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Background  Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer. In this study, we aimed to determine acquired genomic changes in endocrine-resistant disease.    Methods  We performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen deprivation and identified acquired genomic changes versus each tumor’s matched primary.    Results  Despite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes,  AKAP9  and  KMT2C , were found to have single nucleotide variant (SNV) enrichments in more than one recurrence. Enriched mutations in single cases included SNVs within transcriptional regulators such as  ARID1A ,  TP53 ,  FOXO1 ,  BRD1 ,  NCOA1 , and  NCOR2  with one local recurrence gaining three  PIK3CA  mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common—including outlier gains in  TP63  ( n  = 5 cases [42%]),  NTRK3  ( n  = 5 [42%]),  NTRK2  ( n  = 4 [33%]),  PAX3  ( n  = 4 [33%]),  FGFR4  ( n  = 3 [25%]), and  TERT  ( n  = 3 [25%]) .  Recurrent losses involved  ESR1  ( n  = 5 [42%]),  RELN  ( n  = 5 [42%]),  SFRP4  ( n  = 4 [33%]), and  FOSB  ( n  = 4 [33%]).  ESR1- depleted recurrences harbored shared transcriptional remodeling events including upregulation of  PROM1  and other basal cancer markers.    Conclusions  Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease; highlights the importance of longitudinal RNA profiling; and identifies a common  ESR1- depleted endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.

Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences