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

Significant association of the CYP2D6 genotype with plasma concentration and molecular ratio of tamoxifen metabolites. a (Z)-endoxifen, b The MR of (Z)-endoxifen/sum of the remaining measured compounds, c (Z)-4-OH-tamoxifen, d MR of (Z)-4-OH-tamoxifen/sum of the remaining compounds, eN-desmethyl-tamoxifen, f 4′-OH-N-desmethyl-tamoxifen, g (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide. The number of patients (N) was as follow: EM/UM (18), EM/EM (87), EM/IM (43), EM/PM (97), IM/IM (3), IM/PM (11), PM/PM (20). The horizontal line indicates the median plasma concentration, the box covers 25th-75th percentiles and the maximum length of each whisker is 1.5× the interquartile range; dots outside the whiskers are outliers. Linear model (ordinary least squares) was fitted independently in six functional groups with EM/EM as a reference to examine whether there was an association between the measured metabolite concentration and CYP2D6 phenotype. Student’s t statistics was used to test if fitted coefficients were different than 0. The Bonferroni corrected p-value of less than 6.9 × 10−4 was considered significant. Significant associations are marked with asterisk (*)
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Fig1: Significant association of the CYP2D6 genotype with plasma concentration and molecular ratio of tamoxifen metabolites. a (Z)-endoxifen, b The MR of (Z)-endoxifen/sum of the remaining measured compounds, c (Z)-4-OH-tamoxifen, d MR of (Z)-4-OH-tamoxifen/sum of the remaining compounds, eN-desmethyl-tamoxifen, f 4′-OH-N-desmethyl-tamoxifen, g (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide. The number of patients (N) was as follow: EM/UM (18), EM/EM (87), EM/IM (43), EM/PM (97), IM/IM (3), IM/PM (11), PM/PM (20). The horizontal line indicates the median plasma concentration, the box covers 25th-75th percentiles and the maximum length of each whisker is 1.5× the interquartile range; dots outside the whiskers are outliers. Linear model (ordinary least squares) was fitted independently in six functional groups with EM/EM as a reference to examine whether there was an association between the measured metabolite concentration and CYP2D6 phenotype. Student’s t statistics was used to test if fitted coefficients were different than 0. The Bonferroni corrected p-value of less than 6.9 × 10−4 was considered significant. Significant associations are marked with asterisk (*)

Mentions: Additional file 1 includes the list of measured plasma concentrations of analyzed compounds and assigned CYP2D6 genotypes of all patients studied. The linear modeling indicated that the concentrations of five tamoxifen metabolites were significantly (p < 6.9 × 10−4) correlated with CYP2D6 genotype (Fig. 1a, c, e-g). The level of NDM-Tam and 4′-OH-NDM-Tam tended to decrease in accordance with the number of functional enzyme alleles, showing significantly higher values for EM/PM and PM/PM genotypes, compared with EM/EM. Conversely, significantly lower concentrations of (E/Z)-4-OH-NDM-Tam-gluc were observed among EM/PM and PM/PM patients than in EM/EM patients.Fig. 1


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)

Significant association of the CYP2D6 genotype with plasma concentration and molecular ratio of tamoxifen metabolites. a (Z)-endoxifen, b The MR of (Z)-endoxifen/sum of the remaining measured compounds, c (Z)-4-OH-tamoxifen, d MR of (Z)-4-OH-tamoxifen/sum of the remaining compounds, eN-desmethyl-tamoxifen, f 4′-OH-N-desmethyl-tamoxifen, g (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide. The number of patients (N) was as follow: EM/UM (18), EM/EM (87), EM/IM (43), EM/PM (97), IM/IM (3), IM/PM (11), PM/PM (20). The horizontal line indicates the median plasma concentration, the box covers 25th-75th percentiles and the maximum length of each whisker is 1.5× the interquartile range; dots outside the whiskers are outliers. Linear model (ordinary least squares) was fitted independently in six functional groups with EM/EM as a reference to examine whether there was an association between the measured metabolite concentration and CYP2D6 phenotype. Student’s t statistics was used to test if fitted coefficients were different than 0. The Bonferroni corrected p-value of less than 6.9 × 10−4 was considered significant. Significant associations are marked with asterisk (*)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Significant association of the CYP2D6 genotype with plasma concentration and molecular ratio of tamoxifen metabolites. a (Z)-endoxifen, b The MR of (Z)-endoxifen/sum of the remaining measured compounds, c (Z)-4-OH-tamoxifen, d MR of (Z)-4-OH-tamoxifen/sum of the remaining compounds, eN-desmethyl-tamoxifen, f 4′-OH-N-desmethyl-tamoxifen, g (E/Z)-4-OH-N-desmethyl-tamoxifen-β-D-glucuronide. The number of patients (N) was as follow: EM/UM (18), EM/EM (87), EM/IM (43), EM/PM (97), IM/IM (3), IM/PM (11), PM/PM (20). The horizontal line indicates the median plasma concentration, the box covers 25th-75th percentiles and the maximum length of each whisker is 1.5× the interquartile range; dots outside the whiskers are outliers. Linear model (ordinary least squares) was fitted independently in six functional groups with EM/EM as a reference to examine whether there was an association between the measured metabolite concentration and CYP2D6 phenotype. Student’s t statistics was used to test if fitted coefficients were different than 0. The Bonferroni corrected p-value of less than 6.9 × 10−4 was considered significant. Significant associations are marked with asterisk (*)
Mentions: Additional file 1 includes the list of measured plasma concentrations of analyzed compounds and assigned CYP2D6 genotypes of all patients studied. The linear modeling indicated that the concentrations of five tamoxifen metabolites were significantly (p < 6.9 × 10−4) correlated with CYP2D6 genotype (Fig. 1a, c, e-g). The level of NDM-Tam and 4′-OH-NDM-Tam tended to decrease in accordance with the number of functional enzyme alleles, showing significantly higher values for EM/PM and PM/PM genotypes, compared with EM/EM. Conversely, significantly lower concentrations of (E/Z)-4-OH-NDM-Tam-gluc were observed among EM/PM and PM/PM patients than in EM/EM patients.Fig. 1

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