Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients

Abstract

1. This study investigates the impact of single nucleotide polymorphisms in genes (SLC22A16 and CBR1) involved in the pharmacokinetics and toxicity of doxorubicin (DOX) in Egyptian female patients with breast cancer.

2. Patients administered DOX (60 mg/m²) for 4 cycles every 3 weeks. The peak DOX plasma concentration was measured using a validated chromatographic method. The genotyping for the selected SNPs, SLC22A16 T > C (rs714368), and CBR1 C > T (rs20572), was performed by RT-PCR. Patients were monitored for hematological and cardiac toxicities.

3. The variant carriers of CBR1 C > T (rs20572) exhibited significantly higher DOX concentration, but no significant association to DOX-induced hematological toxicity. On the other hand, SLC22A16 T > C (rs714368) had no significant influence on DOX plasma concentration, but was significantly correlated with lower risk of neutropenia (OR 0.31, 95% CI 0.12–0.75, p = 0.01) and leukopoenia (OR 0.18, 95% CI 0.07–0.5, p = 0.001). DOX-related cardiotoxicity was correlated with the cumulative dose of DOX (R = 0.238, p = 0.017), but not with any of the two examined SNPs.

4. Genetic polymorphisms in SLC22A16 and CBR1 may explain the inter-individual variations in DOX pharmacokinetics and toxicity. Using pharmacogenetic testing is important to customise drug therapy for cancer patients treated with anthracyclines.

Keywords:

• Doxorubicin
• pharmacokinetics
• SLC22A16
• CBR1
• breast cancer
• SNPs
• toxicity

Acknowledgements

The nursing staff with excellent technical assistance is gratefully acknowledged. This work was supported at the Clinical Oncology and Nuclear Medicine Department, Menoufia University, Egypt.

Author contributions

All authors have: Made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; Been involved in drafting the manuscript or revising it critically for important intellectual content; Given final approval of the version to be published; participated sufficiently in the work to take public responsibility for appropriate portions of the content; and Agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethical approval

The study was performed according to the guidelines of Declaration of Helsinki and approved by the Ethical Committee of Menoufia University, Egypt. Written informed consent was obtained from all patients in this study or from their relatives if they are not capable of giving consent.

Disclosure statement

All authors declare no financial or non-financial conflict of interest, and confirm that the study was approved by the appropriate ethics committee for research involving humans.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

The authors received no funding for this study. The research did not receive any specific grant from funding agencies in the public. Commercial or not-for-profit sectors.