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TAMOXIFEN IN HORMONE DEPENDENT BREAST CANCER

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. Is the most common cancer in women.

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TAMOXIFEN IN HORMONE DEPENDENT BREAST CANCER

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  1. TAMOXIFEN IN HORMONE DEPENDENT BREAST CANCER Cecilia Gallego Irene Gallego Ignacio Gallego Beatriz Galván Yanira García Rafael García Rubén García Alberto García

  2. PHARMACOGENETICS OF TAMOXIFEN

  3. BREAST CANCER • 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 womenwillsufferfrombreastcancer. • 3.5% will die fromcancer.

  4. TAMOXIFEN 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

  5. PHARMACOGENETIC AND METABOLISM

  6. PHARMACOGENETIC

  7. 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

  8. CYP2D6 • 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 Cr. 22, CYP 450,family 2, subfamily D No relatedtothemetabolism of precarcinogenesis Polymorphism do no show interindividual differences in theprobability of developingcancer MutantallelesGene polymorphismsEnzyme activity increased, decreased or void

  9. NORMAL ALLELES CYP2D6*1Enzyme with catalytic activity MUTANT ALLELES CYP2D6*2, *33,*35 Enzyme with catalytic activity CYP2D6*4, *5 Reduced metabolic activity CYP2D6*3, *4, *5, *6 Nonfunctional enzyme activity(white people) CYP2D6 amplified Enzyme activity increased

  10. TAMOXIFEN AND GENETIC STUDY????? • A gene test couldpredicttheefectiveness of Tamoxifen searchingchanges in CYP2D6 genes • Thestudybeheldbecausethemetabolism of Tamoxifen shows a greatvariability: - FAST METABOLICERS: 60% - INTERMEDIATE METABOLICERS: 33% - SLOW METABOLICERS: 7% • Theutilitycouldprevent: • Therapeuticfailure • Toxicity • Impredecible interactions

  11. BUT ... • ONLY RECOMMENDED IN PATIENTS WITH A RELEVANT PHARMACOLOGICAL HISTORY • Treatmentfailureisalsoduetotheinfluence of enviromentalfactorsnotdetected in thegenetic test. • Genetic mutations in the 2 alleles (homozygous) • Recurrence time and Survival • affecting only 7% of the population Inheritance of genetic variants Increased risk of recurrence: - FAST METABOLICERS: 14,9% - INTERMEDIATE METABOLICERS: 20,9% - SLOW METABOLICERS: 29%

  12. CURRENT USES OF TAMOXIFEN Adjuvanttreatmentaftersurgery. Neoadjuvanttreatmentbeforesurgery. Advanced stages of the disease palliative. Prevention of breast cancer in women at high risk.  In pre- and postmenopausalwomen.

  13. OTHER ALTERNATIVE DRUGS (I) Anti-estrogenic of SECOND GENERATION A. Nonsteroidal: Raloxifen. • Similar totamoxifen. B. Steroidal: Pureantiestrogen(ICI). • Reduce side effects of tamoxifen and improve efficiency. • Experienceshorter. • Secondchoice.

  14. OTHER ALTERNATIVE DRUGS (II) AROMATASE INHIBITORS • The most used: anastrozole, letrozole, formestane. • Action: adrenal suppressionchemical. • Block the synthesis of androgens (-) estrogens. • Postmenopausal.

  15. OTHER ALTERNATIVE DRUGS (III) LHRH ANALOGS More used: goserelin. Action:chemicalsuppression. Adjuvanttamoxifen. Premenopausal. PROGESTOGENS • More used: megestrolacetate. • Action:- Cell cytotoxic effect.- Anti-estrogenic effect and gonadotropins. • Adjuvanteffect.

  16. BREAST CANCER TREATMENT PREMENOPAUSAL WOMEN POSTMENOPAUSAL WOMEN TREATMENT OF FIRST CHOICE: TAMOXIFEN - Adjuvants: LHRH analogs or progestogens. TREATMENT OF SECOND ELECTION: RALOXIFEN, FULVESTRANT. TREATMENT OF THIRD ELECTION: AROMATASE INHIBITORS. TREATMENT OF FIRST CHOICE: TAMOXIFEN. Adjuvants:Progestogens. TREATMENT OF SECOND ELECTION: AROMATASE INHIBITORS.

  17. BREAST CANCER TREATMENT ADJUVANT TREATMENT: Chemotherapy + Tamoxifen. NEOADJUVANT TREATMENT: Chemotherapy + Surgery + Chemotherapy/Radiotherapy + Tamoxifen. ADVANCED STAGES: Tamoxifen/Aromataseinhibitors + Polichemotherapy. PREVENTION: Tamoxifen.

  18. DRUG INTERACTIONS OF TAMOXIFEN

  19. 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. • Rifampicinisthemostpowerfulinducer. • Tamoxifenis a weak PXR activator.

  20. MITOMYCIN C + TAMOXIFEN • Thisassociation can provokeanhaemolyticuraemicsyndrome: • Mitomycin C causes subclinical endotelial damage. • Tamoxifen has gotthromboticeffect.

  21. AROMATASE INHIBITORSFIRST GENERATION • Doestheassociationwithaminoglutethimideimprovethe response at treatment? • Yes. Plasmaticlevels of estrogendecrease. • No. Sensibility of estrogenicreceptors of tumor cellsincreases. • No. Toxicityincreasesduetoadministration of twodrugs.

  22. AROMATASE INHIBITORS THIRD GENERATION • There are relevant pharmacokinetic interactions resulting in decreased plasma concentrations of third generation 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.

  23. 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.

  24. Concomitant use of tamoxifen and medroxyprogesterone increases the liver enzymes. • Tamoxifen induces signs of autophagy, which was enhanced when it was combined with MPA.

  25. HORMONE REPLACEMENT THERAPY (HRT) When we use tamoxifen with HRT may occur: • 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.

  26. Drug Interactions in the Treatment of Breast Cancer and Depression

  27. Depression in Breast Cancer • 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 breastcancer is estimated to be in the range of 10%–25%

  28. Endocrine Therapy for Breast Cancer • Analyses of thousands of womentreatedwith 5 years of tamoxifen versus no endocrinetherapyforinvasivebreastcancerdemonstrate a 31% decrease in annualbreastcancerdeathratewithtamoxifen. • Tamoxifenisantiestrogenic in thebreast, resulting in decreasedbreastcancerdevelopment and recurrence, as well as in thebrain, leadingtohot flashes as sideeffect

  29. Treatments for Concurrent Hot Flashes and Depression • Prospective randomized clinical trials have demonstrated that selective serotonin reuptake inhibitors (SSRIs) decrease vasomotor symptoms in healthy menopausal women and women with breastcancer. • 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.

  30. Tamoxifen Metabolism • Tamoxifenisconvertedtoendoxifenprincipallyby a noninducible P450 enzymethatiscodedforbythemostpolymorphic, and moststudied, gene in thecytochrome P450 system: CYP2D6. • In onestudy, breastcancerpatientstreatedwithtamoxifenwhowerehomozygousfor a poormetabolizergenotype (*4/*4) hadsignificantlylowerserumconcentrations of endoxifenthanthosewiththe active.

  31. Coadministration of Tamoxifen and an SSRI or SNRI • 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 breastcancer 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 breastcancer development or recurrence. Several SSRIs and SNRIs are potent, moderate, or mild inhibitors of CYP2D6.

  32. Anobservationalstudy of womentreatedwithtamoxifendemonstratedlowserumconcentrations of endoxifen in thoseconcomitantlytreatedwithstronginhibitors of CYP2D6, such as paroxetine and fluoxetine, and intermediatelevels of endoxifen in thoseconcomitantlytreatedwithweakinhibitors, such as sertraline and citalopram. • Itisnoteworthythatvenlafaxine, whichdoesnotinhibit CYP2D6, hadlittleeffectonendoxifenconcentration. • Womenwithdecreased CYP2D6 metabolismhadincreasedrates of breastcancerrecurrence and decreasedrelapse-free survival time.

  33. Possible recommendations • Routine CYP2D6 genotyping for patients being treated with tamoxifen. • 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.

  34. QUESTIONS

  35. Endoxifen • Whatisthemainmetabolite of thetamoxifen? • Whatisthemaincitochromeimplicated? • Whenwouldwe do a genetic test? CYP2D6 In patients with a relevant pharmacological history

  36. - Adjuvanttreatmentaftersurgery. - Neoadjuvanttreatmentbeforesurgery. - Advanced stages of the disease palliative. - Prevention of breast cancer in women at high risk. • Whatisthe use of tamoxifen?

  37. Venlafaxine • What SSRI wouldyou use in a woman in treatmentwithtamoxifen?

  38. BIBLIOGRAPHY • Stockley’s Drug Interactions. Sixth edition. • www.ncbi.nlm.nih.gov/pubmed • ajp.psychiatryonline.org • jama.ama-assn.org • www.thelancet.com

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