Influence of CYP3A4 inhibition on the tamoxifen metabolic pathway and the implications for breast cancer recurrence in a pre-menopausal cohort Öffentlichkeit
West, Casey (Spring 2020)
Published
Abstract
Background: Tamoxifen has been the guideline, most effective treatment for pre-menopausal breast cancer patients with non-metastatic estrogen receptor positive (ER+) tumors because it reduces the risk for breast cancer recurrence by almost fifty percent. Phase 1 metabolic enzymes, like CYP3A4, play a key role in metabolizing tamoxifen because the metabolites can compete with estrogen more effectively than the parent compound, and at lower concentrations. CYP3A4 expression can be decreased in patients due to a gene variant or by taking inhibiting drugs. Little is known about CYP3A4 and how its decreased expression may impact pre-menopausal patients who are taking tamoxifen and may be taking CYP3A4 inhibiting drugs.
Methods: This study used a cohort of strictly pre-menopausal Danish breast cancer patients, diagnosed between 2002 and 2011, split into ER+/TAM+ and ER-/TAM- groups who had genotyped tumor samples.
Results: The hazard ratios estimated for having one or no functional alleles for CYP3A4 and for taking a CYP3A4 inhibiting drug did not show a strong association for either group, which is in concordance with previous observations. When the gene variant and drug data were combined, a hazard ratio of 2.63 (95% CI 1.33, 5.20) was obtained in the ER+/TAM+ group for having the CYP3A4 variant and ever taking an inhibiting drug through modelling and was cross checked using the common referent approach. This interaction was not seen in the ER-/TAM- group (HR=1.45; 95% CI 0.49,4.26) through modelling, but interaction on the additive scale was suggestive for both strata when using the common referent approach.
Conclusion: Overall, these results agree with the recommendation against genotype-guided prescribing of tamoxifen and while the interaction hazard ratio is large, the minor allele frequency for the CYP3A4 variant is 8% in European ancestry populations so it is unlikely many patients would have the variant allele and take an inhibiting drug.
Table of Contents
Introduction………………………………………………………………………………………...1
Methods…………………………………………………………………………………………….3
Results……………………………………………………………………………………………...6
Discussion………………………………………………………………………………………….8
References………………………………………………………………………………………...11
Tables……………………………………………………………………………………………..14
Table 1. ER/TAM strata descriptive frequencies and proportions for CYP3A4 variant,
inhibiting drug prescription, recurrence, and cofactors……………………14
Table 2. Associated hazard between CYP3A4 inhibition and breast cancer recurrence within
ER/TAM strata…………………………………………………….15
Table 3. Common referent approach to analyze interaction between CYP3A4 mutation and
drug inhibition compared to wildtype and no drug and within CYP3A4 variant strata…………………………………………………………………15
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