P4-01-04: Effects of CYP2D6 Phenotype and Drug Adherence on Tamoxifen Metabolite Levels.
Bibliographic record
Abstract
Abstract Background Although the activity of cytochrome P450 2D6 (CYP2D6), the enzyme responsible for conversion of tamoxifen (TAM) to its most important active metabolite endoxifen, varies significantly with genotype. Routine genotype testing in patients on TAM has recently been discouraged. Conflicting results in publications regarding the prognostic utility of this test remain unexplained. Confounding factors could be lack of predicted correlation between CYP2D6 genotype and TAM active metabolites, or variability of patient compliance Methods: Consecutive breast cancer patients on TAM were asked to enroll in a study to examine the relationship between CYP 2D6 phenotype, patient-reported treatment adherence, and TAM metabolites levels. Patients were genotyped for CYP2D6 polymorphisms using long-range PCR allele-specific amplification and single-nucleotide primer extension assay. From the genotypes, four phenotype groups were defined: Ultra rapid Metabolizer (UM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM) and Poor Metabolizer (PM). Plasma was collected after at least 6 weeks of TAM (20 mg daily). The parent drug TAM, as well as 4-hydroxy N-desmethyl tamoxifen (endoxifen), 4 hydroxy tamoxifen (4OHtam) and N-desmethyl-tamoxifen (NDtam), were determined by Liquid Chromatography tandem mass-spectrometry (LC-MS/MS). Patients also completed a questionnaire about ethinicity, side effects, concurrent medications and tamoxifen adherence. Correlation between metabolite/TAM ratio and phenotype was tested by Spearman correlation test. Relationship between metabolite levels and adherence was tested by Wilcoxon rank sum test. Chi square test was used to compare proportions. Results: Of the 100 patients enrolled there were 62 Caucasians, 25 Asians, 4 Africans and 6 Unknown. We found a strong correlation between ratio of endoxifen/TAM and phenotype (p <.0001) (Table 1) Over a 2 week period 68 never missed a TAM dose, 25 missed 1–2 times, 2 missed 3–5 times and 2 > 5times (2 missing data). In EM group we found significantly lower levels of TAM (p <.0001), NDtam (p=.008), 4OHtam (p=.003) in less adherent patients. A trend to decreased levels was also shown for endoxifen (p=.081). No associations were found between adherence or phenotype activity and side effects. Conclusions: Our data suggests the predicted association between endoxifen levels and genotype. However, non-adherence may have a significant confounding effect. Prospective studies to evaluate the prognostic impact of CYP2D6 variants for patients on adjuvant tamoxifen should be done but results could be confounded by variable drug adherence if this is not measured concurrently. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-04.
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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 | 0.001 | 0.003 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".