title: Nuclear estrogen receptor-α expression is an independent predictor of recurrence in male patients with pT1aN0 lung adenocarcinomas, and correlates with regulatory T-cell infiltration.
abstract: BACKGROUND
  Tumor biology of estrogen receptor-α (ERα) and progesterone receptor (PR) has been studied in breast cancers. However, clinical impact in lung cancer remains controversial. In our study, we investigate whether ERα and PR expression predicts disease recurrence and correlates with immunologic factors in stage I lung adenocarcinoma.
  
  
  METHODS
  We reviewed patients with pathologic stage I resected lung adenocarcinoma. Tumors were classified according to the IASLC/ATS/ERS classification. Immunostaining of ERα and PR was performed using tissue microarrays (n = 913). Immunostaining of CD3+ and forkhead box P3 (FoxP3)+ lymphocyte infiltration, interleukin-7 receptor (IL-7R), and IL-12Rβ2 were performed. Cumulative incidence of recurrence (CIR) analysis was used to estimate probability of recurrence.
  
  
  RESULTS
  Nuclear ERα expression was observed in 157 (17%) patients and presented more frequently in females (P = 0.038) and smaller tumors (P = 0.019). Nuclear ERα expression was not identified in mucinous tumors. In pT1a patients, 5-year CIR of patients with ERα-positive tumors was significantly higher (5-year CIR, 20%) than those with ERα-negative tumors (8%; P = 0.018). This difference was statistically significant in males (P = 0.003) but not females (P = 0.55). On multivariate analysis, nuclear ERα expression was an independent predictor of recurrence (hazard ratio = 2.27; P = 0.030). In pT1a patients, nuclear ERα expression positively correlated with tumoral FoxP3+ lymphocytes (P < 0.001), FoxP3/CD3 index (P < 0.001), and IL-7R (P = 0.022).
  
  
  CONCLUSIONS
  Nuclear ERα expression is an independent predictor of recurrence in pT1a lung adenocarcinomas and correlates with poor prognostic immune microenvironments.
authors: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors: Kyuichi
authors: K
authors: Kadota
authors: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Takashi
authors: T
authors: Eguchi
authors: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Jonathan
authors: J
authors: Villena-Vargas
authors: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Kaitlin M
authors: KM
authors: Woo
authors: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Camelia S
authors: CS
authors: Sima
authors: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: David R
authors: DR
authors: Jones
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: William D
authors: WD
authors: Travis
authors: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Prasad S
authors: PS
authors: Adusumilli
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017252:CD3 Complex / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology; D055815:Young Adult
chemical_list: D017252:CD3 Complex; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C508439:IL12RB2 protein, human; C508605:IL7 protein, human; D015851:Interleukin-7; D053707:Receptors, Interleukin-12; D011980:Receptors, Progesterone
keywords: adenocarcinoma; estrogen receptor; lung; recurrence; regulatory T-cell