title: Comprehensive Biomarkers for Personalized Treatment in Pulmonary Large Cell Neuroendocrine Carcinoma: A Comparative Analysis With Adenocarcinoma.
abstract: BACKGROUND
  The prognosis for patients with large cell neuroendocrine carcinoma (LCNEC) of the lung is extremely poor, and optimal treatment strategies have not yet been established. To improve prognoses in patients with LCNEC, this study analyzed immunohistochemical expression and gene mutations of several known molecular targets in LCNECs and compared the expression levels of these targets with those in lung adenocarcinomas.
  
  
  METHODS
  Twenty-six patients with primary LCNEC and 40 patients with adenocarcinoma were analyzed. Excision repair cross-complementation group 1 (ERCC1), class III β-tubulin, topoisomerase I, topoisomerase II, epidermal growth factor receptor (EGFR)-L858R, and somatostatin receptor expression were evaluated by immunohistochemistry, and EGFR mutations were evaluated using direct DNA sequencing and the Scorpion-amplified refractory mutation system.
  
  
  RESULTS
  In patients with LCNEC and adenocarcinoma, positive rates of topoisomerase I, topoisomerase II, ERCC1, class III β-tubulin, EGFR-L858R, and somatostatin were 100.0% and 100.0%, 65.4% and 15.0% (p < 0.0001), 42.3% and 17.5% (p = 0.0462), 46.2% and 62.5%, 0.0% and 20.0% (p = 0.0182), and 50.0% and 5.0% (p < 0.0001), respectively. The frequencies of EGFR mutations were 0.0% and 37.5% in LCNEC and adenocarcinoma (p = 0.0002), respectively. Five-year overall survival rates were 64% in LCNEC and 91% in adenocarcinoma in stage I (p = 0.0132). Multivariate analysis showed that LCNEC histologic type was an independent prognostic factor in stage I.
  
  
  CONCLUSIONS
  LCNEC showed overexpression of topoisomerase II, somatostatin, and ERCC1. These findings suggested that it was possible to have good response to treatment with etoposide and octreotide and that LCNEC may be resistant to platinum-based therapy compared with adenocarcinoma. EGFR mutations were not observed in LCNEC. These results may indicate a favorable response to adjuvant treatments that are not typically prescribed for non-small cell lung cancer.
authors.affiliation: Division of Chest Surgery, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Makino
authors.affiliation: Department of Pathology, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Tetuo
authors.initials: T
authors.lastname: Mikami
authors.affiliation: Division of Chest Surgery, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Hata
authors.affiliation: Division of Chest Surgery, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Otsuka
authors.affiliation: Division of Chest Surgery, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Koezuka
authors.affiliation: Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Isobe
authors.affiliation: Department of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Naobumi
authors.initials: N
authors.lastname: Tochigi
authors.affiliation: Department of Surgical Pathology, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Shibuya
authors.affiliation: Division of Respiratory Medicine, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Sakae
authors.initials: S
authors.lastname: Homma
authors.affiliation: Division of Chest Surgery, Toho University School of Medicine, Tokyo, Japan. Electronic address: aiyoda@med.toho-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Iyoda
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism*; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018287:Carcinoma, Large Cell / Q000175:diagnosis / Q000378:metabolism*; D018278:Carcinoma, Neuroendocrine / Q000175:diagnosis / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D017481:Receptors, Somatostatin / Q000378:metabolism; D015996:Survival Rate / Q000639:trends; D014404:Tubulin / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D017481:Receptors, Somatostatin; C498585:TUBB3 protein, human; D014404:Tubulin; D066246:ErbB Receptors; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D004250:DNA Topoisomerases, Type II