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CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study.

ABSTRACT: INTRODUCTION AND AIMS:Tamoxifen is an adjuvant drug effective in treating hormone receptor - positive breast cancer. However, 30%-50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between CYP2D6 polymorphisms and recurrence of breast cancer in patients on tamoxifen had been reported, little evidence exists on association between these polymorphisms and adverse effects to tamoxifen. This study explored the association between CYP2D6 polymorphisms and tamoxifen effects, hitherto not studied in Sri Lanka. METHODS:A retrospective preliminary study was carried out on 24 breast cancer patients on tamoxifen for minimally 3 months attending National Cancer Institute, Maharagama, Sri Lanka. They were not on CYP2D6-inhibiting drugs, chemotherapy or other endocrine therapy, and had no conditions that could occur as adverse effects to tamoxifen before starting the therapy. Their blood samples were collected, DNA was extracted and genotyped using SNaPshot Multiplex sequencing based single-nucleotide polymorphism (SNP) assay. RESULTS:SNP/allele frequencies detected: 1846G>A (confirmatory of *4 null allele)=8.3%; 2549delA (confirmatory of *3 null allele)=50%; 100C>T (suggestive of *10 reduced functional allele, in addition to other alleles)=0%; combination of 2988G>A, -1584C and 2850C>T (strongly suggestive of *41 or other reduced functional allele)=4.8%. Occurrence of heterozygous 2988G>A SNP with -1584C and 2850C>T was significantly higher among those with ultrasound-diagnosed fatty liver following the commencement of tamoxifen therapy (P=0.029). Adverse effects occurred at a significantly higher frequency among postmenopausal women (P=0.041). Three patients who developed recurrence of breast cancer had no association with SNPs tested. CONCLUSIONS:CYP2D6 SNP combination 2988G>A, -1584C and 2850C>T, strongly suggestive of *41 reduced functional allele, is likely to be useful in predicting occurrence of adverse effect fatty liver in breast cancer patients on tamoxifen, thereby alternative treatment can be considered and lifestyle modifications implemented. Larger sample studies are recommended with the measurement of tamoxifen and metabolite levels. Alternative therapy should be considered for postmenopausal patients.

SUBMITTER: Wickramage I

PROVIDER: S-EPMC5345689 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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<i>CYP2D6</i> polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study.

Wickramage Ishani I Tennekoon Kamani Hemamala KH Ariyaratne Merenchi Arachchige Yasantha MA Hewage Asanka Sudeshini AS Sundralingam Tharmini T

Breast cancer (Dove Medical Press) 20170306

<h4>Introduction and aims</h4>Tamoxifen is an adjuvant drug effective in treating hormone receptor - positive breast cancer. However, 30%-50% of patients relapse and many develop adverse effects, such as hot flashes and fatty liver. Allelic variations altering the activity of cytochrome P450-2D6 enzyme affect response to tamoxifen by modulating metabolism of tamoxifen into its pharmacologically active metabolite endoxifen. Although association between <i>CYP2D6</i> polymorphisms and recurrence o ...[more]

PMID: 28293118

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Project description:ContextThe growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor-positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme.ObjectiveTo determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen.Design, setting, and patientsRetrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism.Main outcome measuresTime to recurrence, event-free survival, disease-free survival, and overall survival.ResultsMedian follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51).ConclusionAmong women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.

Project description:BackgroundTamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown.MethodsGermline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS.ResultsAmong women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02).ConclusionThis study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

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CYP2D6 polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study.

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<i>CYP2D6</i> polymorphisms may predict occurrence of adverse effects to tamoxifen: a preliminary retrospective study.

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