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BACKGROUND Treatment advances have improved cancer-related outcomes and shifted interest towards minimising long-term iatrogenic complications, particularly chemotherapy-related cardiotoxicity. High-sensitivity cardiac troponin I (hs-cTnI) assays accurately quantify very low concentrations of plasma troponin and enable early detection of cardiomyocyte injury prior to development of myocardial dysfunction. The profile of hs-cTnI in response to anthracycline-based treatment has not previously been described. PATIENTS AND METHODS This was a multi-centre prospective observational cohort study. Female patients with newly-diagnosed invasive breast cancer scheduled to receive adjuvant or neo-adjuvant anthracycline-based (epirubicin) chemotherapy were recruited. Blood sampling was performed before, during and 24 hours after each treatment cycle. Plasma hs-cTnI concentrations were measured using the Abbott ARCHITECTSTAT assay (limit of detection 1.2 ng/L, coefficient of variation ≤10% at 4.7 ng/L, 99th centile upper reference limit in women 16 ng/L). RESULTS We recruited 78 women with a mean (standard deviation) age of 53.6 (9.6). The median (IQR) baseline troponin concentration was 1 (1 to 4) ng/L and median (IQR) cumulative epirubicin dose was 394 (300 to 405) mg/m2. Following an initial 33% fall 24 hours following anthracycline dosing (p Citation Format: Olga Oikonomidou, Evangelos Tzolos, Philip D Adamson, Peter S Hall, Iain R MacPherson, Morag MacLean, Steff Lewis, Heather McVicars, David E Newby, Nicholas L Mills, Ninian Lang, Peter A Henriksen. Dynamic changes in high-sensitivity cardiac troponin I in response to anthracycline-based chemotherapy-The Cardiac Care Trial pilot data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-13-02.

Purpose: To explore the utility of phosphorus magnetic resonance spectroscopy (31P MRS) in identifying anthracycline-induced cardiac toxicity in patients with breast cancer.Methods: Twenty patients with newly diagnosed breast cancer receiving anthracycline-based chemotherapy had cardiac magnetic resonance assessment of left ventricular ejection fraction (LVEF) and 31P MRS to determine myocardial Phosphocreatine/Adenosine Triphosphate Ratio (PCr/ATP) at three time points: pre-, mid-, and end-chemotherapy. Plasma high sensitivity cardiac troponin-I (cTn-I) tests and electrocardiograms were also performed at these same time points.Results: Phosphocreatine/Adenosine Triphosphate did not change significantly between pre- and mid-chemo (2.16 ± 0.46 vs. 2.00 ± 0.56, p = 0.80) and pre- and end-chemo (2.16 ± 0.46 vs. 2.17 ± 0.86, p = 0.99). Mean LVEF reduced significantly by 5.1% between pre- and end-chemo (61.4 ± 4.4 vs. 56.3 ± 8.1 %, p = 0.02). Change in PCr/ATP ratios from pre- to end-chemo correlated inversely with changes in LVEF over the same period (r = −0.65, p = 0.006). Plasma cTn-I increased progressively during chemotherapy from pre- to mid-chemo (1.35 ± 0.81 to 4.40 ± 2.64 ng/L; p = 0.01) and from mid- to end-chemo (4.40 ± 2.64 to 18.33 ± 13.23 ng/L; p = 0.001).Conclusions: In this small cohort pilot study, we did not observe a clear change in mean PCr/ATP values during chemotherapy despite evidence of increased plasma cardiac biomarkers and reduced LVEF. Future similar studies should be adequately powered to take account of patient drop-out and variable changes in PCr/ATP and could include T1 and T2 mapping.

BACKGROUND Anthracyclines are widely used in the treatment of breast cancer and are well recognised to carry increased risk of cardiotoxicity. This can occur as an early, acute manifestation or many years after treatment as late onset cardiomyopathy. It is increasingly apparent that there may be a chronic subclinical phase associated with low grade cardiac injury with no apparent clinical impact on the contractile function of the heart. This period may remain latent for many years with the patient remaining asymptomatic and with apparently normal cardiac function. Identification of early and subtle cardiac dysfunction during this period could provide a window of opportunity for therapeutic intervention if those at risk or those experiencing this low-grade decline could be accurately identified. This study explores the potential utility of phosphorus magnetic resonance spectroscopy (31P-MRS) to identify very early anthracycline-induced cardiac toxicity and baseline predisposition to cardiac injury. This technique measures the phosphocreatine/adenosine triphosphate concentration ratio (PCr/ATP), which reflects cardiac cellular energetics. The normal range of PCr/ATP is approximately 1.8 - 2.2, whereas decreased PCr/ATP is associated with a drop in available energy reserve in the heart, associated with many forms of heart failure. Conventional cardiac investigations of electrocardiogram, multiple gated acquisition radionuclide scans (MUGA) and ultra-high sensitivity plasma cardiac troponin-I (cTn-I) have also been applied. METHODS 20 newly diagnosed breast cancer patients, receiving anthracycline-based chemotherapy, had magnetic resonance imaging to assess left ventricular ejection fraction and 31P magnetic resonance spectroscopy (31P MRS) to assess phosphocreatine to adenosine triphosphate concentration ratio (“PCr/ATP”). Measurements were performed pre-chemo, mid-chemo and post-chemo. Plasma high sensitivity cardiac troponin-I (cTn-I) and electrocardiograms were performed. RESULTS There was a significant negative correlation between change in PCr/ATP pre- to mid- chemo and change mid- to post-chemo (r=-0.68, p=0.04). Mean ejection fraction reduced significantly (5.1%) pre- to post-chemo (p=0.02). Change in PCr/ATP ratios pre- to post-chemo correlated inversely with changes in LVEF over the same period (r=-0.65, p=0.006) and mid- to post-chemotherapy (r=-0.77, p=0.002). Plasma cTn-I increased pre- to mid-chemo (1.35±0.81 to 4.40±2.64 ng/L; p=0.0001) and mid to post-chemo (4.40±2.64 to 18.33±13.23 ng/L; p=0.0001). CONCLUSIONS This study has demonstrated the use of 31P MRS in exploring cardiac energetics of breast cancer patients undergoing chemotherapy. Pre-chemotherapy PCr/ATP ratios were in line with healthy control values obtained using our system. This technique detected a pattern of recovery of PCr/ATP ratios following an initial 3 cycles of anthracyclines. Changes in PCr/ATP ratios were found to be significantly negatively correlated with changes in LVEF from pre to post chemotherapy. The significant decrease in LVEF from pre-post chemo may be due to the delayed response of LVEF to the initial 3 cycles of anthracyclines. Small but significant increases in plasma levels of cardiac troponin-I were observed early after initiation of anthracyclines. PCr/ATP ratios were not found to be related to cTn-I values but LVEF and cTn-I were found to be positively correlated. Future studies should take account of background factors that could influence cardiac PCr/ATP ratio such as age, physical fitness and regular medication whilst the improved sensitivity of 7T MRI scanners may also help in detecting earlier changes in cardiac energetics in this patient group. Citation Format: Olga Oikonomidou, Gillian Macnaught Macnaught, Christopher T Rodgers, William Clarke, Annette Cooper, Heather McVicars, Arran K Turnbull, Saeed Mirsadraee, Scott Semple, Martin Denvir. Association of cardiac energetics and plasma biomarkers with anthracycline-based chemotherapy in breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-01-03.

Treatment advances have improved cancer outcomes and shifted interest towards minimising iatrogenic complications. High-sensitivity cardiac troponin I (hs-cTnI) assays accurately quantify very low concentrations of troponin and may allow early detection of anthracycline-related myocyte injury.