Serum Proteomics of Ribociclib‐Mediated Cardiovascular Toxicity: An Exploratory Case–Control Study

Cyclin-dependent kinase 4/6 inhibitors have transformed hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (BC) therapeutics. Ribociclib has been associated with survival gain, yet its potential cardiovascular toxicities (CVTs) remain an area of uncertainty. Our single-center study prospectively recruited adult patients in order to assess treatment-related CVT incidence and spectrum as well as decipher proteins' differential expression in affected patients by data-independent acquisition liquid chromatography-tandem mass spectrometry (DIA LC-MS/MS). After a median follow-up of 27.2 months, five cases of CVT have occurred among the 62 enrolled participants (8.06%; mean age, 67 years). CVTs were in the form of asymptomatic QTc prolongation, transient ischemic attack, deep vein thrombosis, syncope, and pericardial effusion, which developed within 7.56 months. The in-depth proteomics quantified 144 differentially expressed proteins, of which 109 and 35 were down- and up-regulated, respectively, in these five cases (enrolled participants with CVT) compared to five sex- and age-matched controls (enrolled participants without CVT). Negative regulation of endopeptidase activity, phosphatidylcholine metabolism, and immune response were the most affected signaling pathways in the subsequent functional analysis. Large-scale external validation of our hypothesis-generating findings could potentially support individualized cardiovascular prevention in BC patients under ribociclib combinational therapy. SUMMARY: Ribociclib has unequivocally revolutionized hormone-dependent metastatic breast cancer therapeutics. Its potential cardiotoxicity, however, remain inadequately characterized, whereas the underlying pathophysiological mechanisms are poorly understood so far. Our prospective case-control study revealed that despite cardiovascular toxicity was not very common (<10%), its phenotype was not limited to QTc prolongation. Moreover, utilizing mass spectrometry-based serum proteomics, we highlighted for the very first time a number of distinct proteins, which could be of predictive value to identify patients at high risk. The prospective validation of our preliminary, proof-of-concept study's results in larger cohorts could inform optimized preventive strategies.