Thomas Helland1,2, Kari Britt Hagen2,3, Martha Eimstad Haugstøyl1,2, Jan Terje Kvaløy4,5, Siri Lunde6, Kirsten Lode5, Ragna Anne Lind2, Birgitta Haga Gripsrud7, Kristin Jonsdottir6,5, Jennifer Gjerde1,2, Ersilia Bifulco2,8, Steinar Hustad2,8, Janne Jonassen6, Turid Aas3, Tone Hoel Lende6,9, Ernst Asbjørn Lien1,2, Emiel Adrianus Maria Janssen4,10, Håvard Søiland2,6, Gunnar Mellgren11,12. 1. Hormone Laboratory, Haukeland University Hospital, 5020, Bergen, Norway. 2. Department of Clinical Science, University of Bergen, Bergen, Norway. 3. Department of Breast and Endocrine Surgery, Haukeland University Hospital, Bergen, Norway. 4. Department of Mathematics and Natural Science, University of Stavanger, Stavanger, Norway. 5. Department of Research, Stavanger University Hospital, Stavanger, Norway. 6. Department of Breast and Endocrine Surgery, Stavanger University Hospital, Stavanger, Norway. 7. Department of Caring and Ethics, Faculty of Health Sciences, University of Stavanger, Stavanger, Norway. 8. Core Facility for Metabolomics, University of Bergen, Bergen, Norway. 9. Department of Clinical Medicine, University of Bergen, Bergen, Norway. 10. Department of Pathology, Stavanger University Hospital, Stavanger, Norway. 11. Hormone Laboratory, Haukeland University Hospital, 5020, Bergen, Norway. gunnar.mellgren@uib.no. 12. Department of Clinical Science, University of Bergen, Bergen, Norway. gunnar.mellgren@uib.no.
Abstract
PURPOSE: Tamoxifen is an important targeted endocrine therapy in breast cancer. However, side effects and early discontinuation of tamoxifen remains a barrier for obtaining the improved outcome benefits of long-term tamoxifen treatment. Biomarkers predictive of tamoxifen side effects remain unidentified. The objective of this prospective population-based study was to investigate the value of tamoxifen metabolite concentrations as biomarkers for side effects. A second objective was to assess the validity of discontinuation rates obtained through pharmacy records with the use of tamoxifen drug monitoring. METHODS: Longitudinal serum samples, patient-reported outcome measures and pharmacy records from 220 breast cancer patients were obtained over a 6-year period. Serum concentrations of tamoxifen metabolites were measured by LC-MS/MS. Associations between metabolite concentrations and side effects were analyzed by logistic regression and cross table analyses. To determine the validity of pharmacy records we compared longitudinal tamoxifen concentrations to discontinuation rates obtained through the Norwegian Prescription database (NorPD). Multivariable Cox regression models were performed to identify predictors of discontinuation. RESULTS: At the 2nd year of follow-up, a significant association between vaginal dryness and high concentrations of tamoxifen, Z-4'-OHtam and tam-NoX was identified. NorPD showed a tamoxifen-discontinuation rate of 17.9% at 5 years and drug monitoring demonstrated similar rates. Nausea, vaginal dryness and chemotherapy-naive status were significant risk factors for tamoxifen discontinuation. CONCLUSIONS: This real-world data study suggests that measurements of tamoxifen metabolite concentrations may be predictive of vaginal dryness in breast cancer patients and verifies NorPD as a reliable source of adherence data.
PURPOSE:Tamoxifen is an important targeted endocrine therapy in breast cancer. However, side effects and early discontinuation of tamoxifen remains a barrier for obtaining the improved outcome benefits of long-term tamoxifen treatment. Biomarkers predictive of tamoxifen side effects remain unidentified. The objective of this prospective population-based study was to investigate the value of tamoxifen metabolite concentrations as biomarkers for side effects. A second objective was to assess the validity of discontinuation rates obtained through pharmacy records with the use of tamoxifen drug monitoring. METHODS: Longitudinal serum samples, patient-reported outcome measures and pharmacy records from 220 breast cancerpatients were obtained over a 6-year period. Serum concentrations of tamoxifen metabolites were measured by LC-MS/MS. Associations between metabolite concentrations and side effects were analyzed by logistic regression and cross table analyses. To determine the validity of pharmacy records we compared longitudinal tamoxifen concentrations to discontinuation rates obtained through the Norwegian Prescription database (NorPD). Multivariable Cox regression models were performed to identify predictors of discontinuation. RESULTS: At the 2nd year of follow-up, a significant association between vaginal dryness and high concentrations of tamoxifen, Z-4'-OHtam and tam-NoX was identified. NorPD showed a tamoxifen-discontinuation rate of 17.9% at 5 years and drug monitoring demonstrated similar rates. Nausea, vaginal dryness and chemotherapy-naive status were significant risk factors for tamoxifen discontinuation. CONCLUSIONS: This real-world data study suggests that measurements of tamoxifen metabolite concentrations may be predictive of vaginal dryness in breast cancerpatients and verifies NorPD as a reliable source of adherence data.
Entities:
Keywords:
Adherence; Discontinuation; Endocrine therapy; Metabolism; Side effects; Tamoxifen
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