title: Loss of the retinoblastoma tumor suppressor correlates with improved outcome in patients with lung adenocarcinoma treated with surgery and chemotherapy.
abstract: The retinoblastoma tumor suppressor pathway is frequently inactivated in human cancer, enabling unrestrained proliferation. Most cancers, however, maintain expression of a wild-type (WT) retinoblastoma tumor suppressor protein (pRB). It is generally in a hyperphosphorylated state (ppRB) because of mutations in upstream regulators such as p16 and cyclin D. Hyperphosphorylated ppRB is considered inactive, although data are emerging that suggest it can retain some function. To test the clinical relevance of pRB status, we obtained archival tissue sections from 91 cases of lung adenocarcinoma resected between 2003 and 2008. All cases received platinum doublet chemotherapy, and the median survival was 5.9 years. All cases were assessed for pRB and ppRB using immunohistochemistry and quantified based on intensity of signal and proportion of positive cells. pRB expression was lost in 15% of lung adenocarcinoma cases. In tumors that did not express pRB, the survival rate was significantly improved (hazard ratio, 0.21; 95% confidence interval, 0.06-0.69; P = .01) in comparison to tumors that express pRB. pRB status was found to be an independent predictor of overall survival on multivariate analysis (hazard ratio, 0.22; 95% confidence interval, 0.07-0.73; P = .01) along with increased stage and age. pRB status did not alter baseline levels of apoptotic or proliferative markers in these tumors, but the DNA damage response protein 53BP1 was higher in cancers with high levels of pRB. In summary, loss of pRB expression is associated with improved survival in patients treated with surgical resection and chemotherapy. This may be useful in classifying patients at greatest benefit for aggressive treatment regimes.
authors.affiliation: London Regional Cancer Program, London, ON N6A 5W9, Canada; Department of Biochemistry Western University, London, ON N6A 5C1, Canada; Department of Pathology and Laboratory Medicine, London, ON N6A 5C1, Canada.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Cecchini
authors.affiliation: London Regional Cancer Program, London, ON N6A 5W9, Canada; Department of Biochemistry Western University, London, ON N6A 5C1, Canada.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Ishak
authors.affiliation: London Regional Cancer Program, London, ON N6A 5W9, Canada; Department of Biochemistry Western University, London, ON N6A 5C1, Canada; Children's Health Research Institute London Health Sciences Centre London, ON N6C 2V5, Canada.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Passos
authors.affiliation: Department of Radiation Oncology London, ON N6A 5W9, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Warner
authors.affiliation: Department of Radiation Oncology London, ON N6A 5W9, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Palma
authors.affiliation: Department of Pathology and Laboratory Medicine, London, ON N6A 5C1, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Howlett
authors.affiliation: Department of Pathology and Laboratory Medicine, London, ON N6A 5C1, Canada.
authors.forename: David K
authors.initials: DK
authors.lastname: Driman
authors.affiliation: London Regional Cancer Program, London, ON N6A 5W9, Canada; Department of Biochemistry Western University, London, ON N6A 5C1, Canada; Children's Health Research Institute London Health Sciences Centre London, ON N6C 2V5, Canada. Electronic address: fdick@uwo.ca.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011013:Pneumonectomy; D011379:Prognosis; D016160:Retinoblastoma Protein / Q000032:analysis / Q000096:biosynthesis*; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D016160:Retinoblastoma Protein
keywords: Chemotherapy; E2F; Epidermal growth factor receptor; Lung adenocarcinoma; Retinoblastoma tumor suppressor protein