Pharmacogenetics of therapy effectiveness for anthracycline-induced cardiotoxicity
Authors: Kopeva K , Shilov S N , Grakova E V , Berezikova E N , Popova A A , Neupokoeva M N , Ratushniak E T , Teplyakov A T 
Published: October 2021

Abstract

Objective
To evaluate role of genetic factors (polymorphisms of ADRB1 gene (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) for effectiveness assessment of β-blocker (carvedilol) and angiotensin-converting enzyme inhibitor (enalapril) therapy in women with anthracycline- induced cardiotoxicity during 12-month follow-up period.

Methods
A total of 82 women, median age of 45.0 (42.0; 50.0) years with anthracycline-induced cardiotoxicity and without prior cardiovascular diseases were enrolled in the study. All patients received chemotherapy for the treatment of breast cancer included a combination of doxorubicin and cyclophosphamide, or combination of doxorubicin, cyclophosphamide and docetaxel. The cumulative dose of doxorubicin was 300–360 mg/m2. Criteria for the development of cardiotoxicity were a decrease in the left ventricle ejection fraction (LVEF) at the 12 months after chemotherapy completion by &gt;10%, the development of heart failure (HF) with symptoms and clinical signs, and NT-proBNP levels ≥125 pg/mL. Echocardiography and serum levels of NT-proBNP were performed at baseline and at 12 months after enrollment. Average up-titrated dosage of carvedilol was 50 (25; 50) mg per day and enalapril was 10 (10; 20) mg per day. Evaluation of gene polymorphisms of ADRB1 gene and ACE gene were carried out by polymerase chain reaction at baseline before treatment initiation.

Results
The baseline LVEF, end-systolic and end-diastolic dimension indexes, NT-proBNP levels, 6-minute walk test distance did not differ among patients with different genotypes of ADRB1 and ACE genes. However, carriers of T/T genotype of ADRB1 gene had a significant increasing in LVEF (&lt;0.001) by 11% from 50.0 (48.0; 51.0) to 56.0 (53.0; 57.0)% and decreasing in end-systolic dimension index (p&lt;0.001) by 27.7% and end-systolic dimension index (p&lt;0.001) by 6% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.001) by 34.2% from 327.5 (260.1; 381.8) to 213.5 (195.3; 256.7) pg/mL and 6-minute walk test distance increased (0.008) by 10%. Carriers of G/G genotype of ACE gene had the same benefits from this therapy: LVEF (&lt;0.001) increased by 6.5% from 50.5 (47.0; 51.0) to 54.0 (50.0; 57.0)%, end-systolic dimension index (p&lt;0.001) decreased by 5.3% and end-systolic dimension index (p&lt;0.001) by 3% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.005) by 20.3 from 314.1 (279.6; 372.9) to 249.9 (197.3; 267.8) pg/mL and 6-minute walk test distance increased (0.008) by 5%. Carriers of other genotypes had decreasing in LVEF, increasing in LV dimensions and NT-proBNP, and further progression of HF.

Conclusion
Our data suggest that evaluation of gene polymorphisms of ADRB1 (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) can be recommended before treatment initiation of anthracycline- induced cardiotoxicity in women without prior cardiovascular diseases to determine who will benefit of carvedilol and enalapril therapy.

Funding Acknowledgement
Type of funding sources: None.