Cyclophosphamide bioactivation pharmacogenetics in breast cancer patients

• Published in: Cancer chemotherapy and pharmacology Vol. 88; no. 3; pp. 533 - 542
• Main Authors: Helsby, Nuala, Yong, Minghan, Burns, Kathryn, Findlay, Michael, Porter, David
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2021; Springer Nature B.V
• Subjects: Adult; Aged; Antineoplastic Agents, Alkylating - administration & dosage; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Cancer Research; Cyclophosphamide; Cyclophosphamide - administration & dosage; Cyclophosphamide - analogs & derivatives; Cyclophosphamide - metabolism; Cyclophosphamide - pharmacokinetics; Cyclophosphamide - pharmacology; Cytochrome P-450 CYP2B6 - genetics; Cytochrome P-450 CYP2C19 - genetics; Cytochrome P450; Dosage; Dose-Response Relationship, Drug; Female; Genetic diversity; Genotype; Genotype & phenotype; Genotypes; Humans; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original Article; Patients; Pharmacogenetics; Pharmacokinetics; Pharmacology/Toxicology; Phenotypes; Polymorphism, Single Nucleotide; Single-nucleotide polymorphism; Young Adult; Pharmacogenetics; Cyclophosphamide; CYP2B6; CYP2C19
• ISSN: 0344-5704; 1432-0843; 1432-0843
• DOI: 10.1007/s00280-021-04307-0

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).