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Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2018 ASCO Annual Meeting but not presented at the Meeting, can be found online only.

UGT2B17 deletion polymorphism and exemestane-induced toxicity.

Sub-category:
Adjuvant Therapy

Category:
Breast Cancer—Local/Regional/Adjuvant

Meeting:
2018 ASCO Annual Meeting

Abstract No:
e12534

Citation:
J Clin Oncol 36, 2018 (suppl; abstr e12534)

Author(s): Elizabeth Packard, Cynthia Campbell-Baird, Kim Leitzel, Shaman Luo, Gang Chen, Junjia Zhu, Leah Cream, Philip Lazarus, Cristina I. Truica; Penn State College of Medicine, Hershey, PA; Penn State Hershey Medical Center, Hershey, PA; College of Pharmacy , Washington University, Spokane, WA; Penn State Health Milton S. Hershey Medical Center, Hershey, PA

Abstract Disclosures

Abstract:

Background: Genetic polymorphisms in drug metabolizing enzymes can have significant impact on drug toxicity and/or efficacy. Exemestane (Exe), a steroidal aromatase inhibitor, is extensively metabolized by reduction to a major active metabolite, 17β-dihydro-EXE (17β-DHE), and by glucuronidation to inactive 17β-DHE-glucuronide (17β-DHE-gluc). UGT2B17 is the major enzyme responsible for glucuronidation of 17β-DHE. A polymorphic whole-gene deletion of the UGT2B17 gene has an allelic prevalence of 30% in Caucasians and leads to higher plasma levels of the active metabolite 17β-DHE. We hypothesized that UGT2B17 genotype could play a role in the variability of Exe-induced toxicity.Methods: Postmenopausal patients received 25 mg Exe daily for 30 days for treatment of early stage breast cancer or chemoprevention. Blood, urine collection and symptom assessment ( arthralgias, hot flashes) were obtained at baseline and after 30 days of treatment. Hot flashes and joint pain status at 1 month was correlated with UGT2B17 genotype. Presence of symptoms was dichotomized as any (mild/moderate/severe) vs none. Statistical analyses used Fisher’s exact test for categorical variables and nonparametric Wilcoxon Rank Sum test for quantitative variables. Results: 46% of the 130 Exe-treated patients were heterozygous for the UGT2B17 deletion (*1/*2 genotype) while 17% were UGT2B17 null (*2/*2 genotype), with a UGT2B17 deletion allelic frequency of 40%. Patients who were UGT2B17 null (*2*2) exhibited a 39-fold (p < 0.0001) and 29-fold (p < 0.0001) decrease in the levels of creatinine-adjusted urinary and plasma levels of 17β-DHE-gluc, respectively. Plasma levels of Exe–adjusted 17β-DHE were 28% higher (p = 0.004) in these patients. At 1 month post-Exe treatment, no association between UGT2B17 genotype and joint pain status or hot flashes was observed between patients with the UGT2B17 (*2/*2) genotype vs patients exhibiting the wild-type UGT2B17 (*1/*1) genotype (p = 0.062 for joint pains and p = 0.812 for hot flashes). We are currently exploring the role of genetic variants in other metabolic pathways that may be important in Exe metabolism. Conclusions: UGT2B17 genotype did not correlate with the severity of Exe-associated joint pains and hot flashes.

 
Other Abstracts in this Sub-Category:

 

1. TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score.

Meeting: 2018 ASCO Annual Meeting Abstract No: LBA1 First Author: Joseph A. Sparano
Category: Breast Cancer—Local/Regional/Adjuvant - Adjuvant Therapy

 

2. Adjuvant denosumab in early breast cancer: Disease-free survival analysis of 3,425 postmenopausal patients in the ABCSG-18 trial.

Meeting: 2018 ASCO Annual Meeting Abstract No: 500 First Author: Michael Gnant
Category: Breast Cancer—Local/Regional/Adjuvant - Adjuvant Therapy

 

3. Adjuvant denosumab in early breast cancer: First results from the international multicenter randomized phase III placebo controlled D-CARE study.

Meeting: 2018 ASCO Annual Meeting Abstract No: 501 First Author: Robert E. Coleman
Category: Breast Cancer—Local/Regional/Adjuvant - Adjuvant Therapy

 

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