title: Prognostic significance of clinical factors and Akt activation in patients with bronchioloalveolar carcinoma.
abstract: OBJECTIVE
  Lung cancer is the leading cause of cancer related mortality in the world. Bronchioloalveolar carcinoma (BAC) is a subset of NSCLC that has recently gained attention because of distinct biological and clinical features, increased incidence, and enhanced responsiveness to new therapies such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, prognostic features for BAC have not been well defined. Because activation of Akt is highly prevalent and a poor prognostic factor for other types of NSCLC, we assessed the prognostic significance of clinical features and Akt activation in patients with BAC.
  
  
  METHODS
  Forty-six cases of BAC in Iceland were classified according to WHO 1999 criteria. Akt activation was assessed using two phospho-specific antibodies against Akt (S473 and T308) in immunohistochemical (IHC) analysis. Associations between ordered Akt levels and other dichotomous parameters were evaluated using an exact Cochran-Armitage test for trend. Survival was analyzed by the Kaplan-Meier method and log-rank test, with hazard ratios (HR) determined by Cox proportional hazard models. The Cox model was also used to assess the joint effect of multiple factors on survival when they are considered simultaneously.
  
  
  RESULTS
  Age and histology (mucinous versus non-mucinous) were not associated with survival. Activation of Akt was highly prevalent in BAC, with only 2 out of 46 patients exhibiting negative staining with either antibody. Moderate to high Akt activation was observed in 63% of cases and was associated with non-mucinous histology. Akt activation was not associated with differences in survival or smoking status. In contrast, Cox model analysis revealed that male gender (HR 2.24, 95% CI, 1.07-4.71, p=0.032), advanced stage (III or IV) (HR 2.17, 95% CI, 1.004-4.71, p=0.049) and smoking status (HR 6.89, 95% CI, 1.49-31.88, p=0.013) were associated with a worse prognosis.
  
  
  CONCLUSIONS
  Male gender, advanced stage, and especially smoking status (but not Akt activation) are potentially important prognostic features for BAC. These features should be considered in the design and interpretation of clinical trials that enroll BAC patients.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889, United States.
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Marc
authors.initials: M
authors.lastname: Ballas
authors.forename: Matthew
authors.initials: M
authors.lastname: Robertson
authors.forename: Jaclyn
authors.initials: J
authors.lastname: LoPiccolo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Soda
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
authors.forename: Valgardur
authors.initials: V
authors.lastname: Egilsson
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D051057:Proto-Oncogene Proteins c-akt