No association found between<i>CYP2D6</i>genotype and early breast cancer events in tamoxifen-treated patients

Markkula, Andrea; Hjertberg, Maria; Rose, Carsten; Ingvar, Christian; Jernström, Helena

doi:10.3109/0284186x.2013.840739

Cited by 16 publications

(14 citation statements)

References 23 publications

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“…The meta-analysis of the association between the variant/variant genotype (or inferred poor metabolizer phenotype) and breast cancer recurrence or mortality, as compared with the wild-type/wild-type genotype (or inferred extensive or ultrametabolizer phenotype), included 21 of the 31 studies. In 16 (76%) of these 21 studies, researchers extracted DNA from nonneoplastic tissue (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70), and in 5 of them (24%) they extracted DNA from tumor-infiltrated tissue (26-28, 46, 72). The summary estimates of association with and without bias analysis are reported in Table 3 and displayed in Figure 1.…”

Section: Resultsmentioning

confidence: 99%

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Ahern¹,

Hertz²,

Damkier³

et al. 2016

Am. J. Epidemiol.

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Tamoxifen therapy for estrogen receptor-positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (CYP2D6), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-Ndesmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose CYP2D6 genotypes confer poor enzyme function. Thirty-one studies of the association of CYP2D6 genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumorinfiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the CYP2D6 locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor-infiltrated tissues, all of which showed excellent CYP2D6 genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between CYP2D6 genotype and breast cancer survival in tamoxifen-treated women. breast neoplasms; cytochrome P-450 2D6; tamoxifen Abbreviations: ATAC, Arimidex, Tamoxifen, Alone or in Combination; BIG 1-98, Breast International Group 1-98; CI, confidence interval; CYP2D6, cytochrome P-450 2D6; FFPE, formalin-fixed, paraffin-embedded; FFPE-T, formalin-fixed, paraffinembedded tumor tissue; FFPE-TN, formalin-fixed, paraffin-embedded tumor tissue with nonneoplastic tissue; HWE, HardyWeinberg equilibrium; LOH, loss of heterozygosity; RR, relative risk.

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Section: Resultsmentioning

confidence: 99%

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Ahern¹,

Hertz²,

Damkier³

et al. 2016

Am. J. Epidemiol.

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“…Nevertheless, studies investigating the association between CYP2D6 genotype and clinical outcomes following treatment with tamoxifen for breast cancer have yielded conflicting evidence [69,[71][72][73][74]. Kiyotani et al [75] reported an important observation that in breast cancer patients who received tamoxifen therapy in combination with other therapies, there was no significant association between CYP2D6 genotype and recurrence-free survival.…”

Section: Genotype-dependent Susceptibility To Phenoconversionmentioning

confidence: 99%

Addressing phenoconversion: the Achilles' heel of personalized medicine

Shah

Smith

2015

Brit J Clinical Pharma

221

217

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Phenoconversion is a phenomenon that converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, thereby modifying their clinical response to that of genotypic PMs. Phenoconversion, usually resulting from nongenetic extrinsic factors, has a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies and personalizing therapy in routine clinical practice. The high phenotypic variability or genotype-phenotype mismatch, frequently observed due to phenoconversion within the genotypic EM population, means that the real number of phenotypic PM subjects may be greater than predicted from their genotype alone, because many genotypic EMs would be phenotypically PMs. If the phenoconverted population with genotype-phenotype mismatch, most extensively studied for CYP2D6, is as large as the evidence suggests, there is a real risk that genotype-focused association studies, typically correlating only the genotype with clinical outcomes, may miss clinically strong pharmacogenetic associations, thus compromising any potential for advancing the prospects of personalized medicine. This review focuses primarily on co-medication-induced phenoconversion and discusses potential approaches to rectify some of the current shortcomings. It advocates routine phenotyping of subjects in genotype-focused association studies and proposes a new nomenclature to categorize study populations. Even with strong and reliable data associating patients' genotypes with clinical outcome(s), there are problems clinically in applying this knowledge into routine pharmacotherapy because of potential genotype-phenotype mismatch. Drug-induced phenoconversion during routine clinical practice remains a major public health issue. Therefore, the principal challenges facing personalized medicine, which need to be addressed, include identification of the following factors: (i) drugs that are susceptible to phenoconversion; (ii) co-medications that can cause phenoconversion; and (iii) dosage amendments that need to be applied during and following phenoconversion. Pharmacogenetics and personalized medicineThe majority of drug-metabolizing enzymes (DMEs) are subject to genetic polymorphism and show some degree of functionally significant polymorphism in the population. The clearest data in this regard relate to cytochromes P450 CYP2D6 and CYP2C19 and thiopurine methyltransferase (TPMT). These genetically determined polymorphisms give rise to three distinct genotype-based subpopulations with respect to each DME, namely extensive metabolizers (EMs), poor metabolizers (PMs) and a subgroup in between, the intermediate metabolizers (IMs). In addition, for CYP2D6 and CYP2C19, there is a fourth genotype, the ultrarapid metabolizer (UM) genotype, resulting from inheritance of either multiple copies of the functional wild-type allele, such as CYP2D6*1, or a higher metabolic capacity resulting from increased transcription of DME due to the presence of a genetic variant found in the promoter ...

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“…Moreover, single nucleotide polymorphisms (SNPs) in the ESR1 gene, such as the intronic SNPs rs2234693 (PvuII; T > C) and rs9340799 (XbaI; A > G) [6], could influence the tumor response to the drug by a yet unexplored mechanism. Additionally, studies have addressed a genetic link in the metabolism of TAM and the risk of death from BC [7-23]. …”

Section: Introductionmentioning

confidence: 99%

“…TAM and its metabolites are further metabolized and inactivated by phase II enzymes, as SULT1A1 [17, 18]. Genetic variations within these drug-metabolizing enzymes affect TAM metabolism and effectiveness against ER-positive BC, and further pharmacogenomic studies are needed to clarify the available controversial data [19–23]. …”

Section: Introductionmentioning

confidence: 99%

Pharmacogenomic diversity of tamoxifen metabolites and estrogen receptor genes in Hispanics and non-Hispanic whites with breast cancer

Rangel

Taraba

Frei

et al. 2014

Breast Cancer Res Treat

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Ethnic differences in patient genetics and breast cancer (BC) biology contribute to ethnic disparities in cancer presentation and patient outcome. We prospectively evaluated SNPs within phase I and phase II tamoxifen (TAM) metabolizing enzymes, and the estrogen receptor gene (ESR1), aiming to identify potential pharmacogenomic ethnicity patterns in an ER-positive BC cohort constituted of Hispanic and Non-Hispanic White (NHW) women in South Texas. Plasma concentrations of TAM/metabolites were measured using HPLC. CYP2C9, CYP2D6 and SULT1A1 genotypes were determined by DNA sequencing/Pyrosequencing technology. ESR1 PvuII and XbaI SNPs were genotyped using Applied Biosystems Taqman® Allelic Discrimination Assay. Hispanics had higher levels of TAM, 4-hydroxytamoxifen, and endoxifen than NHWs. There was a higher prevalence of CYP2D6 EM within Hispanics than NHWs, which corresponded to higher endoxifen levels, but no differences were verified with regard to CYP2C9 and SULT1A1. We found a higher incidence of the wild type forms of the ESR1 in Hispanics than NHWs. The performance status, the disease stage at diagnosis, and the use of aromatase inhibitors might have overcome the overall favorable pharmacogenomics profile of Hispanics when compared to NHWs in relation to TAM therapy responsiveness. Our data strongly point to ethnical peculiarities related to pharmacogenomics and demographic features of TAM treated Hispanics and NHWs. In the era of pharmacogenomics and its ultimate goal of individualized, efficacious and safe therapy, cancer studies focused on the Hispanic population are warranted because this is the fastest growing major demographic group, and an understudied segment in the U.S.

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No association found betweenCYP2D6genotype and early breast cancer events in tamoxifen-treated patients

Abstract: CYP2D6 genotype was not associated with tamoxifen treatment outcome, even when CYP2D6 inhibitor use, aromatase inhibitor use, or chemotherapy was taken into account. CYP2D6 genotype may be of minor importance for tamoxifen-treated patients in Scandinavia.

Cited by 16 publications

References 23 publications

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

Addressing phenoconversion: the Achilles' heel of personalized medicine

Pharmacogenomic diversity of tamoxifen metabolites and estrogen receptor genes in Hispanics and non-Hispanic whites with breast cancer

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