title: Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation?
abstract: BACKGROUND
  We investigated effects of genetic alterations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS) on overall survival (OS) and local control after stereotactic radiosurgery for brain metastases in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  A cohort of 89 out of 262 NSCLC patients (2003-2013) treated with gamma knife radiosurgery for brain metastases had genotyping available and were selected as our study population.
  
  
  RESULTS
  Median follow-up was 12 months. Median OS rates for the EGFR, KRAS, echinoderm microtubule-associated protein-like 4 (EML4)-ALK mutated, and wild-type cohorts were 17, 7, 27, and 12 months, respectively (P = .019), and for targeted versus nontargeted therapy 21 and 11 months, respectively (P = .071). Targeted therapy was a strong predictor of increased OS on univariate (P = .037) and multivariate (P = .022) analysis. Gender, primary tumor controlled status, recursive partitioning analysis class, and graded prognostic assessment score were associated with OS (P < .05). On multivariate analysis, positive EGFR mutational status was a highly significant predictor for decreased survival (hazard ratio: 8.2; 95% CI: 2.0-33.7; P = .003). However, when we recategorized EGFR-mutant cases based on whether they received tyrosine kinase inhibitor, OS was no longer significantly shorter (hazard ratio: 1.5; P = .471). Median OS for patients with and without local failure was 17 and 12 months, respectively (P = .577). Local failure rates for EGFR, KRAS, EML4-ALK mutated, and wild-type cohorts by lesion were 8.7%, 5.4%, 4.3%, and 5.1%, respectively.
  
  
  CONCLUSIONS
  This study suggests that EGFR tyrosine kinase mutation and ALK translocation results in improved survival to targeted therapies and that mutation status itself does not predict survival and local control in patients with brain metastases from NSCLC.
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Tony J C
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Shumaila
authors.initials: S
authors.lastname: Saad
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Yasir H
authors.initials: YH
authors.lastname: Qureshi
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Ashish
authors.initials: A
authors.lastname: Jani
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Tavish
authors.initials: T
authors.lastname: Nanda
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Yaeh
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Tzlil
authors.initials: T
authors.lastname: Rozenblat
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sisti
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Guy M
authors.initials: GM
authors.lastname: McKhann
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Jeraldine
authors.initials: J
authors.lastname: Lesser
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Stoopler
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Cheng
authors.affiliation: Department of Radiation Oncology (T.J.C.W., S.S., A.J., T.N., A.M.Y., T.R., J.L., S.K.C., S.R.I.); Herbert Irving Comprehensive Cancer Center (T.J.C.W., M.B.Si., J.N.B., G.M.M., B.H., M.B.St., A.B.L., S.K.C., S.R.I.); The Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Y.H.Q.); Department of Neurological Surgery (M.B.Si., J.N.B., G.M.M.); Department of Neurology (A.B.L.); and Division of Hematology/Oncology (B.H., M.B.St.), Columbia University Medical Center, New York, New York.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Isaacson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016634:Radiosurgery; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C117307:KRAS protein, human; D008869:Microtubule-Associated Proteins; D004815:Epidermal Growth Factor; C000626173:ALK protein, human; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: brain metastases; mutations; non-small cell lung cancer; stereotactic radiosurgery; targeted therapy