Abstract 421: Comprehensive genomic analysis of metastatic breast cancers reveals ESR1 fusions as a recurrent mechanism of endocrine therapy resistance
Authors: Hartmaier Ryan J. , Priedigkeit Nolan , Gay Laurie , Goldberg Michael E. , Suh James , Ali Siraj , Ross Jeffery , Tsai Michaela , Haley Barbara , Peguero Julio , Callahan Rena D. , Sachelarie Irina , Cho John , Bahreini Amir , Puhalla Shannon L. , Oesterreich Steffi , Mathew Aju , Lucas Peter C. , Davidson Nancy E. , Brufsky Adam M. , Stephens Philip J. , Chmielecki Juliann , Lee Adrian V. 
Published: July 2017

Abstract
Metastatic breast cancer is often intractable due to its inherent ability to overcome current therapies. Genomic alterations are frequently responsible for therapeutic resistance. To better understand genomic mechanisms of acquired resistance in breast cancer we undertook a detailed characterization of single nucleotide variation (SNV) and structural variation (SV) in paired primary-metastasis metachronous tumors from 6 breast cancer patients (median time to recurrence 7.3 years). In ER-positive recurrent tumors treated with endocrine therapies, we identified multiple metastatic-acquired variants in ESR1 including a novel constitutively active, ligand-independent ESR1-DAB2 gene fusion. Importantly, this fusion resulted from a breakpoint in intron 4, retaining the DNA-binding domain but eliminating the ligand-binding domain (LBD), concordant to a similar fusion reported previously in a xenograft model. Hybrid capture based genomic profiling from &gt;7,800 breast cancers identified similar exon/intron 4 fusions in 5 tumors with direct paired-read evidence. Using a novel copy number shift detection strategy, 58 additional tumors showed indirect evidence of a rearrangement at exon 4 based on a novel copy number shift detection strategy. ESR1 fusion and copy number shift positive tumors are strongly enriched in metastatic disease (78%; p&lt;10-4) supporting their expected involvement in endocrine therapy resistance. Clinical follow up was available for 7 patients. 6/7 tumors were clinically ER-positive and received extensive endocrine therapy with progressive disease. Together, these data indicate that ESR1 fusions involving exon/intron 4 are a recurrent, albeit rare, mechanism of endocrine therapy resistance in breast cancer. The absence of the LBD implies these fusions will not respond to other ERα targeted therapies. Additional studies are needed to identify appropriate treatment options to overcome this mechanism of resistance.
Citation Format: Ryan J. Hartmaier, Nolan Priedigkeit, Laurie Gay, Michael E. Goldberg, James Suh, Siraj Ali, Jeffery Ross, Michaela Tsai, Barbara Haley, Julio Peguero, Rena D. Callahan, Irina Sachelarie, John Cho, Amir Bahreini, Shannon L. Puhalla, Steffi Oesterreich, Aju Mathew, Peter C. Lucas, Nancy E. Davidson, Adam M. Brufsky, Philip J. Stephens, Juliann Chmielecki, Adrian V. Lee. Comprehensive genomic analysis of metastatic breast cancers reveals ESR1 fusions as a recurrent mechanism of endocrine therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 421. doi:10.1158/1538-7445.AM2017-421