Hepatobiliary adverse-event reporting patterns for endocrine therapies in breast cancer: a pharmacovigilance study based on FAERS and VigiAccess

Abstract

Background Endocrine therapy is central to the treatment of hormone receptor-positive breast cancer, yet hepatobiliary adverse-event reporting across endocrine agents remains incompletely characterized. We evaluated hepatobiliary reporting patterns and disproportionality signals using FAERS, with VigiAccess as a supplementary data source. Methods FAERS data from Q1–2004 to Q1–2026 were analyzed for seven endocrine therapies: tamoxifen, toremifene, anastrozole, letrozole, exemestane, fulvestrant, and elacestrant. Hepatobiliary adverse events were identified using prespecified MedDRA Preferred Terms (PTs). Drug-level disproportionality was assessed using reporting odds ratios (RORs) and information components (ICs) within a FAERS reference population restricted by breast cancer indication and primary-suspect drug role. PT- and HLT-level reporting patterns, class-level differences, sensitivity analyses, and time-to-onset (TTO) characteristics were also explored. VigiAccess was used for a non-equivalent exploratory disproportionality comparison based on aggregated adverse-event term counts. Results The FAERS hepatobiliary cohort comprised 2,630 unique case reports meeting the prespecified target-drug, breast cancer indication, primary-suspect, and hepatobiliary adverse-event criteria. Toremifene showed the largest disproportionality estimate [ROR = 5.91, 95% CI: 4.55–7.68; IC = 2.45, IC025 = 1.96], with positive signals also observed for letrozole, exemestane, and fulvestrant. Tamoxifen, anastrozole, and elacestrant did not meet the predefined positive-signal criteria. Signals for toremifene, letrozole, and exemestane were robust across sensitivity analyses, whereas the weak fulvestrant signal was more sensitive to alternative endpoint definitions, drug-role classifications, and clinical-context exclusions. The VigiAccess analysis showed concordance for the prominent toremifene signal but discordant findings for tamoxifen, letrozole, and exemestane. PT- and HLT-level analyses showed exploratory differences in reported hepatobiliary event distributions across drugs and therapy classes. TTO analyses suggested an earlier concentration of reported onset times at the class level, although within-class heterogeneity and incomplete timing data limited interpretation. Conclusions This pharmacovigilance study identified heterogeneous hepatobiliary adverse-event reporting patterns and disproportionality signals across endocrine therapies used in breast cancer. Toremifene, letrozole, and exemestane showed consistent signals across multiple sensitivity analyses, whereas other agents demonstrated more context-dependent patterns. These findings should be regarded as hypothesis-generating pharmacovigilance evidence rather than estimates of clinical incidence, comparative safety, or causal hepatotoxicity and require confirmation in clinical and pharmacoepidemiologic studies.

The authors' abstract, as published at the source. Frontiers in Endocrinology, 2026 · DOI ↗