Neprilysin Inhibition in the Prevention of Anthracycline-Induced Cardiotoxicity.

Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. AIC is characterized by myocardial systolic dysfunction and remodeling, caused by cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, or renin-angiotensin-aldosterone system (RAAS) dysregulation. In the past decade, after positive results of a PARADIGM-HF trial, a new class of drugs, namely angiotensin receptor/neprilysin inhibitors (ARNi), was incorporated into the management of patients with heart failure with reduced ejection fraction. As demonstrated in a variety of preclinical studies of cardiovascular diseases, the cardioprotective effects of ARNi administration are associated with decreased oxidative stress levels, the inhibition of myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improvement in the RAAS imbalance. However, data on ARNi's effectiveness in the prevention of AIC remains limited. Several reports of ARNi administration in animal models of AIC have shown promising results, as ARNi prevented ventricular systolic dysfunction and electrocardiographic changes and ameliorated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response associated with anthracyclines. There is currently an ongoing PRADAII trial aimed to assess the efficacy of ARNi in patients receiving breast cancer treatment, which is expected to be completed by late 2025.

Current State of Knowledge on the Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer Treatment: Approaches, Efficacy, and Challenges.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with limited treatment options. Recently, there has been a growing interest in immunotherapy with immune checkpoint inhibitors (ICIs) in TNBC, leading to extensive preclinical and clinical research. This review summarizes the current state of knowledge on ICIs efficacy and their predictive markers in TNBC and highlights the areas where the data are still limited. Currently, the only approved ICI-based regimen for TNBC is pembrolizumab with chemotherapy. Its advantage over chemotherapy alone was confirmed for non-metastatic TNBC regardless of programmed death-ligand 1 (PD-L1) expression (KEYNOTE-522) and for metastatic, PD-L1-positive TNBC (KEYNOTE-355). Pembrolizumab's efficacy was also evaluated in monotherapy, or in combination with niraparib and radiation therapy, showing potential efficacy and acceptable safety profile in phase 2 clinical trials. Atezolizumab + nab-paclitaxel increased the overall survival (OS) over placebo + nab-paclitaxel in early TNBC, regardless of PD-L1 status (IMpassion031). In IMpassion130 (untreated, advanced TNBC), the OS improvement was not statistically significant in the intention-to-treat population but clinically meaningful in the PD-L1 positive cohort. The durvalumab-anthracycline combination showed an increased response durability over placebo anthracycline in early TNBC (GeparNuevo). Several phase 1 clinical trials also showed a potential efficacy of atezolizumab and avelumab monotherapy in metastatic TNBC. ICIs appear to be applicable in both neoadjuvant and adjuvant settings, and are both pretreated and previously untreated patients. Further research is necessary to determine the most beneficial drug combinations and optimize patient selection. It is essential to identify the predictive markers for ICIs and factors affecting their expression.