title: A clinical model for identifying radiosensitive tumor genotypes in non-small cell lung cancer.
abstract: OBJECTIVE
  Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes.
  
  
  METHODS
  Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments.
  
  
  RESULTS
  In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment.
  
  
  CONCLUSIONS
  This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.
authors.affiliation: Authors' Affiliations: Departments of Therapeutic Radiology, Medical Oncology, Neurosurgery, Yale University School of Medicine; and Yale Center for Analytic Sciences, Yale University School of Public Health, New Haven, Connecticut.
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Johung
authors.forename: Xiaopan
authors.initials: X
authors.lastname: Yao
authors.forename: Fangyong
authors.initials: F
authors.lastname: Li
authors.forename: James B
authors.initials: JB
authors.lastname: Yu
authors.forename: Scott N
authors.initials: SN
authors.lastname: Gettinger
authors.forename: Sarah
authors.initials: S
authors.lastname: Goldberg
authors.forename: Roy H
authors.initials: RH
authors.lastname: Decker
authors.forename: Judith A
authors.initials: JA
authors.lastname: Hess
authors.forename: Veronica L
authors.initials: VL
authors.lastname: Chiang
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Contessa
mesh_terms: D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000175:diagnosis / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D012008:Recurrence; D014178:Translocation, Genetic; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases