Dataset Information

Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer.

ABSTRACT: Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrine-sensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretreatment and during anastrozole plasma concentrations of estrone (E1), estradiol (E2), estrone conjugates, androstenedione, and testosterone were determined and correlated with plasma concentrations of anastrozole and anastrozole metabolites. There were large interindividual variations in plasma anastrozole and anastrozole metabolite concentrations, as well as pretreatment and postdrug plasma E1, E2, and E1 conjugate and estrogen precursor (androstenedione and testosterone) concentrations. E1 and E2 concentrations were below the lower limit of quantitation (LLQ) in most patients after anastrozole therapy (83% for both), but those with detectable concentrations had a broad range (1.58-45.2 and 0.635-97.0 pg/mL, respectively). E1 conjugates after anastrozole therapy were above the LLQ in most patients (93%), with wide interpatient variability (3.50-2,990 pg/mL). Two patients seemed to extensively metabolize anastrozole and failed to display substantial decreases in estrogens. Acknowledging the potential factor of variable compliance, our results showed large interindividual variation in anastrozole metabolism and its effect on circulating estrogens in postmenopausal patients. These findings may have implications with regard to efficacy and adverse events and may indicate the need to "individualize" therapy with this drug.

SUBMITTER: Ingle JN

PROVIDER: S-EPMC2855746 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer.

Ingle James N JN Buzdar Aman U AU Schaid Daniel J DJ Goetz Matthew P MP Batzler Anthony A Robson Mark E ME Northfelt Donald W DW Olson Janet E JE Perez Edith A EA Desta Zeruesenay Z Weintraub Randy A RA Williard Clark V CV Flockhart David A DA Weinshilboum Richard M RM

Cancer research 20100330 8

Aromatase inhibitors play a prominent role in the management of postmenopausal women with endocrine-sensitive breast cancer, but there is large variability in both efficacy and tolerability. The purpose of our study was to define interindividual variation in anastrozole metabolism and pharmacodynamics among patients treated with the approved daily dose of 1 mg in a standard practice setting as adjuvant therapy for resected early breast cancer. This study was performed in 191 women in whom pretre ...[more]

PMID: 20354183

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Project description:PurposeAromatase inhibitors (AIs) prolong survival for postmenopausal women with hormone receptor-positive breast cancer (HR + BC) but also burden patients with symptoms, a major reason for suboptimal AI adherence. This study characterizes inter-relationships among symptom measures; describes neuropsychological symptom burden trajectories; and identifies trajectory group membership predictors for postmenopausal women prescribed anastrozole for HR + BC.MethodsThis study utilized prospectively collected data from a cohort study. Relationships among various self-reported symptom measures were examined followed by a factor analysis to reduce data redundancy before trajectory analysis. Four neuropsychological scales/subscales were rescaled (range 0-100) and averaged into a neuropsychological symptom burden (NSB) score, where higher scores indicated greater symptom burden. Group-based trajectory modeling characterized NSB trajectories. Trajectory group membership predictors were identified using multinomial logistic regression.ResultsWomen (N = 360) averaged 61 years old, were mostly White, and diagnosed with stage I HR + BC. Several measures were correlated temporally but four neuropsychological measures had strong correlations and dimensional loadings. These four measures, combined for the composite NSB, averaged (mean ± standard deviation) 17.4 ± 12.9, 18.0 ± 12.7, 19.5 ± 12.8, and 19.8 ± 13.0 at pre-anastrozole, 6, 12, and 18 months post-initiation, respectively. However, the analysis revealed five NSB trajectories-low-stable, low-increasing, moderate-stable, high-stable, and high-increasing. Younger age and baseline medication categories (pre-anastrozole), including anti-depressants, analgesics, anti-anxiety, and no calcium/vitamin D, predicted the higher NSB trajectories.ConclusionThis study found relationships among neuropsychological symptom measures and distinct trajectories of self-reported NSB with pre-anastrozole predictors. Identifying symptom trajectories and their predictors at pre-anastrozole may inform supportive care strategies via symptom management interventions to optimize adherence for women with HR + BC.

Project description:PurposeIn patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non-cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss.Patients and methodsWe designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease-free survival, incidence of contralateral new primary breast cancer, and safety.ResultsIn the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease-free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms.ConclusionThis first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor-positive breast cancer.

Dataset Information

Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer.

Publications

Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer.

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