Circulating neuregulin during the transition from stage A to stage B/C heart failure in a breast cancer cohort

Abstract

Background: Breast cancer (BC) treatments can cause heart failure (HF) in a subset of patients. ACC/AHA guidelines classify patients receiving cardiotoxic medications as stage A, a high-risk population for the development of HF. Circulating neuregulin (NRG) correlates with outcomes in stage C and D HF. We examined the levels of NRG in a BC cohort receiving cardiotoxic chemotherapy and its relationship with adverse cardiac effects during the transition from stage A to stage B or C HF.

Methods and results: In an ongoing prospective study, a planned interim analysis of 78 BC women receiving either anthracycline (AC) or trastuzumab (Tsz) was performed. Biometric data, cardiac risk factors, and NRG levels, were collected before chemotherapy and after completion of AC therapy and/or 3 months into Tsz therapy. Cardiac function was measured by left ventricular ejection fraction (LVEF) by echocardiography at the above time points and longitudinally as standard of care. The interim cohort was predominately white with stage II BC and a median age of 50 years. A reduction of >10 absolute percentage points in LVEF was observed in 21.4% of the cohort, representing a transition from stage A to stage B or C HF. A statistically significant drop in plasma NRG was observed in women treated with AC and/or Tsz (P < .001). Additionally, baseline NRG correlated with the maximal change in LVEF.

Conclusions: More than 20% of women experienced cardiac dysfunction, detected by decline in LVEF, and were reclassified as stage B or C HF. Plasma NRG levels were reduced after exposure to cardiotoxic chemotherapy, suggesting a loss in a cardioprotective growth factor. Higher baseline NRG levels were observed in those with the greatest decline in LVEF, supporting the continued investigation of NRG as a potential prognostic marker in early-stage HF.

Figure 1. Cardiac Risk Factors in Treated BC Patients

Women treated for breast cancer (BC) have significant cardiac risk factors. A personal history of hypertension was reported in 58%, 24% had hyperlipidemia (HL), 10% had diabetes (DM), 1% had coronary artery disease (CAD), 30% had former or ongoing tobacco use, 23% had a family history of heart failure (family Hx HF), 68% were overweight (BMI > 25), and 63% reported low levels of physical activity.

Figure 2. Change in Cardiac Function During Follow-up

Absolute maximum change in left ventricular ejection fraction (LVEF) from baseline in 70 individuals who were treated with either anthracycline chemotherapy or trastuzumab for breast cancer (BC). Seven patients had no change in LVEF from baseline and are represented without bars. Fifteen women (24.1%) experienced a reduction in LVEF of greater than 10 units during the follow-up period as defined by the dotted line.

Figure 3. Change in Plasma NRG Due to Chemotherapy

AC and/or Tsz therapy caused a statistically significant drop in circulating levels of plasma neuregulin (NRG), a cardiac growth factor (baseline NRG median 4.0 ng/ml, Post Chemo NRG median 2.9 ng/ml, n = 62, p = < 0.001).