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Metabolic Pathway Analysis and Effectiveness of Tamoxifen in Danish Breast Cancer Patients
- Source :
- 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
- Publication Year :
- 2020
-
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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- 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
- Accession number :
- edsair.doi.dedup.....1801d69fb5cd7b94c2ec62c58bf25321