A complex approach to continuous cardiac monitoring of neoadjuvant chemotherapy: Observational study
Authors: Buziashvili Yuri I. , Stilidi Ivan S. , Asymbekova Elmira U. , Matskeplishvili Simon T. , Artamonova Elena V. , Akhmediarova Nazli K. , Sherstyannikova Olga M. , Akildzhonov Firdavsdzhon R. 
Published: August 2022

Background. Recent advances in targeted chemotherapy have led to improved outcomes in patients with breast cancer (BC) and reduced overall mortality. Neoadjuvant chemotherapy (NAC) is used to reduce the degree of invasion and dissemination in the body in cancer patients. The traditional approach of assessing serial echocardiography detects significant changes in left ventricular ejection fraction (LV EF) and provides limited predictive sensitivity and specificity for continuous cardiac monitoring. Algorithms for assessing the state of the cardiovascular system, proposed in the world literature, include the assessment of LV EF, tissue Doppler sonography, and the determination of serum biomarker levels. However, the use of this approach in clinical routine practice is limited due to low cost-effectiveness and awareness of physicians.
Aim. To conduct a comprehensive assessment systolic and diastolic function, deformity, myocardial tissue harmonics and levels of cardiac biomarkers as a tool for predicting and stratifying the risk of CAH.
Materials and methods. The prospective study included 72 patients with a confirmed diagnosis of BC during NAC, who underwent a comprehensive assessment of the cardiovascular system at the Bakulev National Medical Research Center for Cardiovascular Surgery, as a continuous cardiac monitoring in the period from March 2021 to February 2022, the average age of all patients was 47.911.9 years, the stages of the tumor process varied between I and IV. Clinical research methods included the collection of clinical and anamnestic data and sequential analysis of echocardiographic parameters and the level of serum biomarkers. All patients underwent 2D and M-mode echocardiography, pulsed wave Doppler to determine the velocity of blood flow through the mitral valve and TD for the right and left ventricles in accordance with the recommendations of the American Society of Echocardiographers (ASE). LV systolic and diastolic function was assessed according to the ASE clinical guidelines. Peak longitudinal deformation of the LV and the left atrium in various projections was analyzed using the Qlab workstation (Philips Qlab, version 10.5, CMQ; Philips Healthcare, Bothell, Washington, USA). Serum levels of cardiac biomarkers such as brain natriuretic peptide (NT-proBNP) and ST-2 protein (growth stimulating factor) were also analyzed. Fasting blood was used to determine the level of soluble ST-2 and NT-proBNP before NAC, at the intermediate and final stages. Soluble ST-2 was measured using ELISA (R/D Systems, Minneapolis, Minnesota) and NT-proBNP using electrochemiluminescent immunoassay (Elecsys proBNP, Roche Diagnostics, Indianapolis, Ind.) according to the manufacturer's instructions.
Results. In our study, we assessed early changes in the LV myocardium during NAC in patients with BC. As can be seen from the figure, the level of both markers begins to increase already during NAC with a subsequent increase after the end of therapy. Thus, NT-ProBNP increased from 74.425 pg/ml to 98.922 pg/ml at the intermediate stage and to 110.721 pg/ml at the final stage. ST-2 increased from 254.5 ng/ml to 293 ng/ml (p=0.00001) and 313 ng/ml. In some patients (24%), at the final stage of the examination, the level of NT-proBNP had pathological values and exceeded 124 pg/ml. The situation is different with LV EF which in group 1 decreases by 11%, and in group 2 by only 6%, but nevertheless significantly. Indicators of LV diastolic function suffer on the background of taking NAC, the main indicators that increased after NAC were the volumes of the left atrium in both groups, the E/A ratio and the systolic filling fraction. Early diastolic lateral wall velocity significantly decreased only in the group with an excessive increase in NT-proBNP after NAC. For other indicators, there was a trend of deterioration in diastolic function. The results of changes in the parameters of LV and left atrium myocardial deformation before and after NAC are also presented. We observe a significant deterioration in overall myocardial deformity and deformity in various positions after NAC. In the analysis of serum biomarkers, the percentage increase in NT-proBNP correlated with the deterioration of LV EF (Spearman coefficient -0.34). A deterioration in the NT-proBNP biomarker of more than 10% has a prognostic value of severe NAC cardiotoxicity with 2=7.17. With multiple regression, a model was obtained where the combination of the following indicators had statistical significance. The degree of change in the other marker ST-2 had significant correlations with the degree of change in CSR, LA volume, total longitudinal strain, strain and strain rate in 4- and 2-chamber studies, as well as LA strain rate. All 72 patients with BC initially had intact LV systolic function before NAC. During NACT, at the stage of the interim study, an increase in the CSR index was noted (p=0.02 compared with the outcome), immediately after the end of the NACT course, further progression of the CSR index was observed (p=0.006 compared with the initial value). EF at the interim study decreased by 4.5% and after the end of NAC by 8.3%.
Conclusion. Based on our results, taking into account the entire patient population, NAC undoubtedly causes changes in systolic and diastolic function, a decrease in wall velocity and LV and LA myocardial deformity, and an increase in serum biomarkers. The most sensitive and specific marker of subclinical LV myocardial dysfunction is indicators of diastolic function and deformation of the LV and LA myocardium, as well as the level of serum biomarkers NT-proBNP and ST-2. The variety of clinical manifestations of cardiotoxicity, the long latency period and the progressive nature of the disease emphasize the need for early screening and long-term follow-up of patients after chemotherapy. This algorithm for comprehensive assessment of the cardiovascular system can become a more widely used non-invasive method and an effective tool in predicting a high risk of cardiotoxicity.