High CYP2C19 phenotypic variability in gastrointestinal cancer patients

• Published in: Cancer chemotherapy and pharmacology Vol. 77; no. 1; pp. 195 - 204
• Main Authors: Burns, K. E., Lo, W.-Y., Findlay, M. P., Sharples, K., Laking, G., Helsby, N. A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2016; Springer Nature B.V
• Subjects: Aged; Cancer Research; Cytochrome P-450 CYP2C19 - genetics; Female; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - pathology; Genotype; Humans; Liver - enzymology; Male; Medicine; Medicine & Public Health; Middle Aged; Neoplasm Staging; Oncology; Original Article; Pharmacology/Toxicology; Phenotype; Drug metabolism; Genotype; Phenotype; CYP2C19; Gastrointestinal cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2923-4

Purpose CYP2C19 contributes to the metabolism of several chemotherapeutic agents. The CYP2C19 homozygous null function genotype strongly predicts activity phenotype in healthy populations. An additional acquired loss of function has been reported in up to one-third of cancer patients. It is not known whether this phenomenon also occurs in patients with earlier stage or in resected disease. Methods This study investigated whether acquired loss of CYP2C19 function was detectable in patients with stage III–IV or resected gastrointestinal cancer. CYP2C19 genotype was determined in 49 patients, and subjects were probed for CYP2C19 activity on three test occasions. Results An acquired loss of CYP2C19 activity was observed in 20 % of stage III–IV and 17 % of resected patients at the first test. Significant ( p  < 0.01) genotype–phenotype discordance was observed in both groups. There were no direct associations between this discordance and inflammatory markers, tumour burden or chemotherapeutic history. Notably, hepatic CYP2C19 function was not stable over time and phenotype conversion occurred in 23 patients over the period of testing. Conclusion Reliance on germ-line genotype to infer a poor metaboliser status could substantially underestimate the number of patients with deficient CYP2C19 function. This could compromise the interpretation of genotype-based clinical association studies.