Clinicopathological and molecular features of HR + /HER2 - breast cancer patients with distinct endocrine resistance patterns.

Objective: Recurrence continues to be a pivotal challenge among hormone receptor-positive (HR⁺)/human epidermal growth factor receptor 2-negative (HER2^-) breast cancers. In the international consensus guidelines, HR⁺/HER2^- breast cancer relapse patterns are divided into three distinct types: primary resistant, secondary resistant, and endocrine sensitive. However, owing to the lack of cohorts with treatment and follow-up data, the heterogeneity among different recurrence patterns remains uncharted. Current treatments still lack precision.

Methods: This analysis included data from a large-scale multiomics study of a HR⁺/HER2^- breast cancer cohort (n=314). Through the analysis of transcriptomics (n=312), proteomics (n=124), whole-exome sequencing (n=290), metabolomics (n=217), and digital pathology (n=228) data, we explored distinctive molecular features and identified putative therapeutic targets for patients experiencing recurrence.

Results: We explored distinct clinicopathological characteristics, biological heterogeneity, and potential therapeutic strategies for recurrence. Based on a shared relapse signature, we stratified patients into high- and low-recurrence-risk groups. Patients with different relapse patterns presented unique molecular features in primary tumors. Specifically, receptor tyrosine kinase (RTK) pathway activation in the primary resistant group suggested the utility of RTK inhibitors, whereas mammalian target of rapamycin (mTOR) and cell cycle pathway activation in the secondary resistant group highlighted the potential of mTOR and CDK4/6 inhibitors. Interestingly, the endocrine-sensitive group displayed a quiescent state and high genomic instability, suggesting that targeting quiescent cells and using poly-ADP-ribose polymerase (PARP) inhibitors could be effective strategies.

Conclusions: These findings illuminate the clinicopathological and molecular landscape of HR⁺/HER2^- breast cancer patients with distinct recurrence patterns, highlighting potential targeted therapies.