Cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-induced hepatotoxicity and its resolution: a study of seven cases

Hepatotoxicity is an increasingly recognised and potentially dose-limiting adverse effect of CDK4/6 inhibitors, but their histopathological spectrum remains incompletely characterised. We aimed to describe the clinicopathological features of histologically characterised CDK4/6 inhibitor-induced liver injury.

We retrospectively identified patients with metastatic breast cancer who developed liver enzyme elevation and underwent liver biopsy while receiving a CDK4/6 inhibitor at a single comprehensive cancer centre (2020-2024). Inclusion required a RUCAM score ≥6 and exclusion of alternative aetiologies. Seven female patients met the criteria (ribociclib, n = 6; palbociclib, n = 1). The mean interval to first enzyme elevation was 60 days (range 20-114) and the mean RUCAM score was 8. Antinuclear antibody (ANA) positivity was noted in three patients, with negative extended autoimmune panels. Liver biopsy demonstrated severe acute hepatitis in five patients (71.4%), mild lobular hepatitis in one (14.3%) and subacute hepatitis with early fibrosis in one (14.3%). All acute biopsies showed perivenular (zone 3) confluent necrosis, with additional bridging necrosis in three biopsies. Portal inflammation was identified in all biopsies and lymphocytic cholangitis in five (71.4%) biopsies. No ANA-positive patient showed histological features of autoimmune hepatitis. All patients achieved biochemical normalisation after drug withdrawal (mean 63 days from peak; range 30-129), and six were successfully switched to an alternative agent.

CDK4/6 inhibitor-induced liver injury predominantly manifests as acute hepatocellular injury with zone 3 necrosis and lymphocytic cholangitis. Despite severe histological abnormalities, it resolves with drug withdrawal, and limited cross-reactivity between agents supports individualised therapeutic strategies.