Cytochrome P450 (CYP) 2A6 Genetic Variation Predicts Letrozole Plasma Concentrations in Postmenopausal Women with Breast Cancer.
Bibliographic record
Abstract
Abstract Background: The potent aromatase inhibitor (AI) letrozole is effective in the treatment of postmenopausal women with steroid-hormone-receptor–positive breast cancer (metastatic, neoadjuvant and adjuvant). The beneficial and adverse effects of letrozole vary widely among patients, and differences in pharmacokinetics may contribute to this variability. Letrozole is primarily cleared by hepatic metabolism. Since CYP2A6 has been implicated in letrozole metabolism in vitro, we tested the influence CYP2A6 genetic variants on plasma concentrations of letrozole in breast cancer patients. Methods: Postmenopausal women with early stage hormone receptor-positive breast cancer were recruited into an ongoing multicenter randomized clinical trial to study the pharmacogenomics of two AIs, exemestane (25 mg/day) and letrozole (2.5 mg/day) given orally. Total accrual to the trial is anticipated to be 250 in each arm. Three months plasma letrozole concentrations were measured by HPLC from 146 patients who were randomized to the letrozole arm and multiple CYP2A6 variants were genotyped from genomic DNA. Results: Plasma concentrations of letrozole showed wide variability among patients (16.6 ng/ml to 141.2 ng/ml; 8.5-fold difference). Genotypes were grouped based in to normal (*1/*1), intermediate (*1/*9 and *1/*12, n=23) and slow (*9/*12, *1/*2, *2/*9, *1/*35, *1/*4E; n=12) metabolizers based on genotyped predicted phenotype. A statistically significant difference in letrozole concentrations was observed among the patients with the different genotype groups (p<0.0001; one-way ANOVA), with strong gene-dose effect relationship (r2=0.28; p<0.0001). Letrozole plasma concentrations were significantly higher in patients with the slow or intermediate genotypes than those with normal genotype (p < 0.0001; Dunn's post-test for multiple comparison correction).Conclusions: Polymorphisms in the CYP2A6 gene account for ∼28% of variability in letrozole concentrations in breast cancer patients. Prior genotyping for CYP2A6 variants may help to identify patients who benefit from letrozole and who experience adverse effects from the drug. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5160.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".