Background Endocrine resistance in hormone receptor positive (HR+)/HER2− metastatic breast cancer is commonly inferred from plasma-based biomarkers or single-site tissue biopsy. These approaches implicitly assume genomic homogeneity across metastatic disease which is an assumption that may not hold in the presence of spatially restricted resistant clones. Methods We report a patient with HR+/HER2− metastatic breast cancer who achieved a complete metabolic response to first line ovarian suppression, aromatase inhibition, and CDK4/6 inhibition, followed by isolated hepatic progression. Comprehensive genomic profiling was performed on the diagnostic liver biopsy and on multiple surgically resected liver metastases, enabling lesion-level comparison of responding and resistant disease. Results Baseline profiling demonstrated activating AKT1 mutation, biallelic ARID1A alterations, and FGFR1 amplification. Following prolonged endocrine control, pathological analysis of six resected liver specimens revealed marked inter-lesional genomic heterogeneity. Despite preserved oestrogen receptor expression across all metastases, canonical mechanisms of endocrine resistance, including an ESR1 Y537N mutation, high-level FGFR1 amplification, and an ERCC2 alteration, were confined to a single non-responding lesion, while other metastases retained genomic features consistent with ongoing endocrine sensitivity. Despite uniform oestrogen receptor expression, divergent genomic evolution defined therapeutic resistance. Conclusions This case demonstrates that endocrine resistance in HR+/HER2− metastatic breast cancer may arise from spatially restricted genomic evolution rather than uniform tumour-wide escape and may not be captured by single-site biopsy or plasma analysis, with direct implications for disease sampling and precision therapy selection.
Naib et al. (Fri,) studied this question.
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