Multi-state modeling associates proliferation genes with early estrogen receptor-positive breast cancer recurrence and survival.

Background: To identify baseline gene expression programs associated with recurrence timing in estrogen receptorpositive (ER+) breast cancer (BC) using a multi-state modeling framework. Methods: We analyzed high-risk ER + BC patients with surgical tumor specimens profiled using a custom NanoString panel (145 genes). Recurrence was classified as none, early (<5 years after surgery), or late (≥ 5 years). Differential gene expression was assessed using negative binomial regression. Transition-specific risks of recurrence and survival were estimated using semi-Markov multi-state Cox models, with sensitivity analyses conducted under alternative definitions of early and late recurrence. Results: Among 79 patients analyzed, 28% developed recurrence (14 early, 9 late), and all BC-specific deaths occurred following early recurrence. In transition-specific models, higher baseline expression of proliferation-related genes, including Conclusions: This study identifies a potential proliferative gene assay associated with early recurrence in ER + BC, while late recurrence appears linked to distinct signaling pathways. These findings prioritize candidate molecular biomarkers for future validation to improve risk stratification and surveillance.