Evidence for association of SNPs in ABCB1 and CBR3, but not RAC2, NCF4, SLC28A3 or TOP2B, with chronic cardiotoxicity in a cohort of breast cancer patients treated with anthracyclines

Abstract

Aims: Validation of associations for SNPs in RAC2, NCF4 and SLC28A3, identification of a novel association with a TOP2B SNP and screening 23 SNPs putatively relevant to anthracycline-induced cardiotoxicity.

Patients & methods: A total of 166 breast cancer patients treated with doxorubicin underwent echocardiogram, including 19 cases with systolic dysfunction (ejection fraction <55%) and 147 controls. Four high priority SNPs were tested in the primary analysis, with appropriate statistical correction, and 23 additional SNPs were screened in an uncorrected secondary analysis.

Results: Previously reported associations for RAC2, NCF4 and SLC28A3 could not be validated and a novel association with TOP2B was not discovered in this cohort (all p > 0.05), likely due to inadequate power. Two SNPs were identified in the uncorrected secondary analysis including a protective SNP in ABCB1 (3435C>T, p = 0.049) and a risk allele in CBR3 (V244M, p = 0.012).

Conclusion: The associations reported in prior publications and those discovered in this secondary analysis require further replication in independent cohorts.

Keywords: ABCB1; CBR3; NCF4; RAC2; SLC28A3; TOP2B; anthracycline; cardiotoxicity; doxorubicin; pharmacogenetic; systolic dysfunction.

Figure 1.. Flowchart of patients from enrollment into the parent study to classification of cases and controls for this pharmacogenetic analysis.

Among the 293 patients enrolled on the clinical study, 166 underwent an echocardiogram, 19 of which were documented to have EF <55% (cases). Patients with normal echocardiograms (EF ≥55%; n = 147) were included as controls. CHF: Congestive heart failure; EF: Ejection fraction determined by transthoracic echocardiogram.

Figure 2.. Association of SNPs in ABCB1 and CBR3 with systolic dysfunction.

Two SNPs were significantly associated with systolic dysfunction (EF <55%) in the secondary pharmacogenetic screen of 23 candidate SNPs. The ABCB1 3435C>T variant (rs1045642, Figure 2A) was more common in controls than systolic dysfunction cases, providing an additive protective effect (odds ratio [OR] = 0.48; 95% CI: 0.23–1.00; p = 0.049). The CBR3 V244M (rs1056892, Figure 2B) SNP was found more often in cases than controls, with significantly increased risk in either an additive (OR = 2.50; 95% CI: 1.22–5.11; p = 0.012) or recessive (OR = 6.19; 95% CI: 1.94–19.76; p = 0.002) genetic model. Note: Numbers do not add up to 166 due to missing genotypes in some patients (ABCB1: 4; CBR3: 3). EF: Ejection fraction.