Dataset Information

SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen.

ABSTRACT: Tamoxifen biotransformation to endoxifen, a potent antiestrogen, is catalyzed by CYP2D6. In addition, CYP2C19 and SULT1A1 have also been implicated in the metabolism of tamoxifen. We sought to evaluate the importance of SULT1A1 copy number and CYP2C19*17 on disease-free survival (DFS) in postmenopausal women randomized to tamoxifen monotherapy in North Central Cancer Treatment Group 89-30-52 from January 1991 to April 1995.We extracted DNA from paraffin-embedded tumors and determined tumor SULT1A1 copy number and CYP2C19*17 genotype. The association of genotype with DFS was determined using the log-rank test. Multivariate cox modeling was performed using traditional prognostic factors, as well as CYP2D6 genotype. SULT1A1 copy number and CYP2C19*17 genotype was determined in 190 out of 256 patients (95% Caucasian).The median follow-up for living patients was 14 years. DFS did not differ according to SULT1A1 copy number (p = 0.482) or CYP2C19*17 genotype (p = 0.667). Neither SULT1A1 copy number or CYP2C19*17 genotype was associated with disease recurrence in this cohort.Future studies are needed to identify whether other genetic and environmental factors which affect tamoxifen metabolism are associated with tamoxifen clinical outcomes.

SUBMITTER: Moyer AM

PROVIDER: S-EPMC3235041 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen.

Moyer Ann M AM Suman Vera J VJ Weinshilboum Richard M RM Avula Rajeswari R Black John L JL Safgren Stephanie L SL Kuffel Mary J MJ Ames Matthew M MM Ingle James N JN Goetz Matthew P MP

Pharmacogenomics 20111003 11

<h4>Aim</h4>Tamoxifen biotransformation to endoxifen, a potent antiestrogen, is catalyzed by CYP2D6. In addition, CYP2C19 and SULT1A1 have also been implicated in the metabolism of tamoxifen. We sought to evaluate the importance of SULT1A1 copy number and CYP2C19*17 on disease-free survival (DFS) in postmenopausal women randomized to tamoxifen monotherapy in North Central Cancer Treatment Group 89-30-52 from January 1991 to April 1995.<h4>Materials & methods</h4>We extracted DNA from paraffin-em ...[more]

PMID: 21961651

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Project description:PURPOSE:To investigate the impact of CYP2D6 and CYP2C19 polymorphisms in predicting tamoxifen efficacy and clinical outcomes in Thai breast cancer patients. METHODS:Polymorphisms of CYP2D6 and CYP2C19 were genotyped by the AmpliChip™ CYP450 Test (Roche Molecular Diagnostics, Branchburg, NJ, USA) for 57 patients, who were matched as recurrent versus non-recurrent breast cancers (n = 33 versus n = 24, respectively, with a 5-year follow-up). RESULTS:Based on the genotype data, five CYP2D6 predicted phenotype groups were identified in this study including homozygous extensive metabolizer (13 of 57, 22.80%), extensive/intermediate metabolizer (23 of 57, 40.40%), extensive/poor metabolizer (3 of 57, 5.30%), homozygous intermediate metabolizer (14 of 57, 24.50%), and intermediate/poor metabolizer (4 of 57, 7.00%), and three CYP2C19 genotype groups including homozygous extensive metabolizer (27 of 57, 47.40%), extensive/intermediate metabolizer (27 of 57, 47.40%), and homozygous poor metabolizer (3 of 57, 5.30%). The CYP2D6 variant alleles were *10 (52 of 114, 45.60%), *5 (5 of 114, 4.40%), *41 (2 of 114, 1.80%), *4 (1 of 114, 0.90%), and *36 (1 of 114, 0.90%); the CYP2C19 variant alleles were *2 (27 of 114, 23.70%) and *3 (6 of 114, 5.30%). Kaplan-Meier estimates showed significantly shorter disease-free survival in patients with homozygous TT when compared to those with heterozygous CT or homozygous CC at nucleotides 100C>T and 1039C>T (CYP2D6*10) post-menopausal (log-rank test; P = 0.046). They also had increased risk of recurrence, but no statistically significant association was observed (hazard ratio 3.48; 95% confidence interval 0.86-14.07; P = 0.080). CONCLUSION:The CYP2D6 and CYP2C19 polymorphisms were not involved in tamoxifen efficacy. However, in the subgroup of post-menopausal women, the polymorphisms in CYP2D6 and CYP2C19 might be useful in predicting tamoxifen efficacy and clinical outcomes in breast cancer patients receiving adjuvant tamoxifen treatment. As the number of breast cancer patients was relatively small in this study, results should be confirmed in a larger group of prospective patients.

Project description:AimThe aim was to examine the influence of CYP2C19 variants and associated haplotypes on the disposition of tamoxifen and its metabolites, particularly norendoxifen (NorEND), in Asian patients with breast cancer.MethodsSixty-six CYP2C19 polymorphisms were identified in healthy Asians (n = 240), of which 14 were found to be tightly linked with CYP2C19*2, CYP2C19*3 and CYP2C19*17. These 17 SNPs were further genotyped in Asian breast cancer patients receiving tamoxifen (n = 201). Steady-state concentrations of tamoxifen and its metabolites were quantified using liquid chromatography–mass spectrometry. Non-parametric tests and regression methods were implemented to evaluate genotypic–phenotypic associations and haplotypic effects of the SNPs.ResultsCYP2C19 functional polymorphisms and their linked SNPs were not significantly associated with plasma concentrations of tamoxifen and its main metabolites N-desmethyltamoxifen, (Z)-4-hydroxytamoxifen and (Z)-Endoxifen. However, CYP2C19*2 and its seven linked SNPs were significantly associated with lower NorEND concentrations, MRNorEND/NDDM and MRNorEND/(Z)-END. Specifically, patients carrying the CYP2C19*2 variant allele A had significantly lower NorEND concentrations [median (range), GG vs. GA vs. AA: 1.51 (0.38–3.28) vs. 1.28 (0.30–3.36) vs. 1.15 ng ml−1 (0.26–2.45, P = 0.010)] as well as significantly lower MRNorEND/(Z)-END [GG vs. GA vs. AA: 9.40 (3.27–28.35) vs. 8.15 (2.67–18.9) vs. 6.06 (4.47–14.6), P < 0.0001] and MRNorEND/NDDM [GG vs. GA vs. AA: 2.75 (0.62–6.26) vs. 2.43 (0.96–4.18) vs. 1.75 (1.10–2.49), P < 0.00001]. CYP2C19 H2 haplotype, which included CYP2C19*2, was also significantly associated with lower NorEND concentrations (P = 0.0020), MRNorEND/NDDM (P < 0.0001) and MRNorEND/(Z)-END (P < 0.0001), indicating significantly lower formation rates of NorEND.ConclusionThese data highlight the potential relevance of CYP2C19 pharmacogenetics in influencing NorEND concentrations in tamoxifen-treated patients, which may influence treatment outcomes.

Project description:ObjectiveTo investigate the potential association among preoperative breast MRI features, axillary nodal burden (ANB), and disease-free survival (DFS) in patients with early-stage breast cancer.Materials and methodsWe retrospectively reviewed 297 patients with early-stage breast cancer (cT1-2N0M0) who underwent preoperative MRI between December 2016 and December 2018. Based on the number of positive axillary lymph nodes (LNs) determined by postoperative pathology, the patients were divided into high nodal burden (HNB; ≥3 positive LNs) and non-HNB (<3 positive LNs) groups. Univariable and multivariable logistic regression analyses were performed to identify independent risk factors associated with ANB. Predictive efficacy was evaluated using the receiver operating characteristic (ROC) curve and area under the curve (AUC). Univariable and multivariable Cox proportional hazards regression analyses were performed to determine preoperative features associated with DFS.ResultsWe included 47 and 250 patients in the HNB and non-HNB groups, respectively. Multivariable logistic regression analysis revealed that multifocality/multicentricity (adjusted odds ratio [OR] = 3.905, 95% confidence interval [CI]: 1.685-9.051, P = 0.001) and peritumoral edema (adjusted OR = 3.734, 95% CI: 1.644-8.479, P = 0.002) were independent risk factors for HNB. Combined peritumoral edema and multifocality/multicentricity achieved an AUC of 0.760 (95% CI: 0.707-0.807) for predicting HNB, with a sensitivity and specificity of 83.0% and 63.2%, respectively. During the median follow-up period of 45 months (range, 5-61 months), 26 cases (8.75%) of breast cancer recurrence were observed. Multivariable Cox proportional hazards regression analysis indicated that younger age (adjusted hazard ratio [HR] = 3.166, 95% CI: 1.200-8.352, P = 0.021), larger tumor size (adjusted HR = 4.370, 95% CI: 1.671-11.428, P = 0.002), and multifocality/multicentricity (adjusted HR = 5.059, 95% CI: 2.166-11.818, P < 0.001) were independently associated with DFS.ConclusionPreoperative breast MRI features may be associated with ANB and DFS in patients with early-stage breast cancer.

Dataset Information

SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen.

Publications

SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen.

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