title: Spatiotemporal T790M Heterogeneity in Individual Patients with EGFR-Mutant Non-Small-Cell Lung Cancer after Acquired Resistance to EGFR-TKI.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) mutation T790M accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Because T790M is mediated by TKI exposure, its penetration and "on-off" may affect T790M status.
  
  
  METHODS
  We retrospectively reviewed T790M status and clinical course of patients who had undergone multiple rebiopsies after acquired resistance to EGFR-TKI.
  
  
  RESULTS
  Of 145 patients with EGFR-mutant NSCLC receiving rebiopsy after acquired resistance, 30 underwent multiple site rebiopsies, and 24 received repeated rebiopsies at the same lesion. In 22 patients who underwent rebiopsies from both central nervous system (CNS; 20 cerebrospinal fluids [CSF] and 2 brain tumoral tissues) and thoracic lesions (7 lung tissues, 14 pleural effusions, and 1 lymph node), 12 were thoracic-T790M-positive. Of these 12 patients, 10 were CNS-T790M-negative, despite exhibiting thoracic-T790M-positive. All 10 thoracic-T790M-negatives were CNS-T790M-negative. Three patients revealed a spatial heterogeneous T790M status among their thoracic lesions. In 24 patients receiving repeated rebiopsies at the same lesion (12 lung tissues, 6 CSFs, and 6 pleural effusions), T790M status of lung lesions varied in five patients after TKI-free interval. In all five patients whose T790M status changed from positive to negative, EGFR-TKI rechallenge was effective. In three of these five patients, after further TKI exposure, T790M status changed from negative to positive again. There was also a patient whose CSF T790M status changed from negative to positive after high-dose erlotinib therapy.
  
  
  CONCLUSIONS
  T790M status in an individual patient can be spatiotemporally heterogeneous because of selective pressure from EGFR-TKI.
authors: *Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan; †Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan; ‡Department of Respiratory Medicine, Kobe University School of Medicine, Kobe, Japan; and §Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.
authors: Akito
authors: A
authors: Hata
authors: Nobuyuki
authors: N
authors: Katakami
authors: Hiroshige
authors: H
authors: Yoshioka
authors: Reiko
authors: R
authors: Kaji
authors: Katsuhiro
authors: K
authors: Masago
authors: Shiro
authors: S
authors: Fujita
authors: Yukihiro
authors: Y
authors: Imai
authors: Akihiro
authors: A
authors: Nishiyama
authors: Tadashi
authors: T
authors: Ishida
authors: Yoshihiro
authors: Y
authors: Nishimura
authors: Yasushi
authors: Y
authors: Yatabe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors