Association of UGT and CYP genotype-predicted activity with tyrosine kinase inhibitor toxicity.

Associations between genetically predicted activity of metabolic enzymes and risks of adverse events from tyrosine kinase inhibitors (TKIs) may inform dosing to optimize treatment outcomes in patients with cancer. The goal of this study is to investigate the associations between UGT1A1, CYP3A4, and CYP1A2 activity and toxicity from nilotinib and pazopanib treatment. A retrospective pharmacogenetic association study was conducted in 117 participants of the Michigan Genomics Initiative who received pazopanib ( n  = 103) or nilotinib ( n  = 14). Clinical information, including patients' disease, treatment, and toxicity was collected via retrospective review of medical records. No associations were found between the genetically predicted activity of any of the three enzymes and the composite endpoint of severe toxicity or treatment modifications because of toxicity. In the secondary hypothesis-generating analyses, patients with reduced UGT1A1 activity had an increased incidence of increased aspartate aminotransferase/alanine aminotransferase (44 vs. 25%; P  = 0.034) and hypertension (52 vs. 31%; P  = 0.024). In addition, patients with increased CYP1A2 activity from carrying CYP1A2*1F had a lower incidence of severe toxicity from pazopanib ( β -coefficient = -0.163, 95% confidence interval: -0.19 to -0.14, P  = 0.008). Future investigations are needed to confirm these associations and determine whether personalized TKI treatment can optimize therapeutic outcomes in patients with cancer.