Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Kim, Richard B.

Abstract

Aromatase inhibitors (AIs) are the most commonly used first-line endocrine treatment for postmenopausal women with estrogen receptor-positive breast cancer. Significant adverse drug reactions are associated with AIs, the most common being arthralgia. We hypothesized that a comprehensive assessment of pharmacogenetic and clinical variables that affect AI tolerability could improve AI selection and treatment for breast cancer patients. We recruited 196 patients diagnosed with breast cancer initiating AI therapy at the London Regional Cancer Program. Patients completed questionnaires regarding arthralgia symptoms and provided blood samples at baseline, 2 months and 6 months after AI initiation. Plasma letrozole drug concentration was measured by liquid chromatography tandem-mass spectrometry (LC-MS/MS). DNA was extracted and used for pharmacogenetic analysis. More than half of patients had increases in pain and stiffness in their hands, shoulders, and arms, hips and knees. A LC-MS/MS analysis demonstrated that plasma concentrations of letrozole were negatively associated with body mass index (P = 0.0003) and positively associated with age (P = 0.0430). 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. However, letrozole concentration level and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. Further pharmacogenetic investigations revealed that four SNPs within the estrogen synthesis and metabolism pathway, namely, CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs930799), were associated with the development of arthralgia. CYP19A1 (rs4775936) was also a significant predictor of discontinuation of drug. Finally, we found that a SNP within the vitamin D pathway CYP27B1 (rs4646536) was associated with an increase in pain in the hands, arms, and shoulders. Patients who had a vitamin D level of at least 50ng/ml were found to be four times less likely to develop AI arthralgia. Understanding the impact of genes and drug levels on AI-induced arthralgia will help clinicians better manage AI therapy. This work will facilitate personalized medicine for women with breast cancer and advance understanding of endocrine biology.

Available for download on Saturday, August 01, 2020

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