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Clinical Trial
. 2021 Sep;88(3):533-542.
doi: 10.1007/s00280-021-04307-0. Epub 2021 Jun 10.

Cyclophosphamide bioactivation pharmacogenetics in breast cancer patients

Nuala Helsby  1 , Minghan Yong  2 , Kathryn Burns  2 , Michael Findlay  3   4 , David Porter  4
Affiliations
Clinical Trial

Cyclophosphamide bioactivation pharmacogenetics in breast cancer patients

Nuala Helsby et al. Cancer Chemother Pharmacol. 2021 Sep.

Abstract

Purpose: Genetic variation in the activation of the prodrug cyclophosphamide (CP) by cytochrome P450 (CYP) enzymes has been shown to influence outcomes. However, CYP are also subject to phenoconversion due to either the effects of comedications or cancer associated down-regulation of expression. The aim of this study was to assess the relationship between CP bioactivation with CYP2B6 and CYP2C19 genotype, as well as CYP2C19 phenotype, in breast cancer patients.

Methods: CP and the active metabolite levels were assessed in breast cancer patients (n = 34) at cycle 1 and cycle 3 of treatment. Patients were genotyped for a series of SNP known to affect CYP2B6 and CYP2C19 function. The activity of CYP2C19 was also assessed using a probe drug.

Results: We found a significant linear gene-dose relationship with CYP2B6 coding SNP and formation of 4-hydroxycyclophosphamide. A possible association with CYP2C19 null genotype at cycle 1 was obscured at cycle 3 due to the substantial intra-individual change in CP bioactivation on subsequent dosing.

Conclusion: Comedications may be the cause for this inter-occasion variation in bioactivation of cyclophosphamide and the ensuing phenoconversion may account for the conflicting reports in the literature about the relationship between CYP2C19 genotype and CP bioactivation pharmacokinetics. Trial registration ANZCTR363222 (6/11/2012, retrospectively registered).

Keywords: CYP2B6; CYP2C19; Cyclophosphamide; Pharmacogenetics.

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References

    1. Helsby NA, Yong M, van Kan M et al (2019) The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes. Br J Clin Pharmacol 85:1925–1934. https://doi.org/10.1111/bcp.14031 - DOI - PubMed - PMC
    1. Helsby NA, Hui C-Y, Goldthorpe MA et al (2010) The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation. Br J Clin Pharmacol 70:844–853. https://doi.org/10.1111/j.1365-2125.2010.03789.x - DOI - PubMed - PMC
    1. Kishino Y, Hasegawa T, Kato A et al (2019) Effect of inter-individual variability in human liver cytochrome P450 isozymes on cyclophosphamide-induced micronucleus formation. Mutat Res Toxicol Environ Mutagen 838:37–45. https://doi.org/10.1016/j.mrgentox.2018.11.016 - DOI
    1. Helsby NA, Burns KE (2012) Molecular mechanisms of genetic variation and transcriptional regulation of CYP2C19. Front Genet. https://doi.org/10.3389/fgene.2012.00206 - DOI - PubMed - PMC
    1. Zanger UM, Klein K (2013) Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. https://doi.org/10.3389/fgene.2013.00024 - DOI - PubMed - PMC

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