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R.J. Downey
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MA12 - Miscellaneous Biology/Pathology (ID 476)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:B. Dome, W.D. Travis
- Coordinates: 12/06/2016, 14:20 - 15:50, Schubert 1
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MA12.10 - Histological Subtyping of Matched Primary and Metastases Sites in Lung Adenocarcinoma: Significance of Solid Predominance (ID 5767)
15:20 - 15:26 | Author(s): R.J. Downey
- Abstract
- Presentation
Background:
Clinical significance of 2015 WHO classification histological subtype of early-stage lung adenocarcinoma (LADC) has been well documented; the incidence and significance of histological subtypes in autologous metastatic tumors is unknown.
Methods:
Histological subtyping was performed on paired primary and metastatic LADC tumor samples from patients who underwent resection of metastases (N=203, 1996-2012). 57 cases with inadequate tumor specimen and 4 cases diagnosed as local recurrence were excluded.
Results:
Location of metastatic sites were – brain 51 (35.9%), lung 48 (33.8%), lymph node 14 (9.9%), pleura 10 (7.0%), and adrenal gland 5 (3.5%). Metastatic tumors demonstrated more frequent solid histological pattern than primary tumors (first predominance: 51% vs. 24%; second predominance 29% vs. 17%, Figure 1). Among all histological subtypes, solid subtype showed the highest concordance between primary and metastatic tumors (Figure 2). In addition, analysis of all available clinicopathological factors showed significantly higher percentage of solid subtype in both primary and metastatic tumors was observed in patients with smoking history (p=0.003 and p=0.004, respectively).
Conclusion:
Analysis of a large cohort of primary and autologous metastatic LADC tumors demonstrated a higher percentage of solid histological pattern metastases, even in cancers with a low solid component in the primary site of disease. Figure 1Figure 2
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OA01 - Risk Assessment and Follow up in Surgical Patients (ID 371)
- Event: WCLC 2016
- Type: Oral Session
- Track: Surgery
- Presentations: 1
- Moderators:W. Zhong, E. Lim
- Coordinates: 12/05/2016, 11:00 - 12:30, Schubert 2
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OA01.03 - Impact of Increasing Age on Cause-Specific Mortality and Morbidity in Stage I NSCLC Patients: A Competing Risk Analysis (ID 4952)
11:20 - 11:30 | Author(s): R.J. Downey
- Abstract
- Presentation
Background:
At the time of diagnosis, two-thirds of patients with lung cancer are ≥65 years of age with significant comorbidities. We sought to determine the short- and long-term cancer- and noncancer-specific mortality and morbidity in patients who underwent resection for stage I non-small cell lung cancer (NSCLC).
Methods:
Of 5371 consecutive patients who had undergone curative-intent resection of primary lung cancer (2000–2011), 2186 patients with pStage I NSCLC were included in the analysis. All preoperative clinical variables known to affect outcomes were considered, including, Charlson comorbidity index, predicted postoperative (ppo) diffusion capacity of the lung for carbon monoxide (DLCO), and ppo–forced expiratory volume in 1 second (FEV1). Association between factors and cause-specific mortality was performed using competing risks approach.
Results:
Of 2186 patients, 1532 patients (70.1%) were ≥65 years of age, including 638 patients (29.2%) ≥75 years of age. In patients ≥65 years of age, for up to 2.5 years after resection, noncancer-specific CID was higher than lung cancer–specific CID, the higher noncancer-specific early-phase mortality was enhanced in patients ≥75 years of age compared with 65-74 years of age (Figure 1a). Multivariable analyses adjusted by age, sex, smoking status, comorbidities, tumor size, and surgical procedures showed that low ppoDLCO was an independent predictor for severe morbidity (p<0.001), 1-year mortality (p<0.001), and noncancer-specific mortality (p<0.001), whereas low ppoFEV1 for lung cancer–specific mortality (p=0.002). PpoDLCO can be used for estimation of 5-year cumulative incidence of noncancer death (Figure 1b, right, red curve) because of its linear relation, whereas ppoFEV1 for lung cancer-specific death (Figure 1b, left, black curve).
Conclusion:
In patients undergoing curative-intent resection of stage I NSCLC, noncancer-specific mortality is a significant competing event, with increasing impact as patient age increases. Figure 1
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P1.03 - Poster Session with Presenters Present (ID 455)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.03-003 - The Warburg Effect: Persistence of Stem Cell Metabolism in Lung Cancer as Failure of Differentiation (ID 4378)
14:30 - 14:30 | Author(s): R.J. Downey
- Abstract
Background:
Two recent observations are relevant to explaining Warburg's observation the cancers constitutively utilize glycolysis in the presence of oxygen sufficient for oxidative phosphorylation. First, the metabolism of stem cells has been shown to be constitutive (‘aerobic’) glycolysis, with differentiation involving a transition to oxidative phosphorylation. Second, the degree of glucose uptake by a cancer has been associated with histologic differentiation. We hypothesized that the high levels of glucose uptake observed in poorly differentiated lung cancers may reflect persistence in cancers of the glycolytic metabolism of stem cells that fail to fully differentiate.
Methods:
Tumor glucose uptake was measured by FDG-PET in 859 patients with histologically diverse cancers including NSCLC. We used normal mixture modeling to explore SUV distributions and tested for association between glucose uptake and histological differentiation, risk of lymph node metastasis, and survival. Using microarray data, we performed pathway and transcription factor analyses to compare tumors with high/low glucose uptake.
Results:
Well-differentiated NSCLC had low FDG uptake, and moderately/poorly differentiated tumors higher uptake. The distribution of FDG-PET uptake was modal with a low peak at SUV 2-4 and a high peak at SUV 8-11. Figure 1 The cancers in the two peaks were clinically distinct in terms of the risk of nodal metastases and of death. Carbohydrate metabolism-related and pentose/nucleotide synthesis-related genes were elevated in the high SUV clusters, Krebs cycle/glutamine metabolism-related genes were elevated in the low SUV mode samples. Expression of Myc target genes was associated with SUV mode, but Nanog, Sox2, Oct4 and PRC2 where not.
Conclusion:
The biological basis for the Warburg effect is persistence of stem cell metabolism in lung cancers as a failure to transition from glycolysis-utilizing undifferentiated cells to oxidative phosphorylation-utilizing differentiated cells. Lung cancers cluster along the differentiation pathway into two groups. Our results have implications for determining prognosis, cancer screening and surveillance after resection.
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P2.01 - Poster Session with Presenters Present (ID 461)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.01-026 - A Mass Spectrometry Based Stem Cell-Oriented Phylogeny of Intra-Tumoral NSCLC Subclones (ID 4385)
14:30 - 14:30 | Author(s): R.J. Downey
- Abstract
Background:
Sub-clones within a cancer diverge due to ongoing accumulation of mutations. We sought to characterize the intratumor heterogeneity and phylogenetic relationships among different histological patterns present in lung adenocarcinomas based on mass spectrometric analysis of tumor subclones.
Methods:
MALDI-TOF mass spectrometry was used to generate proteomics data from different histological regions of 35 resected lung tumors, as well as from 3 basal cell and 3 mesenchymal cell samples. A total of 1985 different histological regions were analyzed from the 35 resected tumors along with the 3 samples each of airway basal cells and mesenchymal stem cells. For each of the 1991 samples, a spectral profile was generated with expression data from 217 peptide mass peaks to allow comparison of the proteomics profiles from the different histological regions from each cancer to the basal and mesenchymal stem cell profiles. Weighted protein co-expression networks were analyzed by using WGCNA package in R. Global and histologic specific networks were generated through using a power adjacency function which defines the similarity between any pairs of proteins The network modules were decided by using average linkage hierarchical clustering and a dynamic tree-cut algorithm. Networks of the different histologies and normal were compared and visualized by heat map methods.
Results:
The clinically more aggressive histologies ( micropapillary/solid) clustered with stem cells and away from normal alveolar tissue (Fig 1) and had severe loss in peptide connectivities (Fig 3). Applying t-SNE dimensionality reduction method showed that subclones from one specimen cluster differently from each other suggesting underlying heterogeneity, with more heterogenous tumors being associated with worse prognosis (Fig 2). Figure 1
Conclusion:
Construction of a phylogenetic tree of lung ACA subclones oriented to stem cells demonstrated that the degree of disruption of a subclone correlated with the degree of similarity of the subclone to stem cells, and with prognosis.
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-059 - A Stem-Cell Oriented Phylogeny of Non-Small Cell Lung Cancers (ID 4387)
14:30 - 14:30 | Author(s): R.J. Downey
- Abstract
Background:
The degree of histologic cellular differentiation of a lung cancer has been associated with prognosis but is subjectively assessed. We hypothesized that information about tumor differentiation of individual cancers could be derived objectively from cancer gene expression data, and would allow creation of a cancer phylogenetic framework that would correlate with clinical, histologic and molecular characteristics of the cancers, as well as predict prognosis.
Methods:
We utilized mRNA expression data from NSCLC samples to explore the utility of ordering samples by their distance in gene expression from that of stem cells. A differentiation baseline was obtained by including expression data of human embryonic stem cells (hESC) and human mesenchymal stem cells (hMSC) for solid tumors, and of hESC and CD34+ cells for liquid tumors.
Results:
We found that the correlation distance (the degree of similarity) between the gene expression profile of a tumor sample and that of stem cells oriented lung cancers in a clinically coherent fashion. Cancers most similar to stem cells in gene expression are in general undifferentiated, larger, more likely to be node positive and more FDG avid on PET imaging. Most importantly,patients with cancers with gene expression patterns most similar to that of stem cells had poorer overall survival. Figure 1
Conclusion:
A stem cell oriented phylogeny of lung cancers objectively orients cancers by level of differentiation in a clinically coherent fashion. Lung cancers most similar to stem cells in expression are associated with a poorer prognosis after treatment.
