Article

Prognostic PET F-18-FDG Uptake Imaging Features Are Associated with Major Oncogenomic Alterations in Patients with Resected Non-Small Cell Lung Cancer

Division of Pulmonary & Critical Care Medicine, Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA.
Cancer Research (Impact Factor: 9.28). 06/2012; 72(15):3725-34. DOI: 10.1158/0008-5472.CAN-11-3943
Source: PubMed

ABSTRACT Although 2[18F]fluoro-2-deoxy-d-glucose (FDG) uptake during positron emission tomography (PET) predicts post-surgical outcome in patients with non-small cell lung cancer (NSCLC), the biologic basis for this observation is not fully understood. Here, we analyzed 25 tumors from patients with NSCLCs to identify tumor PET-FDG uptake features associated with gene expression signatures and survival. Fourteen quantitative PET imaging features describing FDG uptake were correlated with gene expression for single genes and coexpressed gene clusters (metagenes). For each FDG uptake feature, an associated metagene signature was derived, and a prognostic model was identified in an external cohort and then tested in a validation cohort of patients with NSCLC. Four of eight single genes associated with FDG uptake (LY6E, RNF149, MCM6, and FAP) were also associated with survival. The most prognostic metagene signature was associated with a multivariate FDG uptake feature [maximum standard uptake value (SUV(max)), SUV(variance), and SUV(PCA2)], each highly associated with survival in the external [HR, 5.87; confidence interval (CI), 2.49-13.8] and validation (HR, 6.12; CI, 1.08-34.8) cohorts, respectively. Cell-cycle, proliferation, death, and self-recognition pathways were altered in this radiogenomic profile. Together, our findings suggest that leveraging tumor genomics with an expanded collection of PET-FDG imaging features may enhance our understanding of FDG uptake as an imaging biomarker beyond its association with glycolysis.

Download full-text

Full-text

Available from: Olivier Gevaert, Jul 01, 2015
0 Followers
 · 
181 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined pretreatment magnetic resonance imaging (MRI) examinations from 32 patients with glioblastoma multiforme (GBM) enrolled in The Cancer Genome Atlas (TCGA). Spatial variations in T1 post-gadolinium and either T2-weighted or fluid attenuated inversion recovery sequences from each tumor MRI study were used to characterize each small region of the tumor by its local contrast enhancement and edema/cellularity ("habitat"). The patient cohort was divided into group 1 (survival < 400 days, n = 16) and group 2 (survival > 400 days, n = 16). Histograms of relative values in each sequence demonstrated that the tumor regions were consistently divided into high and low blood contrast enhancement, each of which could be subdivided into regions of high, low, and intermediate cell density/interstitial edema. Group 1 tumors contained greater volumes of habitats with low contrast enhancement but intermediate and high cell density (not fully necrotic) than group 2. Both leave-one-out and 10-fold cross-validation schemes demonstrated that individual patients could be correctly assigned to the short or long survival group with 81.25% accuracy. We demonstrate that novel image analytic techniques can characterize regional habitat variations in GBMs using combinations of MRI sequences. A preliminary study of 32 patients from the TCGA database found that the distribution of MRI-defined habitats varied significantly among the different survival groups. Radiologically defined ecological tumor analysis may provide valuable prognostic and predictive biomarkers in GBM and other tumors.
    Translational oncology 02/2014; 7(1):5-13. DOI:10.1593/tlo.13730
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction We previously demonstrated that NF-κB may be associated with 18F-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, 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.
    Lung cancer (Amsterdam, Netherlands) 01/2013; 83(2). DOI:10.1016/j.lungcan.2013.11.001
  • [Show abstract] [Hide abstract]
    ABSTRACT: The fusion of PET and computed tomography, which provide metabolic and structural images, respectively, has improved the diagnostic precision of PET in oncology. Some current procedures in the PET/CT acquisition as contrast enhanced CT/PET, the use of PET/CT in radiotherapy planning and the PET-MRI can drastically change the approach of oncologic patients. Finally, inclusions of PET/CT in oncologic diagnostic algorithm and prognostic nomograms are pending issues.RésuméL’imagerie hybride TEP-TDM donne simultanément des images fonctionnelles et anatomiques et a permis d’améliorer la précision diagnostique de la TEP seule en oncologie. Désormais, l’utilisation de produit de contraste radiologique en TEP-TDM, l’utilisation des images TEP-TDM dans le planning radiothérapeutique, et l’avènement de la TEP-IRM peuvent changer radicalement la prise en charge des patients en oncologie. Enfin, les inclusions des résultats de la TEP-TDM dans les algorithmes décisionnels et dans les nomogrammes pronostiques sont des enjeux prochains en oncologie.
    Medecine Nucleaire 03/2013; 37(3):88–92. DOI:10.1016/j.mednuc.2012.11.001