D2.420 - A challenging case of cardiotoxicity following palbociclib therapy

The advent of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, including palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. While generally well-tolerated, their cardiovascular safety profile is still being defined.

Here in we present the case of a 64-years old female, without significant history of cardiovascular disease or smoking habits, was followed since 22 years for breast cancer, treated with surgery and chemotherapy (6 FAC: fluorouracil, adriamycin, cyclophosphamide 50) and radiotherapy. Fifteen years later, the patient presented pleuropulmonary and bone metastasis treated with carboplatine. In January 2023, palbociclib was initiated for carcinomatous ovarian metastasis with clinical and radiological improvement. Three years later, the patient presented with severe dyspnea with left ventrixular ejection failure (LVEF) of 33%. Palbociclib was withdrawn and a check up 3 months later showed an improvement in the LVEF at 40%. Drug-induced cardiotoxicity was suspected. Given the recent onset of cardiotoxicity, the assessment of Palbociclib was possible. Cardiotoxicity caused by palbociclib is rare but has been reported in the literature and may be reversible upon discontinuation of treatment. The cardiotoxicity of anthracyclines cannot be ruled out given the delayed cumulative effect, but the presence of another drug that could explain the cardiac damage reduces the likelihood of anthracyclines being responsible. Besides, the improvement of cardiac function enhances the assessment of Palbociclib.

The assessment is challenging as in this case the patient had multiple potential contributors to her cardiac dysfunction including prior anthracycline exposure, prior chest radiotherapy which can accelerate coronary artery disease and cause restrictive or dilated cardiomyopathies over the long term and palbociclib which is the most recent cardiotoxic exposure. While the delayed effect of anthracyclines cannot be definitively excluded, the temporal relationship includes Palbociclib as the primary culprit. The patient's cardiac function had remained stable for over two decades following her anthracycline and radiation exposure. The exact mechanism of CDK4/6 inhibitor-induced cardiotoxicity is not fully understood. Preclinical studies suggest that CDK4/6 plays a role in cardiomyocyte homeostasis and response to stress. Inhibition of these pathways may make cardiomyocytes vulnerable to injury, or potentially interfere with mitochondrial function.

This report adds to the growing body of literature documenting the potential cardiotoxic effects of CDK4/6 inhibitors and highlights the possibility of late-onset toxicity and the potential for reversibility.