Adrienne E Borrie1,2, Rhiannon V Rose3, Yun-Hee Choi3, Francisco E Perera4, Nancy Read4, Tracy Sexton4, Michael Lock4, Theodore A Vandenberg4, Karin Hahn4, Robert Dinniwell4, Jawaid Younus4, Diane Logan4, Kylea Potvin4, Brian Yaremko4, Edward Yu4, John Lenehan4, Stephen Welch4, Rachel F Tyndale5,6, Wendy A Teft1,2, Richard B Kim7,8,9. 1. Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada. 2. Department of Physiology and Pharmacology, Western University, London, ON, Canada. 3. Department of Epidemiology and Biostatistics, Western University, London, ON, Canada. 4. Department of Oncology, Western University, London, ON, Canada. 5. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, ON, Canada. 6. Department of Psychiatry, and Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. 7. Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada. richard.kim@lhsc.on.ca. 8. Department of Physiology and Pharmacology, Western University, London, ON, Canada. richard.kim@lhsc.on.ca. 9. LHSC - University Hospital, Western University, Room B9-116, 339 Windermere Road, London, ON, N6A 5A5, Canada. richard.kim@lhsc.on.ca.
Abstract
PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. METHODS: We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CONCLUSIONS: CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.
PURPOSE: The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. METHODS: We enrolled 126 female breast cancerpatients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. RESULTS: More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CONCLUSIONS:CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.
Entities:
Keywords:
Arthralgia; Breast cancer; CYP2A6; Letrozole; Pharmacogenomics
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