@article{9e0adfd9f27343d4a9aa50050e2a89c3,
title = "Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer",
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.",
keywords = "Breast cancer, ESR1 fusion, Endocrine therapy resistance, Genomic profiling, Genomic profiling, Structural variation",
author = "Hartmaier, {Ryan J.} and Trabucco, {S. E.} and N. Priedigkeit and Chung, {J. H.} and Parachoniak, {C. A.} and {Vanden Borre}, P. and S. Morley and M. Rosenzweig and Gay, {L. M.} and Goldberg, {M. E.} and J. Suh and Ali, {S. M.} and J. Ross and B. Leyland-Jones and B. Young and C. Williams and B. Park and M. Tsai and B. Haley and J. Peguero and Callahan, {R. D.} and I. Sachelarie and J. Cho and Atkinson, {J. M.} and A. Bahreini and Nagle, {A. M.} and Puhalla, {S. L.} and Watters, {R. J.} and Z. Erdogan-Yildirim and L. Cao and S. Oesterreich and A. Mathew and Lucas, {P. C.} and Davidson, {N. E.} and Brufsky, {A. M.} and Frampton, {G. M.} and Stephens, {P. J.} and J. Chmielecki and Lee, {Adrian V.}",
note = "Funding Information: We thank D. Boone and M. Sikora for critical discussions and reading of the manuscript. We thank D. Peters, A. Rajkovic, P. Shaw, and K. Bruce for access to sequencing equipment, F. Han for performing immunoblots, and C. Andersen for providing the Nanostring codeset. The authors acknowledge support from the UPMC Hillman Cancer Center, UPMC, and by the University of Pittsburgh Center for Simulation and Modeling through the high-performance computing resources provided. The authors acknowledge support of the Health Sciences Tissue Bank and the rapid autopsy team especially Christina Kline, Lindsay Mock, Michelle Bisceglia, Louise Mazur, Sue Kelly, Rajiv Dhir, Ron Johnson, and many other clinicians and staff, as well as patients at UPMC for making the study possible. Sequence data from Pitt samples will be made available upon request and under regulatory compliance. Samples from Foundation Medicine are part of routine clinical testing and raw data are not available for public release. The study was funded in part by a CDMRP Breast Cancer Postdoctoral Fellowship to RJH (W81XWH-11-1-0582), the Fashion Footwear of New York (FFANY), and Breast Cancer Research Fund (AVL, SO, BP, and NED). This project used UPMC Hillman Cancer Center Cancer Genomics and Tissue and Research Pathology Services, supported by award P30CA047904 from NIH, utilized sequencing services performed in the Genomics Research Core at the University of Pittsburgh, and utilized common equipment supported by NIH UL1-RR024153 and UL1-TR000005 grants to the University of Pittsburgh's Clinical & Translational Science Institute. AVL is a recipient of a Scientific Advisory Council award SAC150021 from Susan G. Komen for the Cure and is a Hillman Foundation Fellow. NP was supported by a training grant from the NIH/NIGMS (2T32GM008424-21) and an individual fellowship from the NIH/NCI (5F30CA203095). AN was supported by a training grant from NIH (T32GM008424). BP was supported from Susan G. Komen for the Cure and the Commonwealth Foundation Funding Information: We thank D. Boone and M. Sikora for critical discussions and reading of the manuscript. We thank D. Peters, A. Rajkovic, P. Shaw, and K. Bruce for access to sequencing equipment, F. Han for performing immunoblots, and C. Andersen for providing the Nanostring codeset. The authors acknowledge support from the UPMC Hillman Cancer Center, UPMC, and by the University of Pittsburgh Center for Simulation and Modeling through the high-performance computing resources provided. The authors acknowledge support of the Health Sciences Tissue Bank and the rapid autopsy team especially Christina Kline, Lindsay Mock, Michelle Bisceglia, Louise Mazur, Sue Kelly, Rajiv Dhir, Ron Johnson, and many other clinicians and staff, as well as patients at UPMC for making the study possible. Sequence data from Pitt samples will be made available upon request and under regulatory compliance. Samples from Foundation Medicine are part of routine clinical testing and raw data are not available for public release. Funding Information: The study was funded in part by a CDMRP Breast Cancer Postdoctoral Fellowship to RJH (W81XWH-11-1-0582), the Fashion Footwear of New York (FFANY), and Breast Cancer Research Fund (AVL, SO, BP, and NED). This project used UPMC Hillman Cancer Center Cancer Genomics and Tissue and Research Pathology Services, supported by award P30CA047904 from NIH, utilized sequencing services performed in the Genomics Research Core at the University of Pittsburgh, and utilized common equipment supported by NIH UL1-RR024153 and UL1-TR000005 grants to the University of Pittsburgh{\textquoteright}s Clinical & Translational Science Institute. AVL is a recipient of a Scientific Advisory Council award SAC150021 from Susan G. Komen for the Cure and is a Hillman Foundation Fellow. NP was supported by a training grant from the NIH/NIGMS (2T32GM008424-21) and an individual fellowship from the NIH/NCI (5F30CA203095). AN was supported by a training grant from NIH (T32GM008424). BP was supported from Susan G. Komen for the Cure and the Commonwealth Foundation. Publisher Copyright: {\textcopyright} The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.",
year = "2018",
month = apr,
day = "1",
doi = "10.1093/annonc/mdy025",
language = "English (US)",
volume = "29",
pages = "872--880",
journal = "Annals of Oncology",
issn = "0923-7534",
publisher = "Oxford University Press",
number = "4",
}