title: Clinical significance of BIM deletion polymorphism in non-small-cell lung cancer with epidermal growth factor receptor mutation.
abstract: BACKGROUND
  Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in tumor response to treatment. To determine the clinical utility of detecting BIM deletion polymorphism in non-small-cell lung cancer positive for epidermal growth factor receptor (EGFR) mutation, we examined outcomes of patients with and without BIM alterations.
  
  
  METHODS
  We studied 70 patients with EGFR mutation-positive non-small-cell lung cancer who were treated with an EGFR tyrosine kinase inhibitor between January 2008 and January 2013. BIM deletion was analyzed by polymerase chain reaction in 58 samples of peripheral blood and 24 formalin-fixed paraffin-embedded slides of surgical specimens (20 of lung tissue and four of brain tissue); both blood and tissue specimens were available for 12 patients. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM deletion.
  
  
  RESULTS
  BIM deletion was present in 13 of 70 patients (18.6%). There were no significant differences between patients with and without BIM deletion in clinical characteristics, rate of response to EGFR tyrosine kinase inhibitor, or incidence of adverse events. Patients with BIM deletion had significantly shorter progression-free survival (PFS) than those without BIM deletion (median, 227 versus 533 days; p < 0.001). Multivariate Cox regression analysis showed that BIM deletion was an independent indicator of shorter PFS (hazard ratio, 3.99; 95% confidence interval, 1.864-8.547; p < 0.001).
  
  
  CONCLUSIONS
  Polymerase chain reaction successfully detected BIM deletion in samples of peripheral blood and formalin-fixed paraffin-embedded slides of surgical specimens. BIM deletion was the most important independent prognostic factor in shorter PFS.
authors.affiliation: Departments of *Respiratory Medicine, †Chest Surgery, and ‡Surgical Pathology, Toho University Omori Medical Center, Tokyo, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Isobe
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hata
authors.forename: Naobumi
authors.initials: N
authors.lastname: Tochigi
authors.forename: Kyohei
authors.initials: K
authors.lastname: Kaburaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Makino
authors.forename: Hajime
authors.initials: H
authors.lastname: Otsuka
authors.forename: Fumitomo
authors.initials: F
authors.lastname: Sato
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ishida
authors.forename: Naoshi
authors.initials: N
authors.lastname: Kikuchi
authors.forename: Nao
authors.initials: N
authors.lastname: Hirota
authors.forename: Keita
authors.initials: K
authors.lastname: Sato
authors.forename: Go
authors.initials: G
authors.lastname: Sano
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugino
authors.forename: Susumu
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Takai
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shibuya
authors.forename: Akira
authors.initials: A
authors.lastname: Iyoda
authors.forename: Sakae
authors.initials: S
authors.lastname: Homma
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012189:Retrospective Studies; D015996:Survival Rate
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors
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