Elección del mejor antidepresivo en pacientes con cáncer de mama en tratamiento con tamoxifeno: revisión de la evidencia básica y clínica / Antidepressants agents in breast cancer patients using tamoxifen: review of basic and clinical evidence

Tamoxifen (Tmf), is a standard of care for women with estrogen receptor positive (ER+) breast cancer. Endoxifen is a Tmf metabolite generated by cytochrome P450 2D6 (CYP2D6). Antidepressive agents (AD) are often prescribed to women with breast cancer not only for depression, but also for anxiety and hot flashes. Some AD are substrates or inhibitors of the Tmf metabolic pathway. Therefore there may be interactions when Tmf and AD are prescribed simultaneously. Oncologic protection afforded by Tmf may become less effective or null when AD are indicated, especially in poor metabolizing patients. We performed an update of the literature about the criteria for choosing AD in women receiving Tmf. Tricyclic AD, paroxetine and fluoxetine should be avoided in patients receiving Tmf, because they are strong inhibitors of CYP2D6. Bupropion, duloxetine and sertraline are only moderate inhibitors of the cytochrome and are not contraindicated. Citalopram, desvenlafaxine, escitalopram, milnacipran and venlafaxine are recommended, because they do not influence the metabolism and clinical efficacy of Tmf and have fewer drug interactions. However, other additional pharmacological and clinical issues should be considered when choosing an antidepressant in women with breast cancer.

Importância do CYP2D6 em usuárias de tamoxifeno no câncer de mama / Importance of CYP2D6 in users of tamoxifen in breast cancer

O tamoxifeno é a terapia hormonal mais usada nas últimas três décadas no tratamento do câncer de mama (CM) hormônio-dependente e, mais recentemente, na prevenção de CM em mulheres de todas as idades. Sua atividade farmacológica depende da sua bioativação pelo citocromo P450 2D6. Os resultados clínicos da terapia com tamoxifeno são influenciados por diversos fatores, incluindo o genótipo metabolizador CYP2D6, aderência ao tratamento e o uso de comedicações inibidoras, como os antidepressivos. Vários estudos sugerem que mulheres que transportam uma ou duas variantes alélicas do CYP2D6, que codificam enzimas com atividade reduzida ou nula podem ter um pior desfecho clínico quando tratadas com terapia adjuvante com tamoxifeno em comparação às mulheres portadoras de dois alelos com função normal. Este artigo de revisão visa resumir os dados disponíveis na literatura sobre a interação do genótipo CYP2D6 e os resultados clínicos de mulheres em terapia hormonal com tamoxifeno

Tamoxifen is a hormone therapy used over the past three decades in the treatment of breast cancer hormone-dependent and, more recently, the prevention of breast cancerin women of all ages. Its pharmacological activity depends on its bioactivation by cytochrome P450 2D6. Clinical results of therapy with tamoxifen are influenced by several factors, including CYP2D6 metabolizer genotype, treatment adherence and use co-inhibitory drugs such as antidepressants. Multiple studies suggest that women who carry one or two variant CYP2D6 alleles that encode enzymes with null or reduced activity may have an inferior breast cancer outcome when treated with tamoxifen in the adjuvant setting compared to women carrying two alleles encoding an enzyme with normal activity. This review article will summarize the available published breast cancer data on the interaction between CYP2D6 genotype and clinical outcomes in women on hormone therapy with tamoxifen

Tamoxifeno y antidepresivos: ¿Antagonistas en la prevención del cáncer de mama? / Antagonism of tamoxifen and antidepressants among women with breast cancer

Tamoxifen is used as an adjuvant therapy to reduce breast cáncer recurrence among women with estrogenreceptor positive tumors. Antidepressants are also com-monly used in such women, to treat depression or to manage hotflush.es, afrequent tamoxifen secondary effect. Some antidepressants couldpotentially inhibit cytochrome P450 2D6, required to actívate tamoxifen, interfering with its action. Although there is not a clear cut directive on the subject, it is nowadays recommended to treat women with antidepressants with the lower cytochrome P450 2D6 inhibition potential to avoid apossible antagonism that may reduce tamoxifen s prevention of breast cáncer recurrence at least in some patients with CYP2D6 genetic variation. The recommended antidepressants are desvenlafaxine, milnacipran, venlafaxin, escitalopram and citalopram.

Determinação da frequência de polimorfismos de cyp2d6 em mulheres brasileiras e revisão de literatura / Determination of the frequency of CYP2D6 polymorphisms in Brazilian women and literature review

O tamoxifeno (TMX),consagrado como terapia padrão no tratamento de pacientes portadoras de câncer de mama com receptores hormonais positivos, é convertido por metabolização primária e secundária no metabólito endoxifeno, que apresenta afinidade muito maior pelos receptores hormonais e é o maior responsável pelos efeitos antitumorais desta droga. A biotransformação do TMX em endoxifeno é dependente da subunidade 2D6 do citocromo P-450 (CYP2D6), cujo gene apresenta inúmeros polimorfismos que reduzem a atividade metabólica dessa via biológica, resultando em menores níveis de seu produto ativo e, possivelmente, da resposta terapêutica ao uso do TMX. Objetivo: O objetivo deste estudo foi determinar a frequência dos polimorfismos CYP2D6*3, *4, *5, *6 e *10 e dos fenótipos de metabolização da droga TMX em pacientes portadoras de câncer de mama atendidas pelos autores no Centro de Oncologia do Hospital Sírio Libanês (HSL), além de revisar os dados sobre este tema disponíveis na literatura. Métodos: Amostras de sangue periférico de 30 pacientes foram enviadas a laboratório de referência para pesquisa dos polimorfismos descritos de CYP2D6 pela técnica de reação em cadeia da polimerase e digestão por enzimas de restrição (PCR-RFLP). Resultados: Os resultados mostraram heterozigose para polimorfismo CYP2D6*4 e *10 em 33 e 38% das mulheres, respectivamente. Utilizando a classificação de fenótipos de metabolização de TMX previamente descrita determinamos que 27% das mulheres avaliadas foram categorizadas com perfil de metabolização intermediária da droga, e 3% como metabolizadoras pobres, as quais, segundo dados atuais, parecem estar duas vezes mais sujeitas a desenvolverem recorrência de câncer de mama durante tratamento com TMX. Foi documentada uma elevada e inesperada prevalência de heterozigose do polimorfismo *10 na população estudada. Conclusões: Estudos prospectivos estão em andamento, visando definir o papel do perfil dos polimorfismos de CYP2D6 na escolha...

Tamoxifen (TMX), established as standard therapy in treating patients with breast cancer with hormone receptor positive, is converted by metabolism in primary and secondary metabolite endoxifeno, which has much higher affinity for hormone receptors and is most responsible the antitumor effects of this drug. Biotransformation of TMX in endoxifeno 2D6 is dependent on the subunit of cytochrome P-450 (CYP2D6), whose gene has many polymorphisms that reduce the metabolic activity of this biological pathway, resulting in lower levels of its active product, and possibly therapeutic response to use of TMX. Objective: The objective of this study was to determine the frequency of CYP2D6 polymorphisms * 3, * 4, * 5, * 6 and * 10 and phenotypes of drug metabolizing TMX in patients with breast cancer treated by the authors at the Centre for Oncology Syrian Lebanese Hospital (HSL), and review the data on this subject available in the literature. Methods: Blood samples from 30 patients were sent to reference laboratory for research of CYP2D6 polymorphisms described the technique of polymerase chain reaction and restriction enzyme digestion (PCR-RFLP). Results: Results showed heterozygosity for polymorphic CYP2D6 * 4 and * 10 in 33 women and 38% respectively. Using the classification of phenotypes of metabolism of TMX described previously determined that 27% of the women studied were categorized with a profile of intermediate metabolites of the drug, and 3% as poor metabolizers, which, according to current data seem to be two times more likely to develop recurrence of breast cancer during treatment with TMX. It was documented and an unexpected high prevalence of heterozygous * 10 polymorphism in the population. Conclusions: Prospective studies are underway, aimed at defining the role of the profile of CYP2D6 polymorphisms on the choice of strategy hormonal therapy in women with breast cancer.