title: NF-κB protein expression associates with (18)F-FDG PET tumor uptake in non-small cell lung cancer: a radiogenomics validation study to understand tumor metabolism.
abstract: BACKGROUND
  We previously demonstrated that NF-κB may be associated with (18)F-FDG PET uptake and patient prognosis using radiogenomics in patients with non-small cell lung cancer (NSCLC). To validate these results, we assessed NF-κB protein expression in an extended cohort of NSCLC patients.
  
  
  METHODS
  We examined NF-κBp65 by immunohistochemistry (IHC) using a Tissue Microarray. Staining intensity was assessed by qualitative ordinal scoring and compared to tumor FDG uptake (SUVmax and SUVmean), lactate dehydrogenase A (LDHA) expression (as a positive control) and outcome using ANOVA, Kaplan Meier (KM), and Cox-proportional hazards (CPH) analysis.
  
  
  RESULTS
  365 tumors from 355 patients with long-term follow-up were analyzed. The average age for patients was 67±11 years, 46% were male and 67% were ever smokers. Stage I and II patients comprised 83% of the cohort and the majority had adenocarcinoma (73%). From 88 FDG PET scans available, average SUVmax and SUVmean were 8.3±6.6, and 3.7±2.4 respectively. Increasing NF-κBp65 expression, but not LDHA expression, was associated with higher SUVmax and SUVmean (p=0.03 and 0.02 respectively). Both NF-κBp65 and positive FDG uptake were significantly associated with more advanced stage, tumor histology and invasion. Higher NF-κBp65 expression was associated with death by KM analysis (p=0.06) while LDHA was strongly associated with recurrence (p=0.04). Increased levels of combined NF-κBp65 and LDHA expression were synergistic and associated with both recurrence (p=0.04) and death (p=0.03).
  
  
  CONCLUSIONS
  NF-κB IHC was a modest biomarker of prognosis that associated with tumor glucose metabolism on FDG PET when compared to existing molecular correlates like LDHA, which was synergistic with NF-κB for outcome. These findings recapitulate radiogenomics profiles previously reported by our group and provide a methodology for studying tumor biology using computational approaches.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, United States. Electronic address: viswamnair@stanford.edu.
authors.forename: Viswam S
authors.initials: VS
authors.lastname: Nair
authors.affiliation: Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, United States.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gevaert
authors.affiliation: Department of Radiology, Division of Nuclear Medicine, Loyola University Chicago, Stritch School of Medicine, 2160 S, 1st Avenue, Maywood, IL 60153, United States.
authors.forename: Guido
authors.initials: G
authors.lastname: Davidzon
authors.affiliation: Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, United States.
authors.forename: Sylvia K
authors.initials: SK
authors.lastname: Plevritis
authors.affiliation: Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: West
mesh_terms: D000368:Aged; D063646:Carcinogenesis; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D011379:Prognosis; D012008:Recurrence; D046888:Tissue Array Analysis; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D019788:Fluorodeoxyglucose F18
keywords: FDG PET; Glucose metabolism; LDH; Lung cancer; NF-κB; NSCLC; Radiogenomics; RelA