Recurrent Hyperactive Esr1 Fusion Proteins in Endocrine Therapy-Resistant Breast Cancer Publisher Pubmed



Hartmaier RJ^{1, 2, 3, 18} ; Trabucco SE¹ ; Priedigkeit N^{2, 3} ; Chung JH¹ ; Parachoniak CA¹ ; Vanden Borre P¹ ; Morley S¹ ; Rosenzweig M¹ ; Gay LM¹ ; Goldberg ME¹ ; Suh J¹ ; Ali SM¹ ; Ross J¹ ; Leylandjones B⁴ Show All Authors
Source: Annals of Oncology Published:2018

Abstract

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patientmatched primary-metastatic tumors and 51 metastases, (ii) high coverage (≥ 500×) comprehensive genomic profiling of 287- 395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage ( > 5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 30 partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies. © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.