Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients

Abstract

Background: Tamoxifen and its metabolites compete with estrogen to occupy the estrogen receptor. The conventional dose of adjuvant tamoxifen overwhelms estrogen in this competition, reducing breast cancer recurrence risk by nearly half. Phase I metabolism generates active tamoxifen metabolites, and phase II metabolism deactivates them. No earlier pharmacogenetic study has comprehensively evaluated the metabolism and transport pathways, and no earlier study has included a large population of premenopausal women. Methods: We completed a cohort study of 5,959 Danish nonmetastatic premenopausal breast cancer patients, in whom 938 recurrences occurred, and a case–control study of 541 recurrent cases in a cohort of Danish predominantly postmenopausal breast cancer patients, all followed for 10 years. We collected formalin-fixed paraffin-embedded tumor blocks and genotyped 32 variants in 15 genes involved in tamoxifen metabolism or transport. We estimated conventional associations for each variant and used prior information about the tamoxifen metabolic path to evaluate the importance of metabolic and transporter pathways. Results: No individual variant was notably associated with risk of recurrence in either study population. Both studies showed weak evidence of the importance of phase I metabolism in the clinical response to adjuvant tamoxifen therapy. Conclusions: Consistent with prior knowledge, our results support the role of phase I metabolic capacity in clinical response to tamoxifen. Nonetheless, no individual variant substantially explained the modest phase I effect on tamoxifen response. Impact: These results are consistent with guidelines recommending against genotype-guided prescribing of tamoxifen, and for the first time provide evidence supporting these guidelines in premenopausal women.

Single-nucleotide polymorphisms and the effectiveness of taxane-based chemotherapy in premenopausal breast cancer: a population-based cohort study in Denmark

“…Findings from this study merit further investigation. They will be used in future work using multiple pathway analysis [ 23 , 57 ] to capture the net effect of these SNPs. Also, future clinical trials are needed to elucidate whether genomic testing could guide dosing of taxane-based therapy to reduce inter-individual variability in effectiveness.…”

“…Procedures for collection of FFPE tumor blocks, preparation of the tumor tissue, and DNA extraction are described in detail elsewhere [ 23 ]. Based on a comprehensive review of the taxane pharmacogenetic literature and underlying biology, we identified 26 candidate SNPs.…”

“…A list of genotyped variants is presented in Table 2 . Seven of these SNPs had been genotyped previously, as described elsewhere [ 23 ]. The remaining 19 SNPs were genotyped using commercially available TaqMan assays on a StepOne Plus real-time instrument (Applied Biosystems, Thermo Fisher Scientific, Foster City, California, USA) in accordance with the manufacturer’s protocol.…”

Bayesian Pathway Analysis for Complex Interactions

“…Therefore, no result from the example data set has any evidential value on the topic of genetic modification of tamoxifen therapy effectiveness. Results from ALPS analysis of the real-world tamoxifen metabolic pathway data are reported in a separate publication (33).…”

Analysis of the complications of endocrine therapy with tamoxifen in breast cancer: clinical and pharmacogenetic aspects. Prospective pharmacogenetic cohort study

“…в 2020 г. [8]. Оно объединило результаты двух исследований: когортного исследования, включавшего 5959 пациенток в пременопаузе с неметастатическим РМЖ, из которых в 938 случаях возникли рецидивы, а также исследования «случай-контроль», включавшего 541 случай рецидива в когорте преимущественно пациенток с РМЖ в постменопаузе.…”