Limits...
Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer.

Hennig EE, Piatkowska M, Karczmarski J, Goryca K, Brewczynska E, Jazwiec R, Kluska A, Omiotek R, Paziewska A, Dadlez M, Ostrowski J - BMC Cancer (2015)

Bottom Line: For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r (2) = 0.23; p < 10(-16)) and increased CYP2D6 functional impairment.The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 allele, compared with EM/EM patients.This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland. hennige@coi.waw.pl.

ABSTRACT

Background: Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy.

Methods: Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method.

Results: In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r (2) = 0.23; p < 10(-16)) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10(-16)) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10(-43)).

Conclusions: The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment.

No MeSH data available.


Related in: MedlinePlus

The (Z)-endoxifen-directed metabolism of tamoxifen according to the association of its metabolites concentration with CYP2D6 genotype. The intensity of gray shading corresponds with the number of CYP2D6 genotype predicted functional groups with a significant (p < 6.9 × 10−4) association with metabolite plasma concentration. White indicates no association and black indicates association with three genotypes, as indicated by linear modeling (see Fig. 1)
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Fig4: The (Z)-endoxifen-directed metabolism of tamoxifen according to the association of its metabolites concentration with CYP2D6 genotype. The intensity of gray shading corresponds with the number of CYP2D6 genotype predicted functional groups with a significant (p < 6.9 × 10−4) association with metabolite plasma concentration. White indicates no association and black indicates association with three genotypes, as indicated by linear modeling (see Fig. 1)

Mentions: According to linear modeling analysis, the plasma concentrations of five metabolites were significantly (p < 6.9 × 10−4) correlated with the CYP2D6 genotype (Fig. 1). For the first time, we have indicated an association between lower (E/Z)-4-OH-NDM-Tam-gluc levels (r2 = 0.23; p < 10−16) and an increasing degree of CYP2D6 functional impairment. In turn, consistent with other reports [12, 31], both NDM-Tam and 4′-OH-NDM-Tam were inversely correlated with the number of CYP2D6 deficient alleles. Furthermore, both active metabolites tended to decrease in proportion to the degree of CYP2D6 deficiency, with the strongest correlation being observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 allele, compared with EM/EM. In total, the CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen and 4-OH-Tam by 27 % (p < 10−16) and 5 % (p < 10−3), respectively. However, the CYP2D6 genotype accounted for 51 % (p < 10−43) of the variability of the MR for (Z)-endoxifen-directed drug metabolism. CYP2D6 deficiency has previously been shown to be associated with lower levels of both tamoxifen active metabolites [2, 12, 20, 27] and the correlation of plasma level variability with CYP2D6 genotype was estimated to be 39 % for (Z)-endoxifen and 9 % for 4-OH-Tam [2]. Altogether, our results strongly confirmed the importance of CYP2D6 function in (Z)-endoxifen-directed metabolism of tamoxifen, as illustrated in Fig. 4 where the metabolic pathway responsible for the production of NDM-Tam and (Z)-endoxifen is highlighted by the strength of association of metabolite concentration with CYP2D6 genotype.Fig. 4


Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer.

Hennig EE, Piatkowska M, Karczmarski J, Goryca K, Brewczynska E, Jazwiec R, Kluska A, Omiotek R, Paziewska A, Dadlez M, Ostrowski J - BMC Cancer (2015)

The (Z)-endoxifen-directed metabolism of tamoxifen according to the association of its metabolites concentration with CYP2D6 genotype. The intensity of gray shading corresponds with the number of CYP2D6 genotype predicted functional groups with a significant (p < 6.9 × 10−4) association with metabolite plasma concentration. White indicates no association and black indicates association with three genotypes, as indicated by linear modeling (see Fig. 1)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4522133&req=5

Fig4: The (Z)-endoxifen-directed metabolism of tamoxifen according to the association of its metabolites concentration with CYP2D6 genotype. The intensity of gray shading corresponds with the number of CYP2D6 genotype predicted functional groups with a significant (p < 6.9 × 10−4) association with metabolite plasma concentration. White indicates no association and black indicates association with three genotypes, as indicated by linear modeling (see Fig. 1)
Mentions: According to linear modeling analysis, the plasma concentrations of five metabolites were significantly (p < 6.9 × 10−4) correlated with the CYP2D6 genotype (Fig. 1). For the first time, we have indicated an association between lower (E/Z)-4-OH-NDM-Tam-gluc levels (r2 = 0.23; p < 10−16) and an increasing degree of CYP2D6 functional impairment. In turn, consistent with other reports [12, 31], both NDM-Tam and 4′-OH-NDM-Tam were inversely correlated with the number of CYP2D6 deficient alleles. Furthermore, both active metabolites tended to decrease in proportion to the degree of CYP2D6 deficiency, with the strongest correlation being observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 allele, compared with EM/EM. In total, the CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen and 4-OH-Tam by 27 % (p < 10−16) and 5 % (p < 10−3), respectively. However, the CYP2D6 genotype accounted for 51 % (p < 10−43) of the variability of the MR for (Z)-endoxifen-directed drug metabolism. CYP2D6 deficiency has previously been shown to be associated with lower levels of both tamoxifen active metabolites [2, 12, 20, 27] and the correlation of plasma level variability with CYP2D6 genotype was estimated to be 39 % for (Z)-endoxifen and 9 % for 4-OH-Tam [2]. Altogether, our results strongly confirmed the importance of CYP2D6 function in (Z)-endoxifen-directed metabolism of tamoxifen, as illustrated in Fig. 4 where the metabolic pathway responsible for the production of NDM-Tam and (Z)-endoxifen is highlighted by the strength of association of metabolite concentration with CYP2D6 genotype.Fig. 4

Bottom Line: For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r (2) = 0.23; p < 10(-16)) and increased CYP2D6 functional impairment.The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 allele, compared with EM/EM patients.This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland. hennige@coi.waw.pl.

ABSTRACT

Background: Tamoxifen, the most frequently used drug for treating estrogen receptor-positive breast cancer, must be converted into active metabolites to exert its therapeutic efficacy, mainly through CYP2D6 enzymes. The objective of this study was to investigate the impact of CYP2D6 polymorphisms on (Z)-endoxifen-directed tamoxifen metabolism and to assess the usefulness of CYP2D6 genotyping for identifying patients who are likely to have insufficient (Z)-endoxifen concentrations to benefit from standard therapy.

Methods: Blood samples from 279 Polish women with breast cancer receiving tamoxifen 20 mg daily were analyzed for CYP2D6 genotype and drug metabolite concentration. Steady-state plasma levels of tamoxifen and its 14 metabolites were measured by using the ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method.

Results: In nearly 60 % of patients, including over 30 % of patients with fully functional CYP2D6, (Z)-endoxifen concentration was below the predefined threshold of therapeutic efficacy. The most frequently observed CYP2D6 genotype was EM/PM (34.8 %), among which 83.5 % of patients had a combination of wild-type and *4 alleles. Plasma concentration of five metabolites was significantly correlated with CYP2D6 genotype. For the first time, we identified an association between decreased (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide levels (r (2) = 0.23; p < 10(-16)) and increased CYP2D6 functional impairment. The strongest correlation was observed for (Z)-endoxifen, whose concentration was significantly lower in groups of patients carrying at least one CYP2D6 allele, compared with EM/EM patients. The CYP2D6 genotype accounted for plasma level variability of (Z)-endoxifen by 27 % (p < 10(-16)) and for the variability of metabolic ratio indicating (Z)-endoxifen-directed metabolism of tamoxifen by 51 % (p < 10(-43)).

Conclusions: The majority of breast cancer patients in Poland may not achieve a therapeutic level of (Z)-endoxifen upon receiving a standard dose of tamoxifen. This finding emphasizes the limited value of CYP2D6 genotyping in routine clinical practice for identifying patients who might not benefit from the therapy. In its place, direct monitoring of plasma steady-state (Z)-endoxifen concentration should be performed to personalize and optimize the treatment.

No MeSH data available.


Related in: MedlinePlus