title: Overall survival and the response to radiotherapy among molecular subtypes of breast cancer brain metastases treated with targeted therapies.
abstract: BACKGROUND
  The current study was conducted to investigate survival and the response to radiotherapy among patients with molecular subtypes of breast cancer brain metastases treated with or without targeted therapies.
  
  
  METHODS
  Patients diagnosed with breast cancer brain metastases at a single tertiary care institution were included. The primary outcome was overall survival, whereas secondary outcomes included the cumulative incidences of distant intracranial failure, local failure, and radiation necrosis. Competing risks regression was used to model secondary outcomes.
  
  
  RESULTS
  Within the study period, 547 patients presented with 3224 brain metastases and met inclusion criteria. Among patients with human epidermal growth factor receptor 2 (HER2)-amplified disease, 80% received HER2 antibodies and 38% received HER2/epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The median survival was significantly shorter in the basal cohort (8.4 months), and progressively increased in the luminal A (12.3 months), HER2-positive (15.4 months), and luminal B (18.8 months) cohorts (P<.001). Among patients with HER2-amplified disease, the median survival was extended with the use of both HER2 antibodies (17.9 months vs 15.1 months; P = .04) and TKIs (21.1 months vs 15.4 months; P = .03). The 12-month cumulative incidences of local failure among molecular subtypes were 6.0% in the luminal A cohort, 10.3% in the luminal B cohort, 15.4% in the HER2-positive cohort, and 9.9% in the basal cohort (P = .01). Concurrent HER2/epidermal growth factor receptor TKIs with stereotactic radiosurgery significantly decreased the 12-month cumulative incidence of local failure from 15.1% to 5.7% (P<.001).
  
  
  CONCLUSIONS
  Molecular subtypes appear to be prognostic for survival and predictive of the response to radiotherapy. TKIs were found to improve survival and local control, and may decrease the rate of distant failure. To preserve neurocognition, these results support a paradigm of upfront radiosurgery and HER2-directed therapy in the HER2-amplified population, reserving whole-brain radiotherapy for salvage. Cancer 2017;123:2283-2293. © 2017 American Cancer Society.
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Miller
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Kotecha
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.|Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Manmeet S
authors.initials: MS
authors.lastname: Ahluwalia
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.|Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Alireza M
authors.initials: AM
authors.lastname: Mohammadi
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Chao
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.|Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Gene H
authors.initials: GH
authors.lastname: Barnett
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Murphy
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.|Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Vogelbaum
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.|Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lilyana
authors.initials: L
authors.lastname: Angelov
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.|Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: David M
authors.initials: DM
authors.lastname: Peereboom
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.|Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: John H
authors.initials: JH
authors.lastname: Suh
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016371:Cranial Irradiation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D000077341:Lapatinib; D059146:Metastasectomy; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D016634:Radiosurgery; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D012189:Retrospective Studies; D015996:Survival Rate; D000068878:Trastuzumab / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D066246:ErbB Receptors; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: brain metastasis; breast cancer; hormone receptor; human epidermal growth factor receptor 2 (HER2); lapatinib; radiation necrosis; stereotactic radiosurgery