Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients
| Autor: | Trine Tramm, Stephen Hamilton-Dutoit, James W. Baurley, Kristina Lystlund Lauridsen, Per Damkier, Anders Kjærsgaard, Peer Christiansen, Lindsay J Collin, Kristina B. Christensen, Maret L. Maliniak, Rebecca A. Silliman, Deirdre Cronin-Fenton, Timothy L. Lash, Michael E. Zwick, Thomas P. Ahern, Bent Ejlertsen, R. Benjamin Isett, Rebecca Nash, Henrik Toft Sørensen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Oncology Adult medicine.medical_specialty Antineoplastic Agents Hormonal Genotyping Techniques Pharmacogenomic Variants Epidemiology medicine.drug_class Denmark Estrogen receptor Datasets as Topic Breast Neoplasms Article 03 medical and health sciences 0302 clinical medicine Breast cancer Internal medicine medicine Biomarkers Tumor Humans Breast Registries skin and connective tissue diseases Mastectomy business.industry Middle Aged medicine.disease Pharmacogenomic Testing Tamoxifen 030104 developmental biology Treatment Outcome Estrogen Chemotherapy Adjuvant 030220 oncology & carcinogenesis Case-Control Studies Cohort Population study Female Neoplasm Recurrence Local business Drug metabolism Metabolic Networks and Pathways medicine.drug Cohort study Follow-Up Studies |
| Zdroj: | Ahern, T P, Collin, L J, Baurley, J W, Kjærsgaard, A, Nash, R, Maliniak, M L, Damkier, P, Zwick, M E, Isett, R B, Christiansen, P M, Ejlertsen, B, Lauridsen, K L, Christensen, K, Silliman, R A, Toft Sørensen, H, Tramm, T, Hamilton-Dutoit, S, Lash, T L & Cronin-Fenton, D 2020, ' Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients ', Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, vol. 29, no. 3, pp. 582-590 . https://doi.org/10.1158/1055-9965.EPI-19-0833 Ahern, T P, Collin, L J, Baurley, J W, Kjærsgaard, A, Nash, R, Maliniak, M L, Damkier, P, Zwick, M E, Isett, R B, Christiansen, P M, Ejlertsen, B, Lauridsen, K L, Christensen, K B, Silliman, R A, Toft Sorensen, H, Tramm, T, Hamilton-Dutoit, S, Lash, T L & Cronin Fenton, D 2020, ' Metabolic pathway analysis and effectiveness of tamoxifen in Danish breast cancer patients ', Cancer Epidemiology, Biomarkers & Prevention, vol. 29, no. 3, pp. 582-590 . https://doi.org/10.1158/1055-9965.EPI-19-0833 Cancer Epidemiol Biomarkers Prev |
| DOI: | 10.1158/1055-9965.EPI-19-0833 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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