The influence of CYP3A5, CYP2D6, CYP2C19 and ABCB1 gene polymorphisms on the levels of minimum steady-state concentration of doxorubicin and troponin I in patients with breast cancer: an observational cross-sectional study

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Abstract

Background. Chemotherapeutic drugs have a wide range of side effects, in particular, a characteristic side effect of doxorubicin is the occurrence of cardiotoxicity, including asymptomatic. In our study, we determined the relationship between polymorphisms of genes encoding proteins involved in doxorubicin metabolism, minimum steady-state concentration of doxorubicin, and troponin I levels, a laboratory marker of myocardial damage, in patients with breast cancer (BC).

Objective. Determination of the effect of CYP3A5, CYP2D6, CYP2C19, and ABCB1 gene polymorphisms on minimum steady-state concentration of doxorubicin and troponin I levels in BC patients.

Methods. The study included 69 patients with a confirmed diagnosis of BC, hospitalized for the third or fourth course of chemotherapy in the AC regimen (doxorubicin and cyclophosphamide). Blood was collected to determine the minimum steady-state concentration of doxorubicin, troponin I levels, and to perform genotyping.

Results. The median plasma doxorubicin concentration was 132.4 ng/ml (95% CI: 126.118–144.029). An increase in troponin I levels above the reference value was observed in 11 patients, while in 10 of them the doxorubicin concentration was higher than the median value (OR=5.76, 95% CI: 1.36–24.4; p=0.018]. To determine the statistically significant relationship between the concentration of doxorubicin and the level of troponin I, the AUC was calculated (0.757, 95% CI: 0.639–0.852). A statistically higher concentration of doxorubicin was observed in carriers of the 1236TT, 3435TT and 2677TT genotypes.

Conclusion. Carriage of the 1236TT, 3435TT and 267TT genotypes may be associated with an increased risk of developing acute anthracycline cardiotoxicity and an increase in the troponin I level due to the effect on the plasma concentration doxorubicin.

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About the authors

A. A. Bagdasaryan

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: bagdasaryan_a_a@staff.sechenov.ru
ORCID iD: 0000-0003-3994-8766

Assistant Professor, Department of Clinical Pharmacology and Propaedeutics of Internal Medicine

Russian Federation, Moscow

E. V. Shikh

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: bagdasaryan_a_a@staff.sechenov.ru
ORCID iD: 0000-0001-6589-7654
Russian Federation, Moscow

V. N. Drozdov

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: bagdasaryan_a_a@staff.sechenov.ru
ORCID iD: 0000-0002-0535-2916
Russian Federation, Moscow

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Supplementary files

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2. Fig. 1. Study design

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3. Fig. 2. Plasma doxorubicin concentration values ​​in patients who participated in the study

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4. Fig. 3. The result of determining the level of troponin I in the blood plasma of patients who took part in the study

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5. Fig. 4. Calculation of AUC for the occurrence of an increase in troponin I levels in patients due to doxorubicin administration

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