Cognitive dysfunction associated with endocrine therapy and CDK4/6 inhibitors in breast cancer: A real-world analysis...

Endocrine therapies (ETs) and CDK4/6 inhibitors are cornerstone treatments for hormone receptor-positive (HR+) breast cancer, but their association with cognitive dysfunction remains poorly characterized. Given the clinical significance of treatment-related cognitive impairment, we aimed to systematically assess cognitive adverse events (AEs) associated with ETs and CDK4/6 inhibitors using real-world pharmacovigilance data.

The FDA Adverse Event Reporting System (FAERS) database (2004-2024) was analyzed, excluding confounders (e.g., pre-existing cognitive disorders, concomitant neurotoxic medications). Reporting odds ratios (RORs) identified significant AEs; Time-to-onset analysis and Kaplan-Meier curves evaluated temporal patterns. Subgroup analyses compared monotherapies (aromatase inhibitors, SERMs, GnRHa, CDK4/6 inhibitors) and combination regimens.

Among 68,832 ET/CDK4/6 inhibitor reports, 2827 cognitive AEs (4.11%) were identified. Memory impairment (31.98%), confusional state (16.98%), and amnesia (9.98%) predominated. Nine neuropsychiatric AEs showed significant associations, with SERMs having the highest risk (ROR = 2.12, 95% CI:1.76-2.55). Median time-to-onset was 88 days (IQR:1-2231); 50% occurred within three months. Abemaciclib monotherapy had the shortest onset (36 days), tamoxifen monotherapy the longest (496 days). Affected patients were primarily older (>65 years: 60.28%) and female (98.37%); most reports involved CDK4/6 inhibitor monotherapy (46.34%) or AI combinations (28.48%). Fatal outcomes occurred in 5.8% of cases.

This study delineates the spectrum, timing, and risk profiles of cognitive dysfunction linked to ETs and CDK4/6 inhibitors, highlighting the need for proactive monitoring, particularly in older patients and combination regimens. While limitations inherent to FAERS data apply, these hypothesis-generating findings provide a foundation for mechanistic research and clinical risk stratification.