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A. Spira
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MINI 12 - Biomarkers and Lung Nodule Management (ID 109)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:J.M. Siegfried, H.I. Pass
- Coordinates: 9/07/2015, 16:45 - 18:15, 401-404
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MINI12.15 - Discussant for MINI12.11, MINI12.12, MINI12.13, MINI12.14 (ID 3478)
16:45 - 18:15 | Author(s): A. Spira
- Abstract
- Presentation
Abstract not provided
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.07 - The Airway Field of Injury Reflects Metabolic Changes Associated with the Presence of Lung Squamous Premalignant Lesions (ID 2251)
16:45 - 18:15 | Author(s): A. Spira
- Abstract
Background:
Lung SCC arises in the epithelial layer of the bronchial airways and is preceded by the development of premalignant lesions (PMLs). The molecular events involved in the progression of PMLs to lung SCC are not clearly understood as not all PMLs that develop go on to form carcinoma. Our group is using high-throughput genomic techniques to characterize the process of premalignant progression by examining PMLs and non-lesion areas of individuals with PMLs (“field of injury”) to identify events that lead to the development of SCC. Pathway analysis revealed enrichment oxidative phosphorylation (OXPHOS) /respiratory electron transport among genes up-regulated in the airways of subjects with PMLs. OXPHOS is the most efficient metabolic pathway that generates energy in the form of ATP by utilizing the structures and enzymes of the mitochondria. OXPHOS is often elevated during epithelial tissue repair and is superseded by glycolysis in the development of cancer.
Methods:
mRNA-Seq was conducted on cytologically normal airway epithelium collected from indviduals with (n=50) and without (n=25) PMLs. Linear modeling strategies were used to identify genes altered between subjects with and without PMLs (n=206 out of 13,900, genes at FDR<0.001). Pathway analysis by GSEA revealed enrichment (FDR<0.05) of oxidative phosphorylation (OXPHOS)/respiratory electron transport genes among genes up-regulated in subjects with PMLs. To validate these findings, we examined oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) in primary airway epithelial cells cultures from PMLs and non-lesion areas and cancer cell lines that have high OXPHOS/ moderate glycolytic (H1299), moderate OXPHOS/ high glycolytic (HCC4006) or low OXPHOS/ low glycolytic (H2085) gene expression. In addition, protein expression of genes elevated in the field of injury including, translocase of the outer mitochondrial membrane (TOMM 22) and cytochrome C oxidase (COX-IV) were measured in FFPE sections of human PMLs and PMLs from the N-nitroso-tris-chloroethylurea (NTCU) mouse model of lung SCC.
Results:
OCR and ECAR values in the lung cancer cell lines were consistent with gene expression patterns. Perturbations of OXPHOS resulted in 3 fold (H1299) and 2 fold (HCC4006) higher OCR vales than those in H2085 cells (p<0.05) reflecting higher OXPHOS activity. Whereas the ECAR values were 2.5 fold (HCC4006) and 1.5 fold (H1299) higher than those in H2085 cells (p<0.05), reflecting higher glycolytic metabolism. The OCR and ECAR patterns in the primary premalignant cultures also supported the computational findings in the field of injury of PMLs. The baseline OCR/ECAR values were 1.5 fold higher in the cultures from PMLs compared to non-lesions controls (p<0.001). Additionally the OCR and ECAR values were elevated in response to perturbations in OXPHOS in the PMLs compared to controls. Protein levels of TOMM 22, and COX-IV were found to be elevated in dysplastic lesions compared to controls.
Conclusion:
Together these data suggest that metabolism-associated gene expression is correlated with cellular metabolism and there is an increase in OXPHOS associated with the development of PMLs. Furthermore, there is potential that therapeutically increasing or maintaining OXPHOS in premalignant lesions or the field of injury may be a mechanism of prevention for lung cancer.
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MTE 18 - Chemoprevention Trials: Past, Present, and Future (Ticketed Session) (ID 70)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 07:00 - 08:00, 108+110+112
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MTE18.01 - Chemoprevention Trials: Past, Present, and Future (ID 2003)
07:00 - 08:00 | Author(s): A. Spira
- Abstract
- Presentation
Abstract:
Outcomes for the majority of cancer prevention trials overall have been disappointing at best. Lung cancer remains the leading cause of cancer-related mortality worldwide, causing an estimated 156,000 deaths in the United States for 2013. Most lung cancers (>60%) are diagnosed at an advanced stage, with associated 5-year survival of less than 15%. Efforts in early diagnosis and cancer prevention remain crucial to reverse the impact of this deadly disease. For this session, I will be joined by Dr. Eva Szabo and Dr. Avi Spira to review perspectives on the past, present, and future of lung cancer chemoprevention trials. We will review a number of current concepts and important themes in lung cancer chemoprevention, including: 1. Genomic alterations in pre-malignant lesions for both lung adenocarcinoma and squamous cell carcinoma. 2. Patient stratification for applying chemoprevention. 3. Novel agents. 4. Strategies for individualized or precision chemoprevention. 5. Trial designs for rapid and efficient testing of chemoprevention hypotheses. 6. Priorities for further study. To reduce the mortality rate of lung cancer, and to prevent cancer initiation, progression and development, new techniques and approaches to cancer prevention must be developed. We will present both data and opinion regarding promising leads, routes to evaluation, and a vision for research priorities to advance the science of lung cancer chemoprevention.
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ORAL 07 - Lung Cancer Pathogenesis (ID 91)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:J. Sage, E. Brambilla
- Coordinates: 9/07/2015, 10:45 - 12:15, 102+104+106
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ORAL07.02 - Metabolic Reprogramming in the Airway Epithelium of Individuals at High Risk for Lung Cancer (ID 2493)
10:45 - 12:15 | Author(s): A. Spira
- Abstract
- Presentation
Background:
What defines the high risk airway epithelium for lung cancer remains a major challenge. Airway epithelium is prone to assault by the risk factors and considered to be the primary cell type involved in the field cancerization. Transcriptomic aberrations in the airway epithelium of individuals at risk for lung cancer have been reported earlier. However, very limited information exists about proteomic alterations in the airway epithelium. We investigated the molecular underpinnings of risk from proteomic alterations in the cytologically normal airway epithelium from individuals at risk for developing lung cancer.
Methods:
Bronchial brushings specimens were collected from individuals categorized as low, medium and high risk groups based on Bach risk model. Shotgun proteomic profiling data were acquired by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Proteins were identified using a combination of database search tools and candidate proteins were selected based on Jonckheere-Terpstra trend analysis. Pathway analysis was performed using WebGestalt. In vitro model of human bronchial epithelial cell line treated with cigarette smoke condensate (CSC) was used for metabolic flux experiments by gas chromatography mass spectrometry (GC MS) analyses.
Results:
We identified 2901 proteins in bronchial epithelial cells from risk stratified individuals. Jonckheere-Terpstra trend test resulted significantly altered expression of 315 proteins (trend p <0.05) with 238 up and 77 down trends. KEGG pathway analysis with the 315 proteins revealed very early events of possible metabolic reprogramming in the cytologically normal bronchial epithelium of individuals at high risk for lung cancer development. Fourteen enzymes of the glycolytic pathway, TCA cycle, pentose phosphate pathway, and glycogenolysis were over expressed. Six of these fourteen enzymes, PYGB, PFKP, PFKL, PKM2, IDH1, and IDH2 were rate limiting enzymes. In in vitro culture of human bronchial epithelial cells treated with CSC, lactate production and glucose consumption were increased suggesting Warburg effect and metabolic reprogramming. Evidence of glutamine metabolism through reductive carboxylation in CSC treated cells was obtained from the metabolic flux analyses of cells from this in vitro model. Contribution of labeled carbon from [U-[13]C5]-glutamine to TCA cycle in CSC treated cells were more than untreated control cells and there was strong M+5 citrate labeling in CSC-treated cells.
Conclusion:
Shotgun proteomic analysis of cytologically normal bronchial epithelial cells in individuals at increasing risk for lung cancer revealed over expression of carbohydrate metabolic enzymes in high risk individuals suggesting possible metabolic reprogramming. The altered profile of metabolic enzymes may provide a signature of lung cancer risk assessment and serve as the basis of patient selection for surveillance programs and chemoprevention.
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ORAL 23 - Prevention and Cancer Risk (ID 121)
- Event: WCLC 2015
- Type: Oral Session
- Track: Prevention and Tobacco Control
- Presentations: 1
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ORAL23.01 - A Randomized Phase IIb Trial of Myo-Inositol in Smokers with Bronchial Dysplasia (ID 856)
10:45 - 12:15 | Author(s): A. Spira
- Abstract
- Presentation
Background:
Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.
Methods:
Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).
Results:
Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.
Conclusion:
The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.
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ORAL 39 - Potential Biomarkers for CT Screening (ID 149)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
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ORAL39.07 - A Bronchial Genomic Classifier Measured in Airway Epithelial Cells Improves Diagnostic Sensitivity of Bronchoscopy for Lung Cancer (ID 2215)
16:45 - 18:15 | Author(s): A. Spira
- Abstract
- Presentation
Background:
Bronchoscopy is often used for the diagnosis of lung cancer however its sensitivity is imperfect, especially for small and peripheral lesions. Adjunctive methods to improve the sensitivity of cancer detection would reduce the need for more invasive follow-up procedures when bronchoscopy is non-diagnostic. It has previously been shown that gene expression of cytologically-normal bronchial airway epithelial cells is altered in smokers with lung cancer. In this study we evaluated the performance of a bronchial genomic classifier to predict malignancy in an independent cohort of suspect lung cancer patients.
Methods:
A bronchial genomic classifier consisting of the expression of 23 genes measured in the airway epithelium was evaluated in a previously published, independent cohort (n=163) of current and former undergoing bronchoscopy for suspect lung cancer. In cases where bronchoscopy was non-diagnostic for malignancy, the performance of the classifier was evaluated using ROC-AUC, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
Results:
In the test set, bronchoscopy led to a diagnosis in 40 of 78 patients with cancer (sensitivity=51%, 95% CI 40-63%). The combination of the classifier with bronchoscopy improved the sensitivity to 96% (95% CI 89-99%; p <0.001); see Table. The prediction accuracy of the classifier was similar in lesions <3cm, as well as across cancer stage and histology. Among the 123 patients with a non-diagnostic bronchoscopy, 38 were ultimately diagnosed with lung cancer (prevalence of 31%). In this group of patients, the classifier had an AUC of 0.81 (95% CI, 0.73-0.88), accurately identifying 35 of the 38 lung cancer patients (sensitivity=92%; 95% CI, 78-98%), and 45 of 85 patients with benign lesions (specificity=53%; 95% CI, 42-63%). Of the 48 patients with a negative classifier result, 45 were diagnosed with benign lesions (NPV=94%, 95% CI 83-99%).Table. Performance of bronchoscopy, classifier, and the combined procedures in the test set
a) The performance of the classifier was evaluated for patients in whom bronchoscopy did not result in a finding of lung cancer (n=123).Category Bronchoscopy Classifier[a] Combined Total, N 163 123 163 Lung Cancer, N 78 38 78 Benign Lesion, N 85 85 85 Sens. (95% CI) 51% (40-62%) 92% (78-98%) 96% (89-99%) Spec. (95% CI) 100% (95-100%) 53% (42-63%) 53% (42-63%) NPV (95% CI) 69% (60-77%) 94% (83-99%) 94% (83-98%) PPV (95% CI) 100% (90-100%) 47% (36-58%) 65% (56-73%)
Conclusion:
A gene expression classifier measured in bronchial epithelial cells is able to accurately identify those at low risk for lung cancer in patients who have undergone bronchoscopy with non-diagnostic results. Due to the high sensitivity and NPV of the classifier, it could potentially inform clinical decisions regarding the need for further invasive testing for lung cancer in patients whose bronchoscopy is non diagnostic.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-063 - The Mutational Landscape of Pulmonary Premalignancy in the Context of Lung Adenocarcinoma (ID 1614)
09:30 - 17:00 | Author(s): A. Spira
- Abstract
Background:
While genomic alterations in lung cancer are being actively investigated, the early mutational events that occur within the pulmonary field of cancerization that subsequently drive early carcinogenesis are poorly understood. As a result, the clinical importance of premalignant lesions remains enigmatic. Epithelial cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may progress to invasive cancer, however the mutational landscape that may predict progression has not been determined. In the present study we performed whole exome DNA sequencing to measure the incidence of somatic DNA alterations in matched sets of primary tumor, premalignant lesions and adjacent normal lung tissues.
Methods:
FFPE tissue blocks from 41 patients were obtained from the UCLA Lung Cancer SPORE Tissue Repository. The following regions were dissected from distal airways utilizing Laser Capture Microdissection: a) normal airway epithelial cells (1-3 regions), b) premalignant atypical adenomatous hyperplasia (AAH, 2-4 regions), c) adenocarcinoma in situ (AIS, 1-3 regions) and, d) adenocarcinoma (ADC, 1-3 regions). DNA was extracted and sequencing libraries were constructed followed by exome capture. Sequencing was performed on an Illumina HiSeq2000 with a mean coverage of ~50x per base.
Results:
Data analysis included analyses for germline and somatic variants, loss of heterozygosity and copy number alternations. Within each case, position-specific missense and nonsense mutations were compared. Different cases were compared for the mutations at a gene-specific level. Mutations found only in AAH lesions were defined as premalignant, in ADC as malignant, and in both AAH and ADC as progression-associated mutations. The analysis demonstrated that AAH lesions from the same patient often have different mutational profiles. We identified novel recurring progression-associated mutations in 33 genes, most of which have not been previously described as key drivers for lung cancer. Interestingly, recurring mutations were found in genes involved in calcium signaling and extracellular matrix/receptor interaction. The data was compared to the TCGA and COSMIC databases. Among affected proteins, only 3% overlapped with the COSMIC and approximately 6% with the TCGA database. Interestingly, all of the mutations overlapping with the COSMIC, were found to be common mutations in AAH. Furthermore, pathways affected by the mutated genes were identified utilizing Gene Ontology and pathways from the KEGG, Biocarta or Reactome databases. The observation that few genes mutated in both AAH and ADC are known as key drivers, indicates that: a) progression-associated mutations might facilitate malignant transformation by mutated key driver(s), or b) a combination of two or more progression-associated mutations that are not oncogenic alone, might drive malignant transformation. These hypotheses will be further tested by mapping progression- and malignant-associated genes in the context of pathways.
Conclusion:
Our data indicate that premalignant lesions from the same patient may have different mutational profiles. This inter-lesion heterogeneity suggests that a progression-associated mutational landscape could be defined in longitudinal studies of pulmonary premalignancy. These results could help identify targets for the development of targeted chemopreventive strategies for lung cancer. Supported by EDRN (U01CA152751-AS).
