Pharmacogenetics of Tamoxifen: Who Should UndergoCYP2D6Genetic Testing?

Abstract

Many women with hormone receptor-positive breast cancer will receive tamoxifen at some point in their treatment course. Tamoxifen is biotransformed to the potent antiestrogen endoxifen almost exclusively through the cytochrome P450 (CYP) 2D6 isoform. Although prospective data are lacking, the balance of evidence available currently suggests that a single nucleotide polymorphism in the CYP2D6 gene, particularly the presence of 2 null alleles, predicts for reduced tamoxifen metabolism and possibly poorer outcome than expected in patients with a wild-type genotype. Studies evaluating the impact of genetic polymorphisms that result in CYP2D6 with reduced or no activity on long-term outcome have been mostly retrospective and conducted on archival tissues or those obtained previously in prospective studies of tamoxifen. Until data are available from retrospective examinations of the large prospective trials already conducted, or adequately powered prospective analyses, transforming this information into guidelines for individual patients remains challenging. The authors do not currently recommend routine testing for CYP2D6 genotype for making clinical decisions regarding tamoxifen. Use of concomitant strong or intermediate inhibitors of CYP2D6 should be avoided when alternate medications are available. Ongoing research is directed toward identifying other polymorphisms that may influence the efficacy and safety of tamoxifen, other hormonal agents, and chemotherapies used to treat breast cancer. The hope is that in the future, not only tumor-associated factors but also germ-line host genetics can be used to determine whether a woman should receive treatment, and with which specific agents, to prevent breast cancer recurrence or death or avoid drug-related toxicities.

Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy

“…The influence of CYP2D6 polymorphisms on outcome in tamoxifentreated, ER-positive breast cancer patients remains controversial [9][10][11][12][13][14][15][16][17][18][19]. The current study was conducted in routine practice and supports the association between CYP2D6 polymorphisms and clinical outcome [9][10][11][12][13][14]22,23], but highlights the importance of comprehensive genotyping and particularly the adverse effect of poor adherence [6,26,29,30].…”

“…Such conflicting evidence may reflect the relatively small study sizes, disparate patient populations and the range of CYP2D6 alleles determined [5]. A number of recent reviews have stated that routine testing of CYP2D6 genotype is still not yet established in the evaluation of women with ER positive breast cancer [1,[17][18][19].…”

Tamoxifeno y antidepresivos: ¿Antagonistas en la prevención del cáncer de mama?

“…Sin embargo, la ASCO 2007, decidió no implementar aún esta medida por falta de evidencias concluyentes sobre la interacción TAM-AD [46][47][48] .…”

“…Estos factores no han sido tomados en cuenta en los estudios publicados sobre este tema. Más conocimiento al respecto, permitiría entender mejor la variabilidad interindividual de la respuesta a TAM y su interacción con los AD 39,[46][47][48] .…”

Biomarker-Guided Therapies in Heart Failure: A Forum for Unified Strategies

“…Historical and biologic factors affecting the focus of research to date may also explain the relatively more thorough investigation of biomarkers in oncology. For instance, estrogen receptor status in breast cancer directly dictates treatment with tamoxifen, thus mechanistically linking the marker to a biologic process and treatment 4 da success that has not yet been achieved in HF.…”