Dynamics of SERPINA3 in response to anthracycline treatment and cardiovascular dysfunction

Abstract

Background: SERPINA3 recently emerged as potential prognostic biomarker in heart failure. In a population of cancer survivors with cancer therapy-related cardiac dysfunction (CTRCD) circulating SERPINA3 was elevated compared to age-matched controls. We aimed to assess the longitudinal dynamics of circulating SERPINA3 levels in patients with cancer treated with anthracycline chemotherapy (AnC) and its relation to CTRCD.

Methods: In this single centre cohort study, 55 patients with cancer scheduled for AnC were prospectively enrolled. Cardiac evaluation (echocardiography, high-sensitive cardiac troponin I and NT-proBNP) was performed and SERPINA3 levels in plasma were assessed at 4 timepoints: before chemotherapy, directly after the end of chemotherapy, three months and twelve months after the end of chemotherapy.

Results: Forty-two out of 55 patients (76.4%) developed CTRCD within 1 year after end of treatment. CTRCD was mild in 32 and moderate in 10 patients, defined as a change in cardiac biomarkers or GLS and LVEF decline < 50% respectively. Overall, median SERPINA3 levels decreased from baseline to three months after AnC (215.7 [62.0-984.0] to 176.9 [94.7-678.0] µg/ml, p = 0.031). This decrease was most prominent in patients without CTRCD (30.8% decrease, p = 0.007), followed by mild CTRCD (9.0% decrease, p = 0.022), while patients with moderate CTRCD did not show a reduction in SERPINA3 (5.1% increase, p = 0.987). SERPINA3 values at three months after AnC were positively correlated with NT-proBNP (r = 0.47, p = 0.002). Several malignancy, treatment and patient characteristics were associated with higher SERPINA3 values.

Conclusion: Circulating SERPINA3 levels show dynamic changes in a population of patients with cancer, with an overall decrease following AnC. However, in patients that developed moderate CTRCD, SERPINA3 levels remained elevated. The potential of SERPINA3 dynamics as a biomarker for CTRCD, deserves validation in larger cohorts.

Keywords: Anthracycline; Biomarker; Breast cancer; Cancer therapy-related cardiac dysfunction (CTRCD); Cardiotoxicity; SERPINA3.

Fig. 1

Overview of patients with criteria for the diagnosis of CTRCD. Moderate CTRCD was defined as a decline in LVEF to 40–49%. Mild CTRCD was defined as a rise in biomarkers from baseline (hs-cTnI > 45 ng/l and/or NT-proBNP > 125 pg/ml) and/or a rise in GLS with more than 15% from baseline. CTRCD: Cancer therapy related cardiac dysfunction, LVEF: left ventricular ejection fraction, hs-cTnI: highly sensitive cardiac troponin I; GLS: global longitudinal strain; NT-proBNP: NT-pro brain natriuretic peptide. Created with Lucidchart

Fig. 2

Evolution of echocardiographic and circulating biomarkers during AnC and after chemotherapy. Figure A-D depict the combined results of the whole study population (n = 55). Figure E, F show the results according to CTRCD group. A A significant decline in LVEF over time is seen in up until 12 months after therapy B A significant rise in GLS is seen over time. C An early peak directly after AnC in hs-cTnI is followed by a decline at 12 months. D Three months after AnC, NT-proBNP is significantly higher in patients. E A significantly greater decline is present in patients with moderate CTRCD compared to mild and no CTRCD. F GLS increases in all CTRCD groups without returning to baseline values. G An early peak in hs-cTnI directly after AnC is followed by a subsequent decline at 12 months and is higher in mild and moderate CTRCD. F Three months after AnC, NT-proBNP is significantly higher in patients with moderate CTRCD compared to no CTRCD. For hs-cTnI and NT-proBNP statistics was performed on logarithmic transformations. CTRCD: Cancer therapy related cardiac dysfunction, LVEF: left ventricular ejection fraction, hs-cTnI: highly sensitive cardiac troponin I; GLS: global longitudinal strain; NT-proBNP: NT-pro brain natriuretic peptide. #p < 0.060, *p < 0.050,**p < 0.010,***p < 0.001

Fig. 3

Evolution of SERPINA3 during and after AnC. A Evolution of SERPINA3 in the total cohort. SERPINA3 show a dynamic change over time, with return to baseline levels after 12 months. B Evolution of SERPINA3 according to CTRCD group. A significant decrease is observed (V1-V3) in patients without and with mild CTRCD, while levels remained unaltered in the moderate CTRCD group. C Evolution of SERPINA3 according to presence of a clinically significant decrease in LVEF during follow-up. Only patients with preserved LVEF showed a clinically significant decrease in SERPINA3. CTRCD: cancer therapy related cardiac dysfunction, LVEF: left ventricular ejection fraction. *P < 0.05, **p < 0.01

Fig. 4

ROC curves for moderate CTRCD (LVEF 40–49%). A SERPINA3 has the highest AUC at V2 compared to NT-proBNP and hs-cTnI. B SERPINA3 has the highest AUC at V3 compared to NT-proBNP and hs-cTnI. CTRCD: Cancer therapy related cardiac dysfunction, LVEF: left ventricular ejection fraction, hs-cTnI: highly sensitive cardiac troponin I; NT-proBNP: NT-pro brain natriuretic peptide

Fig. 5

SERPINA3 according to patient characteristics and malignancy. A SERPINA3 values are higher in male than females. B SERPINA3 values are lower in breast cancer patients compared to leukaemia or lymphoma patients. C SERPINA3 values are lower in HER2 negative compared to HER2 positive breast cancer patients. D SERPINA3 values in patients treated with doxorubicin declines over time, but increased if patients were treated with Daunorubicin. E SERPINA3 values were lower in patients treated with radiotherapy compared to patients who did not receive radiotherapy. HER2: human epidermal growth factor receptor 2; RT: Radiotherapy