The Impact of Polymorphisms in ATP-Binding Cassette Transporter Genes on Anthracycline-Induced Early Cardiotoxicity in Patients with Breast Cancer

Abstract

Background. Cardiac side effects associated with anthracycline-based treatment may seriously compromise the prognosis of patients with breast cancer (BC). Evidence shows that genes that operate in drug metabolism can influence the risk of anthracycline-induced cardiotoxicity (AIC). ATP-binding cassette (ABC) transporters could serve as one of the potential biomarkers for AIC risk stratification. We aimed to determine the link between single-nucleotide polymorphisms (SNPs) in several ABC genes (ABCB1 rs1045642, ABCC1 rs4148350, ABCC1 rs3743527) and cardiotoxicity. Methods. The study included 71 patients with BC, who were treated with doxorubicin-based chemotherapy. Two-dimensional echocardiography and speckle-tracking echocardiography were performed. AIC was defined as a new decrease of 10 percentage points in the left ventricular ejection fraction (LVEF). SNPs in ABCB1 and ABCC1 genes were evaluated using real-time PCR. Results. After a cumulative dose of 236.70 mg/m2 of doxorubicin, 28.2% patients met the criteria of AIC. Patients who developed AIC had a larger impairment in left ventricular systolic function compared to those who did not develop AIC (LVEF: 50.20 ± 2.38% vs. 55.41 ± 1.13%, p < 0.001; global longitudinal strain: −17.03 ± 0.52% vs. −18.40 ± 0.88%, p < 0.001). The ABCC1 rs4148350 TG genotype was associated with higher rates of cardiotoxicity (TG vs. GG OR = 8.000, 95% CI = 1.405–45.547, p = 0.019). Conclusions. The study showed that ABCC1 rs4148350 is associated with AIC and could be a potential biomarker to assess the risk of treatment side effects in patients with BC.

Association between genetic variants of transmembrane transporters and susceptibility to anthracycline‐induced cardiotoxicity: Current understanding and existing evidence

“…36,37,40 Besides these ABCC1 variants, the intronic variant rs4148350 was found to be protective for AIC in both, an exploratory and an independent replication cohort. 32,33 Moreover, this association was corroborated by findings from a more recent study that also found decreased risk of AIC in breast cancer patients carrying the variant T allele, 28 while other studies did not confirm the significant impact of the variant allele. 26,37 In conclusion, there is some evidence for a functional significance and also clinical impact of ABCC2 variants such as the rs246221.However, several other studies failed to find significant effects, or gave contradictory results.…”

“…27 Also, in a small study of 71 breast cancer patients, the results of univariate and multivariate logistic regression analyses showed the potential cardioprotective effect of the rs1045642 heterozygous genotype, but it did not reach statistical significance. 28 However, this variant failed to demonstrate any clinical association in non-Hodgkin's lymphoma and diffuse large B-cell lymphoma. 18,29 In the absence of concordance between studies, the findings need to be interpreted with care.…”

“…The authors found that the patients with TT genotype had significantly decreased LVFS compared to the CT genotype, and the rs3743527 variant T allele was associated with increased cardiotoxicity. 36 However again, this association was countered by findings from a study in patients with acute lymphoblastic leukaemia, where the rs3743527 was found to provide a statistically significant protective effect against AIC, 28 thus aligning with the experimentally determined increase in clearance of doxorubicin for the TT homozygosity. Moreover, other studies did not observe significant effects.…”

Precision Cardio-oncology: Update on Omics-Based Diagnostic Methods

“…For example, SNPs (rs1114049) of solute carrier family 28 member 3 have been found to be protective against DIC in hiPSC-CMs [31], and an SNP (rs2229774) in retinoic acid receptor γ (RARG ) is associated with an increased risk of AIC [32]. There is also a link between SNPs and DIC in ATP-binding cassette (ABC) transporters [33]. Transient receptor potential 6 (TRPC6) gene alterations are putative risks for chemotherapy-induced congestive heart failure, and TRPC6 N338S is a gain-of-function mutant that may lead to DIC by increasing Ca 2+ influx within cardiomyocytes [34•].…”