title: Intrinsic Subtype Switching and Acquired ERBB2/HER2 Amplifications and Mutations in Breast Cancer Brain Metastases.
abstract: OBJECTIVE
  Patients with breast cancer (BrCa) brain metastases (BrM) have limited therapeutic options. A better understanding of molecular alterations acquired in BrM could identify clinically actionable metastatic dependencies.
  
  
  OBJECTIVE
  To determine whether there are intrinsic subtype differences between primary tumors and matched BrM and to uncover BrM-acquired alterations that are clinically actionable.
  
  
  METHODS
  In total, 20 cases of primary breast cancer tissue and resected BrM (10 estrogen receptor [ER]-negative and 10 ER-positive) from 2 academic institutions were included. Eligible cases in the discovery cohort harbored patient-matched primary breast cancer tissue and resected BrM. Given the rarity of patient-matched samples, no exclusion criteria were enacted. Two validation sequencing cohorts were used-a published data set of 17 patient-matched cases of BrM and a cohort of 7884 BrCa tumors enriched for metastatic samples.
  
  
  METHODS
  Brain metastases expression changes in 127 genes within BrCa signatures, PAM50 assignments, and ERBB2/HER2 DNA-level gains.
  
  
  RESULTS
  Overall, 17 of 20 BrM retained the PAM50 subtype of the primary BrCa. Despite this concordance, 17 of 20 BrM harbored expression changes (<2-fold or >2-fold) in clinically actionable genes including gains of FGFR4 (n = 6 [30%]), FLT1 (n = 4 [20%]), AURKA (n = 2 [10%]) and loss of ESR1 expression (n = 9 [45%]). The most recurrent expression gain was ERBB2/HER2, which showed a greater than 2-fold expression increase in 7 of 20 BrM (35%). Three of these 7 cases were ERBB2/HER2-negative out of 13 ERBB2/HER2-negative in the primary BrCa cohort and became immunohistochemical positive (3+) in the paired BrM with metastasis-specific amplification of the ERBB2/HER2 locus. In an independent data set, 2 of 9 (22.2%) ERBB2/HER2-negative BrCa switched to ERBB2/HER2-positive with 1 BrM acquiring ERBB2/HER2 amplification and the other showing metastatic enrichment of the activating V777L ERBB2/HER2 mutation. An expanded cohort revealed that ERBB2/HER2 amplification and/or mutation frequency was unchanged between local disease and metastases across all sites; however, a significant enrichment was appreciated for BrM (13% local vs 24% BrM; P < .001).
  
  
  CONCLUSIONS
  Breast cancer BrM commonly acquire alterations in clinically actionable genes, with metastasis-acquired ERBB2/HER2 alterations in approximately 20% of ERBB2/HER2-negative cases. These observations have immediate clinical implications for patients with ERBB2/HER2-negative breast cancer and support comprehensive profiling of metastases to inform clinical care.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania2Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania4Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Nolan
authors.initials: N
authors.lastname: Priedigkeit
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hartmaier
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Yijing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Damir
authors.initials: D
authors.lastname: Vareslija
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania7Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Basudan
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania2Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Watters
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Roby
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City.
authors.forename: Jose P
authors.initials: JP
authors.lastname: Leone
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania10Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania10Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bhargava
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.affiliation: Foundation Medicine, Cambridge, Massachusetts.
authors.forename: Juliann
authors.initials: J
authors.lastname: Chmielecki
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania8Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Puhalla
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania8Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania2Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania8Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brufsky
authors.affiliation: Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Leonie
authors.initials: L
authors.lastname: Young
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania2Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania3Magee-Women's Research Institute, Magee-Women's Research Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania7Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary* / Q000601:surgery; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human