Long-term impact of anthracycline in early-stage breast cancer, bridging of MiRNAs profiler for early cardiotoxicity

Abstract

Background: Anthracyclines are essential in early breast cancer chemotherapy but pose long-term cardiotoxicity risks.

Objectives: This study aims to investigate the long-term incidence of cancer therapy-related cardiac dysfunction (CTRCD), bridging with the miRNAs profiler representing acute cardiac injury.

Methods: We conducted a prospective cohort including stage I-III breast cancer patients who received anthracycline between 2007 and 2012. Echocardiography was performed before and 12 weeks after anthracycline administration. The miRNAs profiler was conducted by NanoString and RT-PCR. Long-term cardiac magnetic resonance imaging (CMR) was evaluated in 24.2% of asymptomatic participants.

Results: At a median follow-up of 11 [IQR 6-12] years, 194 patients who completed follow-up echocardiography after anthracycline were included in the analysis. The median age at diagnosis was 50 [26-72] years. An early LVEF decline of ≥ 10% was found in 32.9% of participants. The cumulative equivalent dose of doxorubicin was 223.2 ± 21.6 mg/m2. At the time of censoring, sixty-four participants (32.9%) died, 70% from breast cancer. Nine participants (4.6%) reported cardiovascular events compatible with the CTRCD definition. Forty-seven participants (24.2%) underwent long-term cardiac evaluation. The miRNAs profiler and RT-PCR at different time points, 3 weeks and 6 weeks, respectively, revealed significantly diverse expressions of miR-1-3p and miR-16-5p in participants with and without an early LVEF decline of ≥ 10%. Despite cardiac injury demonstrated by dynamic miR-1-3p and miR-16-5p, CMR parameters revealed no significant differences.

Conclusions: Our study demonstrates a very low incidence of long-term symptomatic CTRCD. The diverse expression patterns of miR-16-5p and miR-1-3p at different time points also provide valuable biological insights. Within-normal results of an exact and comprehensive CMR, in asymptomatic and any LVEF change participants, indicate the long-term safety of limited-dose anthracycline-containing use.

Keywords: Cancer therapy-related cardiac dysfunction; Cardiac MRI; Long-term cardiotoxicity; MicroRNAs.

Fig. 1

Consort diagram for prospective cohort and long-term evaluation

Fig. 2

Individual correlation between baseline, end-anthracycline, and long-term CMR LVEF between 16 cases and 31 controls (A). Cardiac magnetic resonance imaging with delayed gadolinium enhancement technique demonstrated two scar patterns. The basal short-axis (B) and 4-chamber view (C) showed mid-wall scar (red arrows) at basal inferoseptal and basal inferior segments of the LV. The middle short-axis (D) and 2-chamber view (E) revealed patchy scars (blue arrows) at mid-to-apical inferior segments of the LV. (LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle)

Fig. 3

Heatmap of significant five miRNAs expression and miR-1-3p by NanoString profiler in the discovery cohort (n = 18) at baseline and 3 weeks after anthracycline combination therapy (A). The validation cohort of selected miRNAs was conducted in 37 participants at baseline and 6 weeks after anthracycline combination therapy. The miR-16-5p (B) revealed significantly down-regulated with a mean log2 fold change of -0.77 (p-value 0.02) in the case group compared to the control group. While miR-1-3p was significantly up-regulated in the case compared to the control group with a mean log2 fold change of 2.48 (p-value 0.001) (C)