December 2021 Case Cedars-Sinai Skip to content Close Select your preferred language English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog English English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog Translation is unavailable for Internet Explorer Cedars-Sinai Home 1-800-CEDARS-1 1-800-CEDARS-1 Close Find a Doctor Locations Programs & Services Health Library Patient & Visitors Community My CS-Link Education clear Go Close Academics Academics Faculty Development Community Engagement Calendar Research Research Areas Research Labs Departments & Institutes Find Clinical Trials Research Cores Research Administration Basic Science Research Clinical & Translational Research Center (CTRC) Technology & Innovations News & Breakthroughs Education Graduate Medical Education Continuing Medical Education Graduate School of Biomedical Sciences Professional Training Programs Medical Students Campus Life Office of the Dean Simulation Center Medical Library Program in the History of Medicine About Us All Education Programs Departments & Institutes Faculty Directory Anatomic and Clinical Pathology Residency Back to Anatomic and Clinical Pathology Residency Application Information Explore the Residency Training Curriculum Autopsy Pathology Rotation Bone and Soft Tissue Head and Neck Pathology Rotation Breast Pathology Rotation Cardiovascular Pathology Rotation Clinical Chemistry Rotation Coagulation Rotation Cytopathology Rotation Dermatopathology Rotation Forensic Pathology Rotation Frozen Section Rotation Gastrointestinal and Liver Pathology Genitourinary Pathology Rotation Genomic Pathology Rotation Gynecologic Pathology Rotation Hematopathology Rotation Laboratory Management Rotation Microbiology Rotation Neuropathology Rotation Pulmonary and Mediastinal Pathology Rotation Renal Pathology Rotation Transfusion Medicine Rotation Surgical Pathology Pathology Physician Scientist Training Program Residents Graduates Case of the Month Archive Publications Leadership Frequently Asked Questions December 2021 Case Authors Saleh Heneidi, MD (Fellow), Eric Vail, MD (Faculty) Molecular Pathology Clinical History The patient is a female in her 50’s presents with a large pelvic mass that measures 14.2 x 6.6 x10.4 cm with bony destruction in the left ilium. The pathologist noted that the histomorphologic and immunohistochemical staining characteristics of this malignant tumor are not entirely specific to one primary; however, the strong positive staining for GATA3 and strong positive staining in 100% of the malignant cells for estrogen receptor raises the possibility of breast primary. History includes a previous right lumpectomy for ER+, HER2 negative invasive ductal of the right breast in 2014, treated with Letrozole (Aromatase Inhibitor) therapy until 2019. Other possibilities include but are not limited to, gynecologic, pancreaticobiliary, and some genitourinary primaries. Molecular Analysis Molecular profiling of the patient's pelvic mass biopsy was performed using the Cedars-Sinai comprehensive cancer panel, which is a targeted amplicon based NGS assay that utilizes DNA and RNA to detect single nucleotide variations, indels, copy number variations, and select rearrangements (inter and intragenic) in 161 genes as well as tumor mutational burden. Genomic profiling identified a ESR1::CCDC170 t(6:6) fusion and amplifications of both 11q13 (CCND1, FGF3, and FGF19) and FGFR1. Discussion ER+ breast cancers can be classified into “luminal A” and “luminal B.” The luminal B are typically more aggressive and endocrine-resistant with high proliferative activity Ki-67 index (>10%). Luminal B breast cancer accounts for 15–20% of all breast cancers and is the most common subtype in young women. Recurrent gene rearrangements between ESR1 and its neighboring gene, coiled-coil domain containing 170 (CCDC170), in 6–8% of luminal B breast cancer, the majority of which are likely the result of tandem duplications (PMID 29360925). The molecular profile strongly correlates with an invasive breast cancer, with over 30 cases found with co-amplification of 11q13 and FGFR1 (cBioPortal.org). Additionally, ESR1::CCDC170 fusions are found up to 6-8% of "Luminal B" subtype breast cancer (typically ER+ and HER2 negative), and correlate to more aggressive, endocrine resistant, and high Ki67 cancers (PMID 32771039). Studies profiling ER+ endocrine resistant breast cancers revealed a correlation between 8p11-12 and 11q13 gene co-amplifications, including FGFR1 and CCND1, respectively, and high Ki67 (PMID 28794284). Notably, the same study also found the ESR1::CCDC170 fusion in 4 tumors that did not respond to Letrozole. Amplification of both FGFR1 and CCND1 may be synergistic, as FGFR1 is relevant in the crosslinking of cyclin D (CCND1) and CDK4/6. Of the five FGFRs, FGFR1 is associated with CDK4/6 inhibitor resistance. Clinically, FGFR1 overexpression mediated resistance to Palbociclib or Ribociclib when combined with endocrine therapy (Fulvestrant), however, this resistance could be reversed by the FGFR tyrosine kinase inhibitor (TKI) Lucitanib (PMID 30914635). Estrogen receptor (ESR1) activating mutations are frequently detected in HR-positive HER2 negative patients with prior exposure to aromatase inhibitors (AIs) (NCCN, Breast cancer v1.2022). Tumors with activating ESR1 mutations are generally resistant to both AIs (exemestane, anastrozole, letrozole) and tamoxifen (NCCN, Breast cancer v1.2022). However, this fusion only includes the 5'UTR of the estrogen receptor and not the ligand binding domain or hinge region that are typically altered in treatment resistance (see figure above), and the resistance mechanism in question is yet to be elucidated. The functional portion of the fusion encodes for the protein of CCDC170. The group that initially reported and performed the original functional studies (PMID 25099679) recently published additional studies showing the functional portion of the expressed CCDC170 protein binds to HER2 in the cell, and that treatment these fusions are sensitive to HER2/EGFR inhibitor Lapatanib and/or SRC inhibitor Dasatinib, with best results seen when additionally combined with Fulvestrant (PMID 32771039). References Hartmaier RJ, Trabucco SE, Priedigkeit N, et al. Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer. Ann Oncol. 2018;29(4):872-880. doi:10.1093/annonc/mdy025 Li L, Lin L, Veeraraghavan J, et al. Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance. Breast Cancer Res. 2020;22(1):84. Published 2020 Aug 8. doi:10.1186/s13058-020-01325-3 Giltnane JM, Hutchinson KE, Stricker TP, et al. Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance [published correction appears in Sci Transl Med. 2019 Feb 13;11(479):]. Sci Transl Med. 2017;9(402):eaai7993. doi:10.1126/scitranslmed.aai7993 Formisano L, Lu Y, Servetto A, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun. 2019;10(1):1373. Published 2019 Mar 26. doi:10.1038/s41467-019-09068-2 Veeraraghavan J, Tan Y, Cao XX, et al. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers. Nat Commun. 2014;5:4577. Published 2014 Aug 7. doi:10.1038/ncomms5577 Li L, Lin L, Veeraraghavan J, et al. Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance. Breast Cancer Res. 2020;22(1):84. Published 2020 Aug 8. doi:10.1186/s13058-020-01325-3 Please ensure Javascript is enabled for purposes of website accessibility