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P.E. Postmus
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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: 15
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.01 - Risk of Lung Cancer in Female Non-Smokers Requires Extended Screening Guidelines (ID 2137)
16:45 - 18:15 | Author(s): C.E. Bravo, K.W. Armstrong, Y.L. Colson, C.T. Ducko, C.J. McNamee, R. Bueno, M.T. Jaklitsch, F.L. Jacobson
- Abstract
- Presentation
Background:
The National Lung Screening Trial (NLST) established a 20% reduction in lung cancer-specific mortality with low-dose computed tomography (LDCT) in 30 pack year smokers. However, approximately 25% of all lung cancers occur in non-smokers, and screening guidelines are needed for this large cohort. Pre-test probability of lung cancer can be estimated in this group using a validated risk prediction model [Liverpool Lung Project, LLP]. The LLP compares risk in 579 lung cancer cases with 1157 age and sex matched controls.
Methods:
We used the LLP model to illustrate risk profiles for non-smoking females compared to 30 pack year smokers [the NLST target population]. This tool revealed the individual and cumulative effect of risk factors in non-smoking females. The LLP estimates the probability of developing lung cancer within 5 years based on age, sex, smoking history, family history of lung cancer, infectious and occupational exposures, and prior diagnosis of a malignant tumor other than lung cancer. This tool has been validated in a Caucasian population including never and ever smokers up to 79 years of age (cross validation of tool: AUC=0.70).
Results:
We generated risk profiles for female non-smokers between 65-79 years old and no other co-morbidity, and compared the risk against those for women in the same age bracket with 30-pack year smoking history or additional non-tobacco risk factors (i.e. previous pneumonia, asbestos exposure, having a relative with lung cancer < 60years, and the combination of all factors listed). Significant risk with increasing age was predicted by the LLP model for women with 30 pack year smoking history (peak risk at age 75 years 2.2% over next 5 years). This is less than the risk of 6.7% over the next 5 years (at age 75 years) for non-smoking women with the combination of all mentioned risk factors. Relative risk of lung cancer of non-smoking women with all noted risk factors was 3.5 compared to women with no other risk factors other than 30 pack-years smoking history. Relative risk of smoking women compared to non-smoking without other risk factors was 4, while relative risk of non-smoking women with cumulative risk factors was 14 compared to non-smoking women with no other risk factors. Figure 1
Conclusion:
Therefore, the development of lung cancer risk prediction models is a key advance in the assessment of patients at risk. Individual risk assessment can be judged using the LLP model and could encourage refinement of screening recommendations.
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MINI23.02 - COPD Severity by GOLD Status and Lung Cancer Risk: Results from a Large Prospective Screening Study (NLST-ACRIN Cohort Analysis, N=18, 714) (ID 865)
16:45 - 18:15 | Author(s): R.J. Hopkins, R. Young, F. Duan, C. Chiles, G.D. Gamble, D.R. Aberle
- Abstract
Background:
Epidemiological studies consistently show that chronic obstructive pulmonary disease (COPD) is associated with an increased risk of lung cancer among smokers. However, debate exists as to whether there is a linear relationship between the severity of COPD and risk of lung cancer. The National Lung Screening Study (NLST) and it’s sub-study by the American College of Radiology and Imaging Network (ACRIN), provides the means to re-examine these findings. We examined the effect of spirometry-defined COPD (according to GOLD status at baseline), on the risk of lung cancer in the NLST-ACRIN cohort (according to lung cancer incidence), in a large prospective lung cancer screening study of high risk smokers.
Methods:
In the NLST-ACRIN cohort of 18,475 screening participants eligible for the NLST, 6,436 screening participants had COPD (35%) according to baseline pre-bronchodilator spirometry and were followed for a mean of 6.4 years. From this group, 401 lung cancer cases were identified. The 6,436 screening participants with COPD were sub-grouped according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1 (N=1607), 2 (N=3528), 3 (N=1083) and 4 (211). Lung cancer incidence at the end of follow-up was compared between the GOLD subgroups and those with normal spirometry (N=12,039).
Results:
Compared to those with normal spirometry, where the lung cancer incident rate was 4.63/1000 person years, the lung cancer incident rate was 7.58/1000 person years for GOLD 1, 9.43/1000 person years for GOLD 2, 12.7/1000 person years for GOLD 3 and 15.55/1000 person years for GOLD 4 (all P<0.0001). The lung cancer histology was significantly different, with more squamous and non-small cell cancers in those with COPD but more adenocarcinoma and Bronchoalveolar carcinoma in those with normal lung function (P<0.004). Figure 1
Conclusion:
In a large prospective study of unselected high risk smokers with and without COPD, we report a strong linear association between increasing severity of COPD and increasing lung cancer risk (incidence). This suggests that the risk of lung cancer is greatest in those with the most severe COPD and 3-4 fold greater than those with normal lung function. We also report that lung cancers of more aggressive histology were more common in those with COPD. Funding This study was funded by a grant from Johnson and Johnson and grants U01-CA-80098 and U01-CA-79778 to the American College of Radiology Imaging Network
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MINI23.03 - Targeted Exome Sequencing of Smokers Susceptible and Resistant to Chronic Obstructive Pulmonary Disease (ID 1718)
16:45 - 18:15 | Author(s): Y. Liu, M.H. Cho, F. Kheradmand, C.F. Davis, D.A. Wheeler, S. Tsavachidis, G.N. Armstrong, M.E. Scheurer, C.I. Amos, E.K. Silverman, M.R. Spitz
- Abstract
- Presentation
Background:
Chronic obstructive pulmonary disease (COPD) is a major intermediate phenotype for Lung cancer (LC); the presence of COPD conferring a three- to 10-fold increased risk of LC when compared with smokers without COPD. Variability in lung function and risk for COPD in people with similar cigarette smoking histories, together with studies of familial aggregation, support an important role for genetic factors in COPD. Therefore, we employed a targeted sequencing approach to identify variants associated with susceptibility to COPD. We focused on 107 common susceptibility loci identified in recent genome-wide association studies (GWAS) catalog in LC, COPD, lung function and smoking behavior.
Methods:
We employed an extreme phenotype approach in two carefully phenotyped extreme categories of smokers from the COPDGene study: 1) Long-term smokers with normal lung function defined as post-bronchodilator FEV1 ≥ 80% predicted, FEV1/FVC ≥ 0.7, with smoking histories of 15+ pack-years, considered as resistant to the effects of smoking, n = 318.; 2) Susceptible smokers with severe COPD defined as GOLD Stages 3-4 (post-bronchodilator FEV1 < 50% predicted and FEV1/FVC < 0.7), with smoking histories of 10+ pack-years, n = 309. We performed exome sequencing and analyzed rare (minor allele frequency [MAF] < 0.01 in reference exome databases) substitution and indel variants predicted to be functional in susceptibility loci previously identified by GWAS.
Results:
Our analysis revealed eight potentially causative non-synonymous substitution variants, occurring in 3+ susceptible smokers with COPD, and with none in resistant smokers. The two most intriguing associations were TGM5 Thr42Asn and ZBTB9 Leu43Val, that presented in six and four susceptible smokers with severe COPD, respectively. Moreover, we found an additional TGM5 compound heterozygous mutation, Val202Ile, carried by two severe COPD patients with none in the resistant smokers. TGM5 is located on 15q15.2, a susceptibility locus only reported in LC GWAS, and the p.Thr42Asn in exon 2 is only 1563bp away from the LC GWAS hit (rs504417) in intron 1. ZBTB9 is located on 6p21.31, a locus common to LC, lung function and smoking behavior. Table 1. List of top candidate deleterious mutations in susceptible smokers
LC, lung cancer; COPD, chronic obstructive pulmonary disease; SM, smoking behavior; PF, pulmonary function; MAF, minor allele frequency; KG, thousand genome.Marker Gene Protein # Mutated COPD # Mutated Control MAF in KG rs148913728 TGM5 Thr42Asn 6 0 0.0012 rs144575810 TGM5 Val202Ile 2 0 0.0002 rs41267651 ZBTB9 Leu43Val 4 0 0.0008 rs147018937 NID2 Lys1296Arg 3 0 0.0004 rs147278493 SLC6A18 Gly496Arg 3 0 0.0002 rs116926108 IFIT3 Leu390Arg 3 0 0.0002 rs142934543 LAMA1 Lys2086Thr 3 0 0.0002 rs41316996 DBH Gly482Arg 3 0 0.0004 rs41298243 MYOF Phe1400Leu 3 0 0.0002
Conclusion:
Our targeted exome sequencing results demonstrate highly disruptive COPD risk-conferring TGM5 and ZBTB9 rare mutations that are associated with susceptibility to lung cancer in smokers, and strengthen the concept of a shared genetic link between COPD and LC.
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MINI23.04 - Familial Clustering of Lung Cancer (LC) Cases in a South European Population (sEp) (ID 2540)
16:45 - 18:15 | Author(s): I. Baraibar, E. Castanon, J.M. Lopez-Picazo, A. Gurpide, J.L. Perez-Gracia, J.P. Fusco, P. Martin, L. Zubiri, L. Ceniceros, J. Legaspi, I. Gil-Aldea, J. Zulueta, C. Rolfo, I. Gil-Bazo
- Abstract
- Presentation
Background:
The National Lung Cancer Screening Trial found, after 6.5 years, a 20% reduction in LC mortality in high-risk patients (pts) screened with low-dose computed tomography compared to chest x-ray. However, LC screening programs (SP) result controversial due to potential cost-effectiveness issues. Familial LC aggregation (fLCa) has been described previously. The estimated relative risk of LC is ∼1.8 for offspring of parents with LC. Linkage analysis has mapped a dominant locus to chromosome 6 in LC pedigrees. Therefore, in this high-risk subpopulation, SP may have clear advantages. This is the first study to investigate the incidence of fLCa conducted in a sEp.
Methods:
Overall, 509 cancer pts of Spanish (n = 473) or Portuguese (n = 36) origin were included in the analysis. A cohort of 236 consecutive pts (cases) diagnosed with LC was studied for family history (FH) of any type of cancer including LC. Another cohort of 273 pts (controls) with similar demographic characteristics diagnosed with cancer types other than LC was also studied for FH of cancer. We investigated whether LC pts show a higher incidence of fLCa than subjects with other solid tumors.
Results:
Among LC pts with a positive FH for LC, 36.7% showed one of their parents as the only LC relative, 26.5% showed one or more siblings, 18.4% one or more either uncle or aunt, 6.1% their grandfather/grandmother and 12.2% other combinations. Regarding the number of relatives affected, in our LC cohort one relative was the most frequent finding with 42/49 pts (85.7%), 2 in 3 cases (6.2%) and > 3 relatives in 4 subjects (8.1%). We studied the overall incidence of any type of family cancer among cases and controls. No differences were found between groups (72.9% vs 67.4%; p = 0.18). However, in our cohort of LC cases, 49/236 pts (20.8%) had a FH of LC in first or second degree whereas among cancer controls only 29/273 pts (10.6%) showed a LC FH (p = 0.002).
Conclusion:
This is the first estimation of LC FH in a non-selected sEp with LC. 20.8% of LC cases showed a positive FH for LC, being significantly higher (twofold) compared to other cancer pts. Therefore, the usefulness of directed SP for subjects with positive FH of LC should be prospectively evaluated and potential genomic drivers studied.Table 1. Comparison of incidence of any type of familial cancer and fLCa between a cohort of LC patients and a cohort of subjects with other solid tumors LC patients Other solid tumor patients p value N= 236 N=273 Familial cancer (any type) (n (%)) Yes 172 (72.9) 184 (67.4) 0.18 No 64 (27.1) 89 (32.6) Familial Lung Cancer (n (%)) Yes 49 (20.8) 29 (10.6) 0.002* No 187 (79.2) 244 (89.4) *Statistically significance at p < 0.05 fLCa: familial lung cancer; LC: lung cancer
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- Abstract
- Presentation
Background:
Lung cancer with different molecular profile behaves in different ways in terms of etiology, clinical characteristics, and prognosis. It implies that fighting against lung cancer should be moving forward in the direction of modifying the screening strategies on genetically-defined high risk groups, initiating early chemoprevention trials on selected high-risk subjects, and developing personalized cancer treatments. Lung adenocarcinoma in never-smokers, more often harboring epidermal growth factor receptor (EGFR) mutations especially in Asians, has a remarkable therapeutic response to specific tyrosine kinase inhibitors. Most single nucleotide polymorphisms (SNPs) identified by candidate gene and genome-wide association studies are of genes involved in carcinogen metabolic pathway, DNA repair pathway, inflammatory pathway and tumor suppressor pathway. Conflicting results are likely due to heterogeneity of the study population and lack of focus on specific molecular subgroups (e.g. EGFR-mutants). We therefore embark on the current study to identify susceptibility genes in a molecularly-defined (EGFR-mutated) subgroup of never-smoking lung adenocarcinoma in Hong Kong population.
Methods:
Eligible patients with confirmed primary lung adenocarcinoma were recruited from Queen Mary Hospital, Hong Kong. Voluntary healthy controls were recruited from blood donors in Hong Kong Red Cross. 10mL venous blood samples were taken from both cases and controls for DNA extraction and SNP assays. 51 SNPs of 14 genes involved in four different pathways were tested using MassARRAY. A structured questionnaire including the information of environmental exposures at home and workplace, family history of lung cancer and other cancer for all subjects, and clinical characteristics (cell type, EGFR mutation status, staging and treatment etc.) for lung cancer patients were administered to cases and controls. Using SNPstats package, logistic regression analysis adjusted for age and gender was performed to evaluate the association between the studied SNPs and lung cancer development.
Results:
From September 2006 to February 2015, a total of 614 lung cancer patients regardless of histological type and smoking status were recruited. Out of which, 267 never-smoking lung adenocarcinoma patients (72% females, mean age 61.6+/-12.6 years) were regarded as cases in the study. From July 2013 to August 2014, a total of 453 healthy controls (40% females, mean age 53.8+/- 8.3 years) were recruited. Most cases (69%) were at advanced stage with chemotherapy treatment (67.8%). Higher proportion of cases (41.7% at home; 35.4% at workplace) than controls (24.9% at home; 26.9% at workplace) had been exposed to second-hand smoke. Genetic analysis was restricted to 184 pairs of age and gender well-matched cases and controls. Two of the 51 SNPs showed a significant association with lung adenocarcinoma, which were rs2069840 of IL-6 gene in inflammatory pathway (OR: 5.80; 96%CI: 1.60-20.99) and rs1106087 of XPC gene in DNA repair pathway (OR: 3.72; 95%CI: 1.40-9.83).
Conclusion:
Our results suggest that IL-6 rs2069840 and XPC rs1106087 are susceptibility genes for development of EGFR-driven lung adenocarcinoma in never-smoking Hong Kong population.
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MINI23.06 - Discussant for MINI23.01, MINI23.02, MINI23.03, MINI23.04, MINI23.05 (ID 3424)
16:45 - 18:15 | Author(s): Y.E. Miller
- Abstract
- Presentation
Abstract not provided
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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): S. Mazzilli, G. Lui, S. Lam, M. Lenburg, A. Spira, J. Beane
- 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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MINI23.08 - Comparison of in Vivo Raman and NIR Spectroscopy and EBUS as Confirmatory Method for Ideal Biopsy Area during Bronchoscopic Navigation (ID 2920)
16:45 - 18:15 | Author(s): J. Votruba
- Abstract
- Presentation
Background:
Recently, SPNs have become more frequently encountered in bronchology. Therefore, an efficient and reliable method for detecting SPNs based on their morphological characteristics is needed The aim of this study was to compare the diagnostic value of near infrared (NIR) spectroscopy, in vivo Raman spectroscopy and radial endobronchial ultrasound (EBUS) for solitary pulmonary nodule (SPN). Fluoroscopic guidance with transbronchial biopsy and needle biopsy was performed in all patients.
Methods:
Between February 2014 and February 2015 we examined 22 male and 29 female patients having a median age of 68 years with positron emission tomography-computed tomography findings of metabolically active SPN between 1, 5 to 3 cm in diameter. We used tree types of point monitoring systems. Fluoroscopic guidance (with guide- sheath) was combined with a radial EBUS. In the case radial EBUS conclusively showed catheter position in the centre of SPN (41 cases) than in-vivo Raman Spectroscopy and NIR spectroscopy probes were placed into the guide sheath in order to gather tissue information. Mean measurement time was less than five minutes after establishing ideal position of guide -sheath. Results of in spectroscopy measurements from both Raman spectroscopy and NIR spectroscopy were obtained as differences between spectral characteristics of normal tissue (same side, different lobe) to SPN tissue.
Results:
The results are expressed as sensitivity of RAMAN spectroscopy and NIR spectroscopy towards EBUS navigated biopsies. Statistical analysis of the results showed comparable very high sensitivities for NIR spectroscopy and Raman spectroscopy in confirmation of SPN tissue. From 41 EBUS positive visualisations of SPN there were 38 conclusive histological findings. Both Raman spectroscopy (positive differences in 38 cases) and NIR spectroscopy (positive differences in 36 cases) showed good performance in tissue discrimination.
Conclusion:
Every confirmatory method brings different information about tissue. EBUS describes volume of the SPN and gives valuable information about the position of catheter in the SPN. Raman spectroscopy and NIR spectroscopy bring information about biochemical/ optical characteristics of the tissues.
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- Abstract
- Presentation
Background:
Probe-based confocal laser endomicroscopy (pCLE) allows for real-time noninvasive histological imaging via bronchoscopy. Interpreting pCLE images and correlating with pulmonary disease remains challenging. We performed an in vivo study to evaluate the correlation between pathological diagnosis and pCLE imaging of pulmonary disease.
Methods:
We sequentially enrolled the patients with undiagnosed lung lesion, and randomly grouped into control group (TBLB and peripheral EBUS) and pCLE group (TBLB + pCLE and peripheral EBUS + pCLE). pCLE was performed with Cellvizio system (Mauna Kea Technologies, Paris, France). All patients were consent to the procedure. Pathologists and pulmonologists reviewed the images by the Columbus Classification (CC). Questionnaires were applied post the procedure to collect patients’ condition. We developed a computer assistant diagnostic (CAD) system to calculate alveolar diameter, vessel diameter and optical density percentage and compare the CAD diagnostic accuracy with CC standard. The CAD system involved image processing methods to calculate the diameters in pixel domain and then transformed them into the real value. Pseudo-color processing was used to show the density percentage of different tissues. And the histogram was also calculated to figure out the distribution alone gray scale.
Results:
258 patients enrolled in the study, 98 under pCLE examination, while 160 under control group. Among them 128 lesions were diagnosed as malignant tumor by pathological diagnosis, 87 cases were diagnosed as benign disease. Primary features were observed in the samples using pCLE in the lesion of cancer: The normal alveolar in malignant nodules is smaller than benign nodules. While, the vessel in the malignant nodules is thicker than the benign ones. The cellular structure and vessel domination in various subtypes of lung cancer is different. There was no significance on procedure time between control and pCLE group, as well as patients’ secretion, tolerance and willing for repeat examination.
Conclusion:
pCLE can identify lung carcinoma in in vivo procedure with well tolerance and with limit procedure time. As a non-invasive method, pCLE could improve accuracy and avoid unnecessary biopsy. The Computer Assist Diagnosis system could help pulmonologists to better acquire the right image and to differentiate diseases on the site.
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MINI23.10 - Subtraction of Allelic Fractions (Delta-θ): A Sensitive Metric to Detect Chromosomal Alterations in Heterogeneous Premalignant Specimens (ID 2434)
16:45 - 18:15 | Author(s): I. Nakachi, R.S. Stearman, M. Edwards, W.A. Franklin, J.L. Rice, A. Tan, J. Kim, M. Yoo, A. Fujisawa, T. Betsuyaku, K. Soejima, Y.E. Miller, M.W. Geraci
- Abstract
- Presentation
Background:
Lung squamous carcinoma is believed to arise from premalignant bronchial epithelial dysplasia, which demonstrates progressive histologic changes leading up to invasive cancer. However, only a small subset of these lesions progress to carcinoma. Recent studies have shown that somatic chromosomal alterations (SCAs) status is a better biomarker than premalignant histology alone. Single-nucleotide polymorphism microarray (SNP array) has been frequently used to delineate these genomic alterations across the whole genome. However, the cellular heterogeneity, from clinical samples such as endobronchial specimens, is a basic obstacle to perform sensitive and accurate detection of SCAs.
Methods:
We used: 1) a lung cancer cell line (NCI-H1395) and its matched lymphoblastoid (NCI-BL1395) cell line; 2) frozen lung tissues containing different percentage of invasive cancer cells surgically resected from a patient; and 3) biopsies and brushings obtained at the visually concerning areas during bronchoscopy. The histology of the clinical samples were graded by the study pathologist. Genomic DNA was isolated from each sample, quantified, and labeled for Illumina SNP array (HumanOmni 2.5-Quad BeadChip). Data analysis and visualizations were performed using Partek Genomic Suite 6.6 software.
Results:
Our study focused on the detection of SCAs by the comparison of genomic DNAs from cancer/premalignant cells (subject) to blood/normal cells (reference) from the same individual. We tested a B allele frequency metric, the subtraction of allelic fractions (delta-θ), on a standardized mixture of genomic DNAs from a lung cancer cell line and its matched lymphoblastoid cell line. Delta-θ proved to be a sensitive parameter to clearly delineate SCAs present in the tumor cell line even with a large proportion of normal cells (up to 90%). To explore the utility of using delta-θ for heterogeneous samples, we used clinical lung cancer specimens with known cancer cell content. In comparison to the other publicly available analytical metrics/algorithms (conventional Log R Ratio plot, mirrored B Allele Frequency plot, and GAP algorithm), delta-θ performed as well or better (with lower computational power needed), and enabled the detection of SCAs even in highly heterogeneous clinical samples (<30% tumor cell content). In addition, we completed a study using a number of bronchial biopsies and brushings with histologic grade ranging from normal to squamous cell carcinoma. SCAs were rarely detected in those of low to mild dysplasia, while they were detected in approximately 25% of moderate or severe dysplasia, and in all carcinoma in situ (CIS) and squamous cell carcinoma specimens. Longitudinal, repeated samplings from a high risk patient who persistently showed high grade dysplasia across the bronchus, revealed that delta-θ could identify SCAs continuously across the whole genome. The fact this individual had highly overlapping SCAs between different bronchial locations indicates genomic field cancerization may occur, along with the histological field effect in premalignant epithelium.
Conclusion:
In SNP microarray studies, delta-θ is a highly sensitive metric for detecting SCAs even in heterogeneous dysplastic bronchial specimens. SNP array may be a powerful tool to understand premalignant genetic alterations and field cancerization.
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MINI23.11 - Discussant for MINI23.07, MINI23.08, MINI23.09, MINI23.10 (ID 3425)
16:45 - 18:15 | Author(s): L. Thiberville
- Abstract
- Presentation
Abstract not provided
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MINI23.12 - HAases and HAS in Lung/Bronchial Pre-Neoplastic Lesions: Impact on Prognosis (ID 395)
16:45 - 18:15 | Author(s): V.K. De Sá, T. Prieto, E.R. Olivieri, D.M. Carraro, F.A. Soares, L. Carvalho, A.G. Nicholson, V.L. Capelozzi
- Abstract
- Presentation
Background:
Lung cancer is the result of a multi-step accumulation of genetic and/or epigenetic alterations; therefore, a better understanding of the molecular mechanism, by which these alterations affect lung cancer pathogenesis, would provide new diagnostic procedures and prognostic factors for early detection of recurrence. In this regard, many have studied molecular or other markers in pre-neoplastic and neoplastic lesions to discover what might relate to tumor recurrence and shortened survival.
Methods:
A series of 136 lung/bronchial and lung parenchyma tissue samples from 136 patients consisting of basal cell hyperplasia, squamous metaplasia, moderate dysplasia, adenomatous hyperplasia, severe dysplasia, squamous cell carcinoma and adenocarcinoma were analyzed for the distribution of hyaluronidase 1 (HYAL1) and 3 (HYAL3), and hyaluronan synthases 1 (HAS1), 2 (HAS2) and 3 (HAS3) by immunohistochemistry.
Results:
HYAL 1 was significantly more expressed in basal cell hyperplasia compared to moderate dysplasia (p=0.01), atypical adenomatous hyperplasia (p=0.0001) and severe dysplasia (p=0.03). A lower expression of HYAL 3 was found in atypical adenomatous hyperplasia compared to basal cell hyperplasia (p=0.01) and moderate dysplasia (p=0.02). HAS 2 was significantly higher in severe dysplasia compared to basal cell hyperplasia (p=0.002), and equally higher in squamous metaplasia compared to basal cell hyperplasia (p=0.04). HAS 3 was significantly expressed in basal cell hyperplasia compared to atypical adenomatous hyperplasia (p=0.05) and severe dysplasia (p=0.02). A lower expression of HAS 3 was found in severe dysplasia compared to squamous metaplasia (p=0.01) and moderate dysplasia (p=0.01). Epithelial HYAL 1 and 3 and HAS 1, 2 and 3 expressions were significantly increased in pre neoplastic lesions compared to neoplastic lesions. Comparative Cox multivariate analysis controlled by N stage and histologic types of tumors showed a significant association between poor survival and high pre neoplastic cell associated to HAS3 (HR=1.19; p=0.04).
Conclusion:
We concluded that localization of HYALs and HASs in lung/bronchial pre-neoplastic and neoplastic lesions was inversely related to malignancy, these factors emerging as potentially important diagnostic markers in patients with suspicion of lung cancer.
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MINI23.13 - Extracellular Sulfatase SULF2: A Potential Biomarker for the Early Detection of Lung Cancer (ID 3079)
16:45 - 18:15 | Author(s): Y. Yang, N. Lui, W. Mayer, D. Jablons, H. Lemjabbar-Alaoui
- Abstract
- Presentation
Background:
The extracellular sulfatases (SULF1 and SULF2) are overexpressed in a wide assortment of human cancers. SULF2, in particular, has been shown to drive carcinogenesis in non-small cell lung cancer (NSCLC), malignant astrocytoma, and hepatocellular carcinoma. As extracellular enzymes that are both tethered to the cell membrane and secreted, the SULFs and their heparan sulfate proteoglycan (HSPG) substrates are present in the extracellular environment. We hypothesize that the blood levels of SULF2 can serve as biomarkers for the early detection of NSCLC and malignant astrocytoma. The primary goal of this study is to evaluate the patient tumor and blood samples for the presence of the SULF2 in order to develop novel biomarkers for the early detection of NSCLC.
Methods:
We identified patients who underwent lung resection for adenocarcinoma (ADC) (41 patients) or squamous cell carcinoma (SCC) (51 patients) at our institution from 2000 to 2006. We excluded patients with recurrent lung cancer, or less than 3 mm of invasive tumor on H&E slide. A section from each paraffin-embedded tissue specimen was stained with a monoclonal antibody to SULF2. A pathologist determined the percentage (0-100%) and intensity (0-3) of tumor cells staining. Survival analysis was performed using a multivariate Cox proportional hazards model. We developed an ELISA to detect SULF2 in human blood. After testing a number of different strategies including using different combinations of our anti-SULF2 mAbs, we determined that a sandwich ELISA with capture mAb 5C12 followed by detection with biotinylated mAb 8G1 was best for the most sensitive detection of SULF2.
Results:
SULF2 staining (either tumor or stroma) was positive for 82% of the samples The SCC samples had a higher mean percentage of tumor staining compared to the ADC samples (100% vs. 60%; p<0.0005). However, after adjusting for age, sex, race, histologic type, stage, and neoadjuvant therapy, there was no significant association between percentage of SULF2 tumor staining and overall survival. Nonetheless, these initial findings are very encouraging, because the vast majority of ADC samples, including early stage disease, and all of the SCC tumor samples have some degree of staining for SULF2 protein. Using our SULF2 ELISA assay, we analyzed plasma samples from 54 healthy donors and 85 patients with newly diagnosed early stage NSCLC before surgical resection. The level of SULF2 protein is significantly higher in patients with NSCLC compared with healthy controls (738.4 ± 55.17, vs. 439.4 ± 40.88 pg/mL; p<0.0001).
Conclusion:
SULF2 protein was detected in the vast majority of tumor and blood samples of patients with lung cancer. Although additional studies are required, these data provide the first indication that SULF2 blood level may be a useful biomarker for the early detection of lung cancer.
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MINI23.14 - Circulating Long Non-Coding RNA GAS5 Is a Novel Biomarkers for the Diagnosis of Non-Small Cell Lung Cancer (ID 2315)
16:45 - 18:15 | Author(s): W.J. Liang, X.F. Shi, H.B. Liu, T.F. Lv, Y. Song
- Abstract
- Presentation
Background:
Long non-coding RNAs (lncRNAs) are new-founding RNAs which could regulate many biological processes. Our previous study shown that lncRNA-GAS5 was decreased in lung cancer tissue, which contributed to the proliferation and apoptosis of non-small lung cancer (NSCLC). GAS5 was also associated with the prognosis of lung cancer patients. However, the plasma samples were more easily available than the tissue sample in the clinic. And the expression of GAS5 in the plasma of NSCLC patients was unknown.
Methods:
90 patients with NSCLC and 33 health controls were included in our study. Blood samples were collected before surgery and therapy. We extracted the free RNA in the plasma and analyzed the expression of GAS5 with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Suitable statistics methods were used to compare the plasma GAS5 levels between the NSCLC patients and health controls, preoperative and postoperative plasma samples. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic sensitivity and specificity of plasma GAS5 in NSCLC.
Results:
The 2[-][△][CT ]of GAS5 in the plasma of NSCLC patients and health controls are 1.053774 and 3.019817, respectively. GAS5 in NSCLC plasma was down-regulated compared with health controls (P=0.001), which was significantly correlated with TMN stage (P=0.024). Furthermore, plasma GAS5 increased markedly on day 7 after surgery compared with preoperative levels in NSCLC patients (P=0.003). The CT values of preoperative and postoperative are 2.225909 and 1.050455, respectively. The area under the ROC curve of GAS5 was up to 0.832. The combination of the GAS5 and CEA could produce 0.909 area under the ROC curve in distinguishing NSCLC patients from control subjects (95% CI 0.857–0.962,p=0.000).These results indicated that lncRNA GAS5 may be a more precise biomarker in NSCLC.
Conclusion:
We have demonstrated that GAS5 was decreased in NSCLC plasma expression and the plasma samples were more easily available than the tissue sample in the clinic. So GAS5 could be ideal biomarkers for the early diagnosis of NSCLC.
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MINI23.15 - Discussant for MINI23.12, MINI23.13, MINI23.14 (ID 3426)
16:45 - 18:15 | Author(s): C. Mascaux
- Abstract
- Presentation
Abstract not provided
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MS 14 - Chemo Prevention Clinical Trials (ID 32)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Prevention and Tobacco Control
- Presentations: 4
- Moderators:Y.E. Miller, P.E. Postmus
- Coordinates: 9/08/2015, 14:15 - 15:45, 401-404
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MS14.01 - Preclinical Models: How Good Are They? (ID 1908)
14:15 - 15:45 | Author(s): R.L. Keith
- Abstract
- Presentation
Abstract:
A commonly employed approach to understanding the pathogenesis of lung neoplasia is to use experimental animal models. The testing of potential chemopreventive (and chemotherapeutic) agents involves pre-clinical testing, and numerous animal models have been developed. In primary mouse lung tumor models, lung cancer develops through a predictable series of airway lesions that progress from normal epithelium to invasive cancer. Permanent genomic DNA alterations occur through either spontaneous, chemically, or environmentally-induced initiation events. The lung cancer chemoprevention field is increasingly reliant on animal studies as the results of negative, early, large scale human studies (for example, β-carotene) may have been predicted with extensive pre-clinical testing. Agents progressing to human trials now undergo extensive pre-clinical studies, and this review will focus on the commonly utilized models of adenocarcinoma (ADC) and squamous cell carcinoma(SCC). ADC: Multiple, well-characterized models of murine adenocarcinoma are available in which pulmonary adenomas progress to adenocarcinomas. These progression models also allow for the study of pre-malignant airway lesions. The most commonly studied models include initiator-promoter carcinogenesis(1), mutant KRAS(2) or EGFR(3) and the use of complete carcinogens. Urethane, a component of cigarette smoke, is a complete carcinogen because it leads to tumor development without the need for other carcinogens or promoters(4). 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) , another tobacco smoke carcinogen, is a chemically-induced model where the NNK is typically administered in drinking water or injected intraperitoneally. Tobacco smoke models also exist and they can reproducibly induce pulmonary adenocarcinomas, but they are fairly labor-intensive and do not result in robust tumor multiplicity(5). There are also multiple two-stage murine models of lung tumor promotion. Several of them use 3-methlycholanthrene (3-MCA), a polycyclic aromatic hydrocarbon, as the initiator at a low dose, followed by multiple doses of butylated hydroxytoluene (BHT). BHT is a well known antioxidant found in processed foods and packaging, however it is also an oxidant and well characterized promoter. In addition, genetically modified animal models, in which viral oncogenes or transforming ras mutants are selectively expressed in lung tissue, have been developed and extensively investigated. While there are differences between the human and murine respiratory tracts, the murine tumors derived from these models have many similarities to human adenocarcinoma, ranging from specific markers to gene expression patterns(6). SCC: Models of squamous cell lung cancer have also been developed, but they are much fewer in number. The most commonly utilized SCC model involves NTCU (N-nitroso-tris-chloroethylurea), which is applied topically and histopathological analysis of serial lung sections in this model revealed a range of lung pathology, including squamous-cell carcinoma, carcinoma in situ, and varying levels of bronchial dysplasia(7). Immunohistochemical studies on the premalignant lesions show staining that corresponds to analogous human lesions(8), and the NTCU model also induces dysplastic lesions that are similar to those found during bronchoscopy and can therefore be used to evaluate one proposed surrogate endpoint in pre-clinical studies (endobronchial dysplasia). Several positive murine chemoprevention studies examining ginseng, pomegranate fruit extract, and aerosolized budesonide +/- pioglitazone have also used NTCU (reviewed in (9)). Additional SCC models have been developed, the first consisting of a kinase dead IKKα knockin mouse (Ikkα[K44A/K44A], Ikkα[KA/KA]) that develop spontaneous SCC and marked pulmonary inflammation(10). A recently described model involved biallelic inactivation of LKB1 and PTEN in mouse lung leads to SCC that expresses the squamous markers keratin 5, p63, and SOX2(11). Chemopreventive interventions have been assessed in many of the murine preclinical models. This includes (but is not limited to): inhaled and systemic glucocorticoids; myoinositol; overexpression of prostacyclin synthase; dietary administration of the prostacyclin agonist iloprost; PPARγ overexpression; dietary administration of pioglitazone; COX inhibitors; the VEGF inhibitor vandetanib; and the anti-estrogen fulvestrant. The effect of COX inhibitors on lung cancer prevention has also been tested in murine models. It is likely the chemoprevention world will take a cue from lung cancer therapeutics by determining the altered pathways in specific premalignant lesions and employing targeted (or ‘precision’) chemoprevention in the next generation of trials. Reference List (1) Malkinson AM, Koski KM, Evans WA, Festing MF. Butylated hydroxytoluene exposure is necessary to induce lung tumors in BALB mice treated with 3-methylcholanthrene. Cancer Res 1997;57:2832-4. (2) Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 2001;410:1111-6. (3) Regales L, Balak MN, Gong Y, Politi K, Sawai A, Le C, et al. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS One 2007;2:e810. (4) Malkinson AM. Primary lung tumors in mice: an experimentally manipulable model of human adenocarcinoma. Cancer Res 1992;52:2670s-6s. (5) Witschi H. Tobacco smoke as a mouse lung carcinogen. Exp Lung Res 1998;24:385-94. (6) Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA, Jr., et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol 2005;167:1763-75. (7) Wang Y, Zhang Z, Yan Y, Lemon WJ, LaRegina M, Morrison C, et al. A chemically induced model for squamous cell carcinoma of the lung in mice: histopathology and strain susceptibility. Cancer Res 2004;64:1647-54. (8) Hudish TM, Opincariu LI, Mozer AB, Johnson MS, Cleaver TG, Malkoski SP, et al. N-nitroso-tris-chloroethylurea induces premalignant squamous dysplasia in mice. Cancer Prev Res (Phila) 2012;5:283-9. (9) Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013;10:334-43. (10) Xiao Z, Jiang Q, Willette-Brown J, Xi S, Zhu F, Burkett S, et al. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 2013;23:527-40. (11) Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 2014;25:590-604.
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MS14.02 - Clinical Trials: Who Are the Proper Cohorts and How Do You Recruit Subjects? (ID 1909)
14:15 - 15:45 | Author(s): S. Lam
- Abstract
- Presentation
Abstract:
Although chemoprevention as a means of reducing cancer incidence has been successful for basal cell carcinoma of skin, breast, and prostate cancer, after three decades of research, none of the phase III trials with agents such as Beta-carotene, retinol, 13-cis-retinoic acid, alpha-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium have demonstrated beneficial and reproducible results in preventing lung cancer, likely due to the complexity of genomic alterations in lung cancer (1). Intermediate endpoint biomarkers such as bronchial metaplasia or dysplasia have been used in Phase II trials (2). Studies on the natural history of pre-neoplastic lesions in the central airways showed that patients with high-grade dysplasia or carcinoma in-situ are more likely to develop invasive cancer at the same or another site in the lungs than those with low grade lesions. However, pre-invasive bronchial lesions may be more of a marker of lung cancer risk because more cancers developed from a separate site in the same individual than progression from an initially biopsied dysplastic site and a significant proportion of the cancers are found by CT rather than by bronchoscopy (3,4). The advantage of using bronchial metaplasia/dysplasia for phase II chemoprevention trials is that these lesions can be localized and biopsied using white light and autofluorescence bronchoscopy for histopathology confirmation. However, with a steady decline in the prevalence of centrally located squamous cell carcinomas and a shift to adenocarcinomas which are usually located in the peripheral lung beyond the range of sampling by standard flexible bronchoscopes, it has become increasingly difficult to enrol participants with bronchial dysplasia for clinical trial. With the implementation of low dose computed tomography for screening of lung cancer, alternative intermediate endpoint biomarkers, such as CT detected non-calcified lung nodules are being investigated for phase II lung cancer chemoprevention trials (5). The limitations of using CT-detected lung nodules as an intermediate endpoint are the lack of confirmation of the underlying pathology and variable growth behaviour of sub-solid nodules especially non-solid nodules (6,7). Without confirmation of the pathology (atypical adenomatous hyperplasia versus adenocarcinoma in-situ versus minimally invasive or invasive adenocarcinoma), when a nodule is first seen, volume doubling time measurement is meaningless to determine malignant behaviour. Endoscopic optical imaging tools such as combined auto-fluorescence-optical coherence tomography (8) are promising methods to localize and characterize small peripheral lung lesions for tissue or liquid biopsy for pathological diagnosis and molecular characterization (Example shown in Figure 1). The availability of accurate lung cancer risk prediction models such as the one developed by Tammemagi and co-workers (9 ) opens the possibility of using lung cancer as the endpoint for chemoprevention trials in high risk ever smokers instead of intermediate endpoint biomarkers to test chemopreventive agents that have sound biological basis. Prospective evaluation of a prototype PLCOm2012 lung cancer risk prediction model in the Pan-Canadian early Detection of Lung Cancer Study showed that a 3 years lung cancer risk of ≥2% can reliably identify a sufficient number of ever smokers who will develop lung cancer within 3 years to make it feasible to use lung cancer incidence as the endpoint for chemoprevention trials with a sample size of approximately 2500 participants. The sample size can be significantly reduced by using a nodule malignancy risk prediction model (10). There is great potential to partner with lung cancer screening programs for developing and testing biologically rationalized agents for chemoprevention clinical trials within this framework, which may lead to their eventual implementation in screening programs to improve patient outcomes. Figure 1. Autofluorescence –Optical Coherence Tomography images of a CT-detected lung nodule showing the invasive and lepidic components of the adenocarcinoma confirmed by transbronchial lung biopsy. Figure 1 Supported by the Terry Fox Research Institute, Canadian Partnership Against Cancer, the Canadian Institute of Health Research and Lung Cancer Canada. References 1. Szabo E, Mao JT, Lam S, Reid ME, & Keith RL (2013) Chemoprevention of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(5 Suppl):e40S-60S. 2. Keith RL, Blatchford PJ, Kittelson J, Minna JD, Kelly K, Massion PP, et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res (Phila). 2011;4:793-802. 3. Ishizumi T, McWilliams A, MacAulay C, Gazdar A, Lam S. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev. 2010;29:5-14. 4. Jeremy George P, Banerjee AK, Read CA, O'Sullivan C, Falzon M, Pezzella F, et al. Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax. 2007;62:43-50 5. Veronesi G, Szabo E, Decensi A, Guerrieri-Gonzaga A, et al. Randomized Phase II trial of inhaled budesonide versus placebo in high-risk individuals with CT screen-detected lung nodules. Cancer Prev Res 2011; 1:34-42. 6. Massion PP. Walker RC. Indeterminate pulmonary nodules: Risk for having or for developing lung cancer? Cancer Prev Res 2014;7:1173-1178. 7. Pinsky PF, Nath PH, Gierada DS, Sonavane S, Szabo E. Short- and long-term lung cancer risk associated with noncalcified nodules observed on low-dose CT. Cancer Prev Res (Phila). 2014;7:1179-85. 8. Pahlevaninezhad H, Lee AM, Shaipanich T, Raizada R, Cahill L, Hohert G, Yang VX, Lam S, MacAulay C, Lane P. A high-efficiency fiber-based imaging system for co-registered autofluorescence and optical coherence tomography. Biomed Opt Express. 2014 Aug 6;5(9):2978-87. doi: 10.1364/BOE.5.002978. eCollection 2014 Sep 1. 9. Tammemagi MC, et al. (2013) Selection criteria for lung-cancer screening. The New England journal of medicine 368(8):728-736. 10. Tammemagi MC, Lam S. Screening for lung cancer using low dose computed tomography. BMJ. 2014 May 27;348:g2253. doi: 10.1136/bmj.g2253. Review.
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MS14.03 - Pathologic Biomarkers of Risk and Benefit of Treatment (ID 1910)
14:15 - 15:45 | Author(s): D.T. Merrick
- Abstract
- Presentation
Abstract:
Prevention of lung cancer could lead to a significant reduction in the mortality associated with this disease. Identification of individuals at high risk for the development of invasive lung cancer is critical to establishing efficient and effective screening and prevention programs. The presence of premalignant lesions including atypical adenomatous hyperplasia/adenocarcinoma-in-situ (AAH/AIS) and bronchial dysplasia (BD), which represent precursors of adenocarcinoma and squamous cell carcinoma (SCC) respectively, provide targets that can be studied by histologic, radiographic and molecular techniques to define biologic characteristics that are indicative of risk and potential cellular activities that can be targeted for prevention. The histologic features of premalignant lesions have been well described in published WHO defined classification systems (1). Accurate histologic assessment of precursor lesions of lung adenocarcinoma prior to development of invasive cancer is limited by sampling considerations. To establish a diagnosis of premalignant AAH or AIS, the whole lesion must be examined and size criteria and histologic confirmation of lack of invasion must be documented. Because resection is generally restricted to cases of invasive cancer, tissue from AAH or AIS prior to development of invasive adenocarcinoma are rare, and most analyses of these lesions are performed on lesions that are associated with or occur as synchronous independent lesions of invasive cancer in resection specimens. However, a number of recent publications have begun to describe non-lesion associated biomarkers that can be correlated with radiographic features that appear to faithfully distinguish premalignant from invasive peripheral lung lesions. While AAH and AIS are considered to be precursors of adenocarcinomas derived from the terminal respiratory unit (TRU), a recently described premalignant lesion, mucous columnar cell change (MCCC), appears to be the precursor of a less common subset of adenocarcinomas derived from a region of the distal airways that is proximal to the TRU. This lesion has been reported to be present in up to 70% of the mucinous variant adenocarcinomas that are derived from these more central sites (2). This suggests that MCCC may be amenable to sampling at a pre-invasive stage by bronchoscopic means. In contrast, BD is detectable prior to development of invasive cancer by bronchoscopy but cannot be identified by radiographic examination. Higher rates of progression to invasive SCC and/or carcinoma-in-situ for lesions with higher grades of atypia have been suggested in a number of studies and meta-analyses (3). We have assessed the relationship between persistence of BD and risk for development of invasive lung cancer employing a numeric scoring system (1=normal; 2-7=increasing levels of precursor atypia; 8=invasive cancer). These analyses have shown that higher histologic scores on follow-up biopsies at specific sites within the airway of individuals sampled over time are associated with higher baseline histologic score, the presence of papillary angiogenic change, and current smoking status (4). Multivariable analyses including these parameters show that sites in subjects that develop SCC have mean histologic scores on follow-up biopsy that are 1.55 higher than those in patient’s without development of invasive lung cancer. On a per subject basis, the frequency of SCC was significantly increased in subjects that showed multiple sites of BD at baseline that persisted as or progressed to high grade dysplasia (moderate dysplasia or worse, histology score > 5). A 33% increase in risk for development of SCC is associated with every 10% increase in percent of sites that persist/progress to HGD corresponding to an overall hazard ratio of 17.14 (CI 2.4, 123.3) for multifocal persistent BD. These findings lend support to the importance of a field effect in lung carcinogenesis and suggest a potential role for histologic demonstration of persistent field change as an indicator of risk for the development of lung SCC. A number of biomarkers have been studied to determine their relationship with outcomes in premalignant lung lesions. Direct analyses of AAH and AIS have shown that a significant number of these lesions harbor the activating EGFR driver mutations seen in invasive adenocarcinoma of the lung. The potential of these mutational events to act as predictors of progression is under investigation, and a case report has demonstrated response to EGFR inhibitors of radiographically established multifocal premalignant disease in which an EGFR mutation was demonstrated in biopsy tissue of one of the lesions (5). Interestingly, the tumors associated with MCCC show a higher proportion of KRAS mutations. Non-lesional biomarkers of risk such as a recently reported assay measuring germline DNA repair activity that correlates decreased repair capability with increased risk for malignancy show promise for risk prediction (6). BDs, like SCC, demonstrate frequent genetic alterations in tumor suppressor genes and show characteristic associated alterations in gene methylation, loss of heterozygosity and gene copy number gains that have been associated with increased risk (7-10). In an analysis of a small series of cases in which sites with BD were observed to directly progress to invasive SCC, we have demonstrated frequent TP53 and some other mutations in precursor lesions. Furthermore, via pathway analysis of genes that we have found to be differentially expressed between persistent and regressive bronchial dysplasia, we have identified altered control of cell cycle, adhesion and immune activity (see abstract #3026) to be associated with persistence of BD. Overexpression of polo-like kinase 1 (PLK1) is the most prominent cell cycle control alteration associated with persistence and its role as a mediator of progression through the G2-M DNA damage checkpoint suggests a potential mechanism by which genomic instability can be promoted in high risk premalignant BD. PLK1 inhibitor treatment of primary cultures derived from sites of persistent BD causes an arrest of growth in S/G2 phase and induces apoptosis, neither of which occurs when PLK1 inhibitor is applied to primary cultures of normal bronchial epithelium. Histologic features and molecular biomarkers of premalignant lung lesions provide means by which risk can be assessed, appropriate targets for prevention can be identified and efficacy of preventive therapies can be measured. References 1. Travis WD, Brambilla E, Muller-Hermelink HK and Harris CC. Pathology and genetics: tumors of the lung, pleura, thymus and heart. World Health Organization Classification of tumours. Lyon: IARC; 2004. p. 9-124. 2. Weichart W and Warth A. Early lung cancer with lepidic pattern: adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Curr Opin Pulm Med 2014, 20:309–316 3. Ishizumi T, McWilliams A, Macaulay C, Gazdar A and Lam S. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev 2010;29:5-14. 4. Merrick DT, Haney J, Petrunich S, Sugita M, Miller YE, Keith RLet. al. Overexpression of vascular endothelial growth factor and its receptors in bronchial dysplasia demonstrated by quantitative RT-PCR analysis. Lung Cancer 2005;48(1):31-45. 5. Pastorino U, Calabro E, TamboriniE, MarchianoA, Orsenigo M, Fabbri A, Sozzi G, Novello S, and De Marinis F. Prolonged Remission of Disseminated Atypical Adenomatous Hyperplasia Under Gefitinib. J Thorac Oncol 2009;4: 266–267. 6. Sevilya Z, Leitner-Dagan Y, Pinchev M, Kremer R, Elinger D, Rennert HS, Schechtman E, Freedman LS, Rennert G, Paz-Elizur T, and Livneh Z. Low Integrated DNA Repair Score and Lung Cancer Risk. Cancer Prev Res; 7(4); 398–406. 7. Nakachi I, Rice JL, Coldren CD, Edwards MG, Stearman RS, Glidewell SC, Varella-Garcia M, Franklin WA, Keith RL, Lewis MT, Gao B, Merrick DT, Miller YE, and Geraci MW. Application ofSNPMicroarrays to theGenome-Wide Analysis of Chromosomal Instability in Premalignant Airway Lesions. Cancer Prev Res; 7(2); 255–65. 8. Massion, P., Zou, Y., Uner, H., Kiatsimkul, P.,Wolf, H. J., Baron, A. E., et al. Recurrent genomic gains in preinvasive lesions as a biomarker of risk for lung cancer. PLoS ONE 2009;4(6):e5611. 9. Wistuba, I. I., Behrens, C., Virmani, Ak, Mele, G., Milchgrub, S., Girard, L., et al. High resolution chromosome 3p allelotyping of human lung cancer and bronchial epithelium reveals multiple, discontinuous sites of 3pallele loss and three regions of frequent breakpoints. Cancer Res 2000;60:1949–1960. 10. Belinsky SA[1], Liechty KC, Gentry FD, Wolf HJ, Rogers J, Vu K, Haney J, Kennedy TC, Hirsch FR, Miller Y, Franklin WA, Herman JG, Baylin SB, Bunn PA, Byers T. Promoter hypermethylation of multiple genes in sputum precedes lung cancer incidence in a high-risk cohort. Cancer Res 2006; 66(6):3338-44.
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MS14.04 - Chemoprevention Clinical Trials: How Do We Move Forward? How Do We Identify Valid End Points? (ID 1911)
14:15 - 15:45 | Author(s): E. Szabo
- Abstract
- Presentation
Abstract:
The ability to intervene in the process of carcinogenesis is predicated on an understanding of the pathways leading to invasive cancer and availability of targeted tools to abrogate the resulting processes. Thus, effective chemoprevention has been hampered by the evolving understanding of lung cancer as a heterogeneous set of malignancies arising from a multitude of diverse molecular deregulations. The simplistic view that early intervention (before the evolution of multiple complex mutational events that are characteristic of tobacco-related malignancies) is more likely to be effective than late intervention has been replaced by the realization that many complex abnormalities actually do occur early and we simply do not understand which individual abnormalities or combinations of abnormalities would derail the inevitable progression to invasive and metastatic cancer. To assess efficacy, well designed clinical trials need to have end points that are informative. For phase III trials, the ideal end point would be cancer-related mortality so that cancer overdiagnosis does not cloud the issue. Realistically, cancer incidence is a more achievable and sufficiently informative end point. Phase II trials, however, depend on intermediate end points that are surrogates for cancer incidence, in a manner analogous to tumor shrinkage or progression-free survival being a surrogate for survival in phase II cancer treatment trials. Examples of end points that have been used in a variety of phase II chemoprevention trials are premalignant lesions, proliferative indices, and a variety of biomarkers of risk or malignant potential. It must be emphasized that to be useful, intermediate end points should be integrally involved in the process of carcinogenesis, differentially expressed in at-risk vs. normal epithelium, and modulated by effective interventions well above the level of spontaneous fluctuation (1). To date, no intermediate end point has been validated to replace lung cancer incidence, but such biomarkers can significantly inform drug development and decision-making for subsequent phase III trials. Nevertheless, the histologic evolution of squamous carcinogenesis, with progression from bronchial metaplasia through varying grades of dysplasia to carcinoma in situ is well described (2). This knowledge has allowed for clinical trials based on pre- and post-treatment assessment of effect of interventions on bronchial histology. However, the rate of progression of dysplasia to invasive cancer is variable even though high grade histologies are associated with higher rates of progression. Therefore, studies assessing dysplasia need to have placebo controls to correct for spontaneous and biopsy-induced regression. A recent trial of a prostacyclin analogue, iloprost, showed improvement in bronchial histology in former smokers after 6 months of treatment (3). These results will be extended in a soon-to-open trial of inhaled iloprost in a similar population and will include analyses of potential molecular predictors of histologic progression. Ongoing efforts are focusing on understanding the process of carcinogenesis by profiling premalignant lesions, both in a cross-sectional manner with regard to lesions identified at time of lung cancer resection (4) and with longitudinal follow-up. Understanding the natural history of premalignant lesions will help determine which ones progress, why they progress, and, therefore, which end points are likely to be most informative. An alternative way to approach the issue is to examine the at-risk epithelial field to identify biomarkers associated with progressive carcinogenesis. Gustafson et al. showed that the PI3K pathway is upregulated early during lung carcinogenesis and that an intervention with a drug, myo-inositol, that resulted in regression of bronchial dysplasia also inhibited PI3K activation in the histologically normal bronchial epithelium obtained by bronchial brushings (5). These data suggest that upregulated PI3K could potentially identify smokers at increased lung cancer risk and that pathway inhibition could serve as an end point for assessing treatment effect. This hypothesis is undergoing further testing in a recently finished phase II trial of myo-inositol in current and former smokers with dysplasia, where normal bronchial epithelium was collected and will be tested for PI3K activation pre- and post-treatment. Similarly, Spira et al. showed that gene expression classifiers from bronchial brushings of histologically normal epithelium obtained from individuals undergoing bronchoscopy for suspect lung cancer can aid in the diagnosis of lung cancer and can serve as lung cancer biomarkers (6,7). These classifiers have potential to be adapted to surrogate tissues further up in the aerodigestive tract, such as the nasal epithelium, and are being tested in chemoprevention ongoing clinical trials (8; NCT02123849). How do we move forward? A better understanding of the early carcinogenic processes and which processes are operative in individual persons is key to designing clinical trials that bring the prospect of precision medicine to lung cancer chemoprevention. The focus on a molecular understanding of premalignant lesions and the at-risk field is at the center of current efforts to identify informative end points for chemoprevention clinical trials. References Szabo E. Phase II cancer prevention clinical trials. Semin Oncol 2010;37:359-66. Saccomanno G et al. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974;33:256-70. Keith R et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res 2011;4:793-802. Ooi AT et al. Molecular profiling of premalignant lesions in lung squamous cell carcinomas identifies mechanisms involved in stepwise carcinogenesis. Cancer Prev Res 2014;7:487-95. Gustafson AM et al. Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Trans Med 2010;2:26ra25. Spira A et al. Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer. Nat Med 2007;13:361-6. Silvestri GA et al. A Bronchial Genomic Classifier for the Diagnostic Evaluation of Lung Cancer. N Eng J Med 2015 May 17 [Epub ahead of print]. Zhang X et al. Similarities and differences between smoking-related gene expression in nasal and bronchial epithelium. Physiol Genomics 2010;41:1-8.
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HOD 04 - Highlights of the Previous Day: Biology, Pathology, Molecular Testing, Prevention, Tobacco Control, Screening and Early Detection (ID 236)
- Event: WCLC 2015
- Type: Highlights of the Day
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 07:00 - 08:00, Four Seasons Ballroom F3+F4
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HOD04.03 - Screening, Early Detection (ID 3417)
07:00 - 08:00 | Author(s): P.E. Postmus
- Abstract
- Presentation
Abstract not provided
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-058 - <em>nab</em>-Paclitaxel + Carboplatin in Advanced Non-Small Cell Lung Cancer NSCLC: Dose Modification Analysis (ID 1570)
09:30 - 17:00 | Author(s): P.E. Postmus
- Abstract
Background:
Chemotherapy dose modifications may impact clinical outcomes in patients with cancer. In a phase III trial, first-line treatment of patients with advanced NSCLC with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the overall response rate (ORR; primary endpoint) compared with solvent-based paclitaxel plus C (sb-P/C; 33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). This exploratory analysis examined the correlation between patients receiving protocol-specified dose modifications and clinical outcomes in the phase III trial.
Methods:
Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received either nab-P 100 mg/m[2] on days 1, 8, and 15 or sb-P 200 mg/m[2] on day 1, both in combination with C AUC 6 on day 1, every 21 days (randomized 1:1). ORR and progression-free survival (PFS) were assessed by blinded, centralized review. P values for ORR were based on the chi-square test, and those for overall survival (OS) and PFS were based on the log-rank test. Patients who discontinued treatment before cycle 3 or remained on treatment after 6 months were excluded from this analysis unless otherwise specified.
Results:
Dose modification and clinical outcomes for patients treated for ≥ 3 cycles but ≤ 6 months are shown in the Table. In the nab-P/C arm, 268 of 310 patients (86%) who were treated for ≥ 3 cycles and ≤ 6 months had a dose modification compared with 200 of 319 (63%) in the sb-P/C arm. In the nab-P/C cohort, ORR and PFS were significantly higher in patients who received a dose modification vs those who did not (Table), possibly due to better tolerability and longer treatment duration. In the sb-P/C arm, there were no differences in efficacy outcomes between either group. As predicted, patients with a lower numerical incidence of toxicity were those that did not require dose modifications.
Conclusion:
This exploratory analysis suggested that, in this patient subset, protocol-specified dose modifications did not negatively impact the primary endpoint of ORR and in fact resulted in a greater ORR for those receiving nab-P/C. Figure 1
