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High CYP2C19 phenotypic variability in gastrointestinal cancer patients
K E Burns1, W-Y Lo2, M P Findlay3,4
1Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand. k.burns@auckland.ac.nz.
Cancer Chemotherapy and Pharmacology
|November 29, 2015
Summary
Acquired loss of CYP2C19 function occurs in gastrointestinal cancer patients, impacting drug metabolism. Relying solely on genetic profiles may underestimate patients needing altered chemotherapy, potentially affecting treatment efficacy.
Area of Science:
- Pharmacogenomics
- Oncology
- Drug Metabolism
Background:
- Cytochrome P450 2C19 (CYP2C19) is crucial for metabolizing chemotherapeutics.
- Germline CYP2C19 genotype predicts activity in healthy individuals.
- Acquired CYP2C19 loss of function is known in some cancer patients.
Purpose of the Study:
- To determine if acquired CYP2C19 function loss occurs in advanced or resected gastrointestinal cancers.
- To assess genotype-phenotype discordance in these patient populations.
Main Methods:
- Investigated acquired CYP2C19 function loss in 49 patients with stage III-IV or resected gastrointestinal cancer.
- Determined CYP2C19 genotype and probed activity on three separate occasions.
Main Results:
- Acquired CYP2C19 activity loss detected in 20% of stage III-IV and 17% of resected patients.
- Significant genotype-phenotype discordance observed, unrelated to inflammation, tumor burden, or prior chemotherapy.
- Hepatic CYP2C19 function varied over time, with phenotype conversion in 23 patients.
Conclusions:
- Germline CYP2C19 genotype alone may underestimate poor metabolizer status in cancer patients.
- This underestimation could compromise genotype-guided clinical studies and treatment decisions.
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