Cardiotoxicity report of letrozole combined with pyrotinib as first-line treatment in HR+/HER2+ patients and new findings on lipid monitoring as predictive markers of efficacy: an analysis from the PLEHERM study

Objective: This study aims to evaluate the cardiotoxicity of letrozole combined with pyrotinib as a first-line treatment in patients with hormone receptor (HR)+/human epidermal growth factor receptor 2 ( HER2 )+ metastatic breast cancer (MBC) and explore its potential association with treatment efficacy. Methods: This study was a multicenter, single-arm, open-label phase II clinical trial that enrolled 53 HR+/HER2+ MBC patients. All patients received 400 mg of oral pyrotinib and 2.5 mg of letrozole daily until disease progression or intolerable toxicity occurred. The primary endpoint was clinical benefit rate, while secondary study endpoints included progression-free survival (PFS) and adverse events, including cardiovascular toxicity. Results: The study results indicated that the combination of letrozole and pyrotinib showed good overall safety in HR+/HER2+ MBC patients, with lipid abnormalities being the primary form of cardiotoxicity. The incidence rates of hypercholesterolemia and hypertriglyceridemia were 52.8 and 75.5%, respectively, with most adverse events being Common Terminology Criteria for Adverse Events grade 1 and the majority of patients recovering during treatment. Further analysis revealed that a history of chemotherapy, trastuzumab therapy, and endocrine therapy was significantly associated with the occurrence of lipid abnormalities. Additionally, patients whose cholesterol levels continuously decreased by more than 10% during treatment had significantly shorter median PFS (8.0 vs. 16.3 months, P = 0.005). Conclusion: Letrozole combined with pyrotinib as a first-line treatment for HR+/HER2+ MBC patients demonstrates good cardiovascular safety, with lipid abnormalities being the main cardiotoxicity. Dynamic lipid monitoring may play an important role in both toxicity management and efficacy prediction. Further studies are needed to confirm these findings.