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High CYP2C19 phenotypic variability in gastrointestinal cancer patients

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Abstract

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.

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Acknowledgments

This study was funded by the Genesis Oncology Trust and the University of Auckland. We wish to thank the research nurses Georgia Wilson, Michelle Davidson and Karen Spells for their help with patient recruitment. This work has previously been reported as a poster at the AACR Annual Meeting 2014; April 5–9, 2014; San Diego, CA, USA [Cancer Res 74 (19 Supplement):5548].

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Authors and Affiliations

  1. Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    K. E. Burns, W.-Y. Lo & N. A. Helsby

  2. Discipline of Oncology, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    M. P. Findlay

  3. Cancer Trials New Zealand, University of Auckland, Auckland, New Zealand

    M. P. Findlay & K. Sharples

  4. Department of Preventive and Social Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand

    K. Sharples

  5. Auckland City Hospital, Private Bag 92024, Auckland, 1142, New Zealand

    G. Laking

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  1. K. E. Burns
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Correspondence to K. E. Burns.

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Burns, K.E., Lo, WY., Findlay, M.P. et al. High CYP2C19 phenotypic variability in gastrointestinal cancer patients. Cancer Chemother Pharmacol 77, 195–204 (2016). https://doi.org/10.1007/s00280-015-2923-4

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