

A gene test could predict the efectiveness of A gene test could predict the efectiveness of TamoxifenTamoxifen

searching changes in searching changes in CYP2D6CYP2D6 genes genes

The study be held because the metabolism of The study be held because the metabolism of Tamoxifen shows a great variability:Tamoxifen shows a great variability:

- FAST METABOLICERS: 60%- FAST METABOLICERS: 60%

- INTERMEDIATE METABOLICERS: 33%- INTERMEDIATE METABOLICERS: 33%

- SLOW METABOLICERS: 7%- SLOW METABOLICERS: 7% The utility could prevent:The utility could prevent:

- Therapeutic failureTherapeutic failure- ToxicityToxicity- Impredecible interactionsImpredecible interactions

Inheritance of genetic variants Increased risk of Inheritance of genetic variants Increased risk of recurrence:recurrence:

- FAST METABOLICERS: 14,9%- FAST METABOLICERS: 14,9%- INTERMEDIATE METABOLICERS: 20,9%- INTERMEDIATE METABOLICERS: 20,9%- SLOW METABOLICERS: 29%- SLOW METABOLICERS: 29%

ONLY RECOMMENDED IN PATIENTS WITH ONLY RECOMMENDED IN PATIENTS WITH A RELEVANT PHARMACOLOGICAL A RELEVANT PHARMACOLOGICAL HISTORY HISTORY Treatment failure is also due to the Treatment failure is also due to the influence of enviromental factors not influence of enviromental factors not detected in the genetic test.detected in the genetic test. Genetic mutations in the 2 alleles Genetic mutations in the 2 alleles (homozygous)(homozygous) Recurrence time and Recurrence time and Survival Survival affecting only 7% of the affecting only 7% of the populationpopulation

CURRENT USES OF TAMOXIFENCURRENT USES OF TAMOXIFEN

Adjuvant treatment after surgery.Adjuvant treatment after surgery. Neoadjuvant treatment before surgery.Neoadjuvant treatment before surgery. Advanced stages of the disease Advanced stages of the disease

palliative.palliative. Prevention of breast cancer in women at Prevention of breast cancer in women at

high risk.high risk.

In pre- and postmenopausal women.In pre- and postmenopausal women.

OTHER ALTERNATIVE OTHER ALTERNATIVE DRUGS (I)DRUGS (I)

Anti-estrogenic of SECOND Anti-estrogenic of SECOND GENERATIONGENERATION

A. Nonsteroidal: A. Nonsteroidal: Raloxifen.Raloxifen. Similar to tamoxifen.Similar to tamoxifen.

B. Steroidal: B. Steroidal: Pure antiestrogen Pure antiestrogen (ICI).(ICI).

Reduce side effects of tamoxifen and Reduce side effects of tamoxifen and improve efficiency.improve efficiency.

Experience shorter.Experience shorter. Second choice.Second choice.

OTHER ALTERNATIVE OTHER ALTERNATIVE DRUGS (II)DRUGS (II)

AROMATASE INHIBITORSAROMATASE INHIBITORSo The most used: The most used: anastrozole, letrozole, anastrozole, letrozole,

formestane.formestane.o ActionAction: adrenal suppression chemical.: adrenal suppression chemical.

o Block the synthesis of androgens (-) Block the synthesis of androgens (-) estrogens.estrogens.

o Postmenopausal.Postmenopausal.

OTHER ALTERNATIVE DRUGS OTHER ALTERNATIVE DRUGS (III)(III)

More used: More used: megestrol megestrol acetateacetate..

Action:Action:- Cell cytotoxic effect.- Cell cytotoxic effect.- Anti-estrogenic effect - Anti-estrogenic effect and gonadotropins. and gonadotropins.

Adjuvant effect.Adjuvant effect.

LHRH ANALOGSLHRH ANALOGS

More used: More used: goserelin.goserelin. Action:Action: chemical chemical

suppression.suppression. Adjuvant tamoxifen.Adjuvant tamoxifen. Premenopausal.Premenopausal.

PROGESTOGENSPROGESTOGENS

BREAST CANCER BREAST CANCER TREATMENTTREATMENT

PREMENOPAUSAL WOMENPREMENOPAUSAL WOMEN

TREATMENT OF FIRST TREATMENT OF FIRST CHOICE: CHOICE: TAMOXIFENTAMOXIFEN- Adjuvants: LHRH - Adjuvants: LHRH analogs or analogs or progestogens.progestogens.

TREATMENT OF TREATMENT OF SECOND ELECTION: SECOND ELECTION: RALOXIFEN, RALOXIFEN, FULVESTRANT.FULVESTRANT.

TREATMENT OF THIRD TREATMENT OF THIRD ELECTION: ELECTION: AROMATASE AROMATASE INHIBITORS.INHIBITORS.

POSTMENOPAUSAL WOMENPOSTMENOPAUSAL WOMEN

TREATMENT OF FIRST TREATMENT OF FIRST CHOICE: CHOICE: TAMOXIFENTAMOXIFEN..

Adjuvants:Progestogens.Adjuvants:Progestogens.

TREATMENT OF SECOND TREATMENT OF SECOND ELECTION: ELECTION: AROMATASE AROMATASE INHIBITORS.INHIBITORS.

BREAST CANCER BREAST CANCER TREATMENTTREATMENT

ADJUVANT TREATMENTADJUVANT TREATMENT: Chemotherapy : Chemotherapy + Tamoxifen.+ Tamoxifen.

NEOADJUVANT TREATMENTNEOADJUVANT TREATMENT: : Chemotherapy + Surgery + Chemotherapy + Surgery + Chemotherapy/Radiotherapy + Tamoxifen.Chemotherapy/Radiotherapy + Tamoxifen.

ADVANCED STAGESADVANCED STAGES: : Tamoxifen/Aromatase inhibitors + Tamoxifen/Aromatase inhibitors + Polichemotherapy.Polichemotherapy.

PREVENTIONPREVENTION: Tamoxifen.: Tamoxifen.

DRUG DRUG INTERACTIONS INTERACTIONS OF TAMOXIFENOF TAMOXIFEN

CYP3A4 INDUCERSCYP3A4 INDUCERS

CYP3A4 inducers act by activating the CYP3A4 inducers act by activating the nuclear nuclear receptor PXRreceptor PXR and stimulate the metabolism of and stimulate the metabolism of tamoxifen.tamoxifen.

The association of tamoxifen with these drugs The association of tamoxifen with these drugs reduces the effectiveness of tamoxifen.reduces the effectiveness of tamoxifen.

CYP3A4 inducers are:CYP3A4 inducers are:• Several Several anticancer drugsanticancer drugs: : cyclophosphamide, docetaxel, erlotinib, cyclophosphamide, docetaxel, erlotinib, flutamide, ifosfamide and paclitaxel.flutamide, ifosfamide and paclitaxel.• RifampicinRifampicin is the most powerful inducer. is the most powerful inducer.• TamoxifenTamoxifen is a weak PXR activator.is a weak PXR activator.

MITOMYCIN C + TAMOXIFENMITOMYCIN C + TAMOXIFEN

This association can provoke an This association can provoke an haemolytic uraemic syndromehaemolytic uraemic syndrome::

- Mitomycin C causes subclinical Mitomycin C causes subclinical endotelial damage.endotelial damage.

- Tamoxifen has got thrombotic effect.Tamoxifen has got thrombotic effect.

AROMATASE INHIBITORSAROMATASE INHIBITORSFIRST GENERATIONFIRST GENERATION

Does the association with Does the association with aminoglutethimideaminoglutethimide improve the response at treatment?improve the response at treatment?

- Yes. Plasmatic levels of estrogen decrease.Yes. Plasmatic levels of estrogen decrease.

- No. Sensibility of estrogenic receptors of tumor No. Sensibility of estrogenic receptors of tumor cells increases.cells increases.

- No. Toxicity increases due to administration of two No. Toxicity increases due to administration of two drugs.drugs.

AROMATASE INHIBITORS AROMATASE INHIBITORS THIRD GENERATIONTHIRD GENERATION

There are relevant pharmacokinetic interactions resulting There are relevant pharmacokinetic interactions resulting in decreased plasma concentrations of third generation in decreased plasma concentrations of third generation aromatase inhibitors when combined with tamoxifen.aromatase inhibitors when combined with tamoxifen.

LETROZOLE

Combination of tamoxifen and letrozole:

The letrozole concentrations approximately 35-40% lower than when letrozole is used alone.

ANASTRAZOLE

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.

MEDROXYPROGESTERONMEDROXYPROGESTERONEE

What do we use them for?What do we use them for?

- - Inducing normal menstruationInducing normal menstruation..

- - Decreasing the risk of developing Decreasing the risk of developing cancer of the uterus in patients cancer of the uterus in patients taking estrogens.taking estrogens.

Medroxyprogesterone treatment in postmenopausal women increases the incidence of breast cancer.

Concomitant use of tamoxifen and medroxyprogesterone Concomitant use of tamoxifen and medroxyprogesterone increases the liver enzymes.increases the liver enzymes.

Tamoxifen induces signs of Tamoxifen induces signs of autophagyautophagy, which was enhanced when it was , which was enhanced when it was combined with MPA.combined with MPA.

When we use tamoxifen with HRT may occur:When we use tamoxifen with HRT may occur:

SIDE EFFECT: SIDE EFFECT: The beneficial effects of tamoxifen on The beneficial effects of tamoxifen on cardiovascular cardiovascular risk risk factors (because tamoxifen reduces the cholesterol level in factors (because tamoxifen reduces the cholesterol level in blood) are unchanged in current HRT users, whereas they may be blood) are unchanged in current HRT users, whereas they may be attenuated in women who start HRT while on tamoxifen. attenuated in women who start HRT while on tamoxifen.

POSITIVE EFFECTPOSITIVE EFFECT: : Increases bone density in Increases bone density in bonesbones, mainly in the , mainly in the femur.femur.

HORMONE REPLACEMENT HORMONE REPLACEMENT THERAPY (HRT)THERAPY (HRT)

Drug Interactions in the Drug Interactions in the Treatment of Breast Cancer Treatment of Breast Cancer

and Depressionand Depression

Depression in Breast Depression in Breast CancerCancer

The estimated point prevalence of major depressive The estimated point prevalence of major depressive disorder in all women is in the range of 3.5%–7% disorder in all women is in the range of 3.5%–7%

In comparison, the rate of depression in women with In comparison, the rate of depression in women with breastbreast cancercancer is estimated to be in the range of 10%–25% is estimated to be in the range of 10%–25%

Endocrine Therapy for Endocrine Therapy for Breast CancerBreast Cancer

Analyses of thousands of women treated with 5 years of Analyses of thousands of women treated with 5 years of tamoxifen versus no endocrine therapy for invasive tamoxifen versus no endocrine therapy for invasive breastbreast cancercancer demonstrate a 31% decrease in annual demonstrate a 31% decrease in annual breastbreast cancercancer death rate with tamoxifen. death rate with tamoxifen.

Tamoxifen is antiestrogenic in the Tamoxifen is antiestrogenic in the breastbreast, resulting in , resulting in decreased decreased breastbreast cancercancer development and recurrence, as development and recurrence, as well as in the brain, leading to hot flashes as side effectwell as in the brain, leading to hot flashes as side effect

Treatments for Concurrent Treatments for Concurrent Hot Flashes and DepressionHot Flashes and Depression Prospective randomized clinical trials have demonstrated Prospective randomized clinical trials have demonstrated

that selective serotonin reuptake inhibitors (SSRIs) that selective serotonin reuptake inhibitors (SSRIs) decrease vasomotor symptoms in healthy menopausal decrease vasomotor symptoms in healthy menopausal women and women with women and women with breastbreast cancercancer..

In general, these studies have shown that most of these In general, these studies have shown that most of these medications decrease hot flash frequency by about 60%, medications decrease hot flash frequency by about 60%, compared with a decrease of 25%–35% with placebo.compared with a decrease of 25%–35% with placebo.

Tamoxifen MetabolismTamoxifen Metabolism

Tamoxifen is converted to endoxifen principally by a Tamoxifen is converted to endoxifen principally by a noninducible P450 enzyme that is coded for by the most noninducible P450 enzyme that is coded for by the most polymorphic, and most studied, gene in the cytochrome polymorphic, and most studied, gene in the cytochrome P450 system: CYP2D6. P450 system: CYP2D6.

In one study, In one study, breastbreast cancercancer patients treated with patients treated with tamoxifen who were homozygous for a poor metabolizer tamoxifen who were homozygous for a poor metabolizer genotype (*4/*4) had significantly lower serum genotype (*4/*4) had significantly lower serum concentrations of endoxifen than those with the active.concentrations of endoxifen than those with the active.

Coadministration of Coadministration of Tamoxifen and an SSRI or Tamoxifen and an SSRI or

SNRISNRI In addition to genetic inactivation of CYP2D6, CYP2D6 In addition to genetic inactivation of CYP2D6, CYP2D6

activity can be decreased by medications that inhibit the activity can be decreased by medications that inhibit the enzyme.enzyme.

Use of CYP2D6 inhibitors in patients who are being treated Use of CYP2D6 inhibitors in patients who are being treated with tamoxifen, even if they have the homozygous active with tamoxifen, even if they have the homozygous active genotype, could potentially affect genotype, could potentially affect breastbreast cancercancer outcomes, in a manner similar to the poor metabolizer outcomes, in a manner similar to the poor metabolizer genotype. genotype.

Inhibition of tamoxifen conversion to endoxifen may Inhibition of tamoxifen conversion to endoxifen may decrease the efficacy of tamoxifen therapy and increase decrease the efficacy of tamoxifen therapy and increase the risk of the risk of breastbreast cancercancer development or recurrence. development or recurrence. Several SSRIs and SNRIs are potent, moderate, or mild Several SSRIs and SNRIs are potent, moderate, or mild inhibitors of CYP2D6.inhibitors of CYP2D6.

An observational study of women treated with tamoxifen An observational study of women treated with tamoxifen demonstrated low serum concentrations of endoxifen in demonstrated low serum concentrations of endoxifen in those concomitantly treated with strong inhibitors of those concomitantly treated with strong inhibitors of CYP2D6, such as CYP2D6, such as paroxetine and fluoxetineparoxetine and fluoxetine, and , and intermediate levels of endoxifen in those concomitantly intermediate levels of endoxifen in those concomitantly treated with weak inhibitors, such as treated with weak inhibitors, such as sertraline and sertraline and citalopramcitalopram..

It is noteworthy that It is noteworthy that venlafaxinevenlafaxine, which does not inhibit , which does not inhibit CYP2D6, had little effect on endoxifen concentration.CYP2D6, had little effect on endoxifen concentration.

Women with decreased CYP2D6 metabolism had Women with decreased CYP2D6 metabolism had increased rates of breast cancer recurrence increased rates of breast cancer recurrence and decreased relapse-free survival timeand decreased relapse-free survival time..

Possible recommendationsPossible recommendations

Routine CYP2D6 genotyping for patients being treated with Routine CYP2D6 genotyping for patients being treated with

tamoxifen.tamoxifen.

Alternative treatment options (such as citalopram, Alternative treatment options (such as citalopram, gabapentin, and venlafaxine)gabapentin, and venlafaxine)

Other therapies. For example, ovarian suppression can be Other therapies. For example, ovarian suppression can be used for treatment of premenopausal women, and used for treatment of premenopausal women, and aromatase inhibitor therapy can be an excellent option for aromatase inhibitor therapy can be an excellent option for postmenopausal women. postmenopausal women.

QUESTIONSQUESTIONS

What is the main metabolite of the What is the main metabolite of the tamoxifen?tamoxifen?

What is the main citochrome implicated?What is the main citochrome implicated?

When would we do a genetic test?When would we do a genetic test?

EndoxifenEndoxifen

CYP2D6CYP2D6

In patients with a In patients with a relevant relevant pharmacological pharmacological historyhistory

What is the use of tamoxifen?What is the use of tamoxifen?

- Adjuvant treatment after - Adjuvant treatment after surgery.surgery.- Neoadjuvant treatment before - Neoadjuvant treatment before surgery.surgery.- Advanced stages of the disease - Advanced stages of the disease palliative.palliative.- Prevention of breast cancer in - Prevention of breast cancer in women at high risk.women at high risk.

What SSRI would you use in a What SSRI would you use in a woman in treatment with woman in treatment with tamoxifen?tamoxifen?

VenlafaxineVenlafaxine

BIBLIOGRAPHYBIBLIOGRAPHY

Stockley’s Drug Interactions. Sixth Stockley’s Drug Interactions. Sixth edition.edition.

www.ncbi.nlm.nih.gov/pubmedwww.ncbi.nlm.nih.gov/pubmed ajp.psychiatryonline.orgajp.psychiatryonline.org jama.ama-assn.orgjama.ama-assn.org www.thelancet.comwww.thelancet.com