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R. Young
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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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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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MINI23.02 - 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. Young
- 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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MS 10 - Management of Screening Detected Lung Cancer (ID 28)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:N. Ikeda, B. Park, P. Goldstraw, L.E. Raez
- Coordinates: 9/07/2015, 14:15 - 15:45, Mile High Ballroom 2c-3c
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MS10.07 - Biomarkers: Current Status and Future Direction (ID 1895)
14:15 - 15:45 | Author(s): R. Young
- Abstract
- Presentation
Abstract:
The need for biomarkers Yearly low-dose computed tomography (CT) screening for lung cancer is now widely recommended in the United States.[1] Published articles reviewing the benefits versus harms of lung cancer screening have highlighted the potential harms from radiation exposure, unnecessary invasive workup and overdiagnosis.[2] While cost-effectiveness analysis has suggested that CT screening for lung cancer is comparable to other existing cancer screening programs, this analysis makes a number of assumptions based on the NLST findings which may not translate to the wider community. These issues highlight the need for identifying biomarkers that may improve patient selection, maximise lung cancer detection, minimizing overdiagnosis and the treatment of indolent disease.[2] The eligibility criteria for the NLST were specifically designed to maximize the number of cancers that could be identified during screening within a relatively high risk group. However, it has been shown that age and pack years alone have only limited utility in identifying those smokers at greatest risk.[3-5] It was never intended that screening eligibility should be based solely on the NLST criteria. The first problem is the NLST screening criteria include low risk individuals for whom the risk of screening far outweighs the benefit.[3-5] The second problem is that between 40-60% of lung cancer cases are currently ineligible for lung cancer screening due to restrictions on age and smoking history.[6,7] The former group is estimated to represent about 30-40% of those currently eligible for screening based on the NLST and can be identified using multivariate risk models incorporating several clinical risk variables such as age, detailed smoking history, past diagnosis of COPD, BMI, occupation and ethnicity.[4] Lung Function and related tests of COPD There have been several studies that show lung function testing adds considerable predictive utility to clinical multivariate models. This approach stratifies smokers with normal lung function (no airflow limitation and/or DLCO reduction) into a low risk group, where it has been shown their lung cancer incidence is only a quarter of that observed in those with COPD.[8] Emphysema identified on CT has also been shown to identify high risk smokers for lung cancer where airflow limitation is absent.[9] These studies confirm past epidemiology identifying that co-existing COPD, characterized by reductions in forced expiratory volume (and its ratio with forced vital capacity) are significant risk factors for lung cancer. Genetic Markers A limited number of studies have found that genetic markers, primarily single nucleotide polymorphic (SNP) variants, add to the predictive utility of clinically-based risk tests.[10 ]These SNP markers reside in genes encoding several important proteins, including epithelial based receptors, involved in mediating smoking-related inflammation in the lungs.[10 ]The value of identifying these genetic markers lies in their predictive utility to recognize high risk individuals long before the clinical manifestations of smoking damage (airflow limitation or emphysema) are clinically evident. The addition of SNP modestly increases the sensitivity and specificity of the risk models which use clinical variables alone. More importantly, the addition of these markers improves the correct assignment of risk in up to 25-30% of people participating in lung cancer screening trials. Other Molecular Biomarkers Other molecular markers for lung cancer currently under investigation are protein markers, antibody assays and expression (RNA) profiles.[11-14] These types of assay are potentially subject to biological interference from smoking status (eg. current vs ex-smokers) or co-existing COPD, where drug therapies (eg. inhaled corticosteroids or antibiotics) and bacterial colonisation of the lung (eg. effects from the lung microbiome) are present. The “noise” from these co-existing conditions may cause confounding or mediating effects that reduce the predictive utility of the assay of interest. One of the more promising of these biological assays involves the analysis of exhaled volatile compounds from the lung which can now be measured with more accurate devices.[14] These molecular assays are currently being validated in large prospective clinical trials. Biomarkers in CT screening – risk assessment While the utility of these assays in the context of CT screening remains to be established, they all have the potential to improve the current risk-benefit ratio of CT screening. First, this might involve identifying low risk individuals currently eligible for screening based on the age and pack year criteria (“NLST approach”) but who gain little benefit from screening. Alternatively, wider risk assessment would help identify those smokers who are at high risk despite not meeting the NLST criteria (“NCCN approach”). In this setting, markers related to a predisposition to COPD, such as airflow limitation based on spirometry, reduced DLCO (as a marker of emphysema and interstitial lung disease) or CT-based emphysema, are particularly relevant. Genetic (SNP) markers associated with an increased predisposition to COPD or lung cancer may also help in this regard.[10] Second, expression-based markers may be helpful in distinguishing benign from malignant nodules. With time, greater refinement of these techniques for identifying and validating novel biomarkers will provide greater confidence in their use in conjunction with serial CT screening. This approach might augment existing risk models based on clinical parameters. However, these biomarkers are competing with serial CT -based volumetric analyses which appears on initial studies to considerably reduce the false positive rate (discriminate benign from malignant based on growth rate). These novel biomarkers would be combined with multivariate risk models to reduce the treatment of indolent nodules, reducing overdiagnosis and minimize harm. In a recent post-hoc analysis of the NLST-ACRIN data, we found that airflow limitation based on pre-bronchodilator spirometry is associated with little if any overdiagnosis. This finding is consistent with the results of others showing COPD to be associated with more aggressive lung cancer. Other biomarkers may have a similar utility. Biomarkers in CT screening – smoking cessation Smoking cessation is the only proven lifestyle modification that reduces the risk of lung cancer. Little thought is given to the use of biomarkers in smoking cessation. In a limited number of studies it has been shown that risk assessment tools have some contribution to make to smoking cessation.[15] Inconsistency of findings with respect to the effects of lung function testing and CT nodule identification on quit rates means there is more work to be done here. The basic psychology of smoking suggests that challenging some smokers with personal biodata enhances their perception of smoking-related risks. In particular, showing a smoker they are at greater risk than the average smoker based on personal data increases their interest in quitting.[15] This is believed to occur because personal biodata increases motivational tension and undermines the smoker’s denial which maintains their smoking habit. This aspect of CT screening programmes is not one that has received as much attention as it warrants. However CT screening programmes, with routine use of personalised risk appraisal, are uniquely positioned to reinforce existing public health strategies aimed at reducing smoking rates. Summary While there remains much to do to confirm the utility of biomarkers in the CT screening process , existing data suggests that significant gains may be made by their use in improving risk-benefit appraisal of screening participants, better management of nodules and perhaps significant gains in reducing smoking rates among high risk smokers. References 1. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. Benefits and harms of CT screening for lung cancer: A systematic review. JAMA 2012; 307(22):2418-29. 2. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive Services Task Force recommendation. Ann Int Med 2013; 159(6):411-20. 3. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Int Med 2012, August 14. 4. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung cancer death. N Eng J Med 2013; 369: 245-254 5. Young RP, Hopkins RJ, MidthunDE. Benefits and harms of CT screening for lung cancer: A systematic review – Letter. JAMA 2012; 308: 1320-1321. 6. Young RP, Hopkins RJ. Lung cancer risk prediction to select smokers for screening. Cancer Prev Res 2012; 5: 697-698. 7. Wang Y, MidthunDE, Wampfler JA, et al. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA 2015; 313: 853-855. 8. Young RP, Hopkins RJ. Diagnosing COPD and targeting lung cancer screening. Eur Respir J 2012; 140: 1063-1064. 9. Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med 2008; 178: 738-744. 10. Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. Plos One 2011; 6: e16476. 11. Silvetsri GA, Vachani A, Whitney, D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N Eng J Med 2015; May 17. 12. Hassanein M, Rahman JSM, Chaurand P, Massion P. Advances in proteomic strategies towards the early detection of lung cancer. Proc Am Thorac Soc 2011; 8: 183-188. 13. Healey GF, Lam S, Boyle P, et al. Signal stratification of autoantibody levels in serum samples and its applications to the early detection of lung cancer. J Thorac Dis 2013; 5: 618-625. 14. Dent AG, Sutedja, Zimmerman PV. Exhaled breath analysis for lung cancer. J Thorac Dis 2013; 5: S540-S550. 15. Young RP, Hopkins RJ. Genetic susceptibility testing to lung cancer and outcomes in smokers. Tob Control 2012; 21: 347-354.
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P1.06 - Poster Session/ Screening and Early Detection (ID 218)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 2
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.06-003 - Low-Dose CT Lung Cancer Screening in the Community: A Prospective Cohort Study Incorporating a Gene-Based Lung Cancer Risk Test (ID 879)
09:30 - 17:00 | Author(s): R. Young
- Abstract
Background:
Following the publication of the National Lung Screening Trial (NLST) results in 2011, CT screening for lung cancer is now widely recommended in the US. However concerns remain with regards to patient selection according to risk level and overdiagnosis.Moreover adherence outside screening trials is typically about 50-60% and has been shown to be highly dependent on an individual's risk perception. This feasibility study explores the relevance of gene-based data on lung cancer risk assessment and adherence to screening, in a pilot screening program.
Methods:
This feasibility study was initiated in 2010 prior to NLST results being published. Following local media-based advertising, 157 current or former smokers (>50 years old with ≥20 pack year history), volunteered for lung cancer risk assessment and CT screening (using the IELCAP protocol). Participants were followed up for a mean of 2.4 years.At baseline CT screening, participants were assigned their lung cancer risk category according to a published and prospectively validated gene-based risk algorithm. This algorithm combines clinical risk variables with risk genotypes, derived from analysis of 20 risk single nucleotide polymorphisms (SNPS), to derive a composite lung cancer risk score categorised as moderate, high or very high.
Results:
SNP genotype results contributed to overall lung cancer risk in 88% of participants compared to the contribution from age = 68%, family history of lung cancer = 29% and self reported chronic obstructive pulmonary disease =15%. The SNP genotype results were the sole basis of risk in 18% of participants and contributed to risk in a further 70% of participants (total 88%). Adding SNP scores to the clinical risk score re-assigned screening participants into different risk categories in 28% (44/157) of participants (Figure 1). Importantly, timely adherence to the CT screening protocol was two-fold greater in those with a very high risk score compared to the high and moderate risk categories (71% vs 52% vs 52% respectively, OR =2.3, P<0.05). Figure 1
Conclusion:
In this feasibility study of a pilot community-based CT screening program we found gene-based risk assessment was of interest to all screening volunteers. As part of risk assessment, personalised SNP data made the greatest contribution to overall assignment of lung cancer risk in association with established clinical variables and significantly improved screening adherence. We conclude that gene-based risk stratification helps assign lung cancer risk and appears to improve adherence to screening.
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P1.06-019 - A Comparison of Demographic Risk Variables for Lung Cancer in New Zealand Europeans and Maori: Are Maori More Susceptible to the Effects of Smoking? (ID 867)
09:30 - 17:00 | Author(s): R. Young
- Abstract
Background:
Lung Cancer is the leading cause of cancer death among New Zealand (NZ) Maori. Over the past twenty years lung cancer incidence has decreased in New Zealand for non-Maori but has increased for Maori, and is recognised to be the highest in the world of any ethnic group. Nationally, the incidence of lung cancer in Maori is 3.5 times higher than that in New Zealand Europeans, and lung cancer mortality in Maori males and females respectively, is 2.4 and 4.2 times higher than NZ Europeans. Maori have a higher incidence of lung cancer than countries with similar smoking rates. This suggests that there are additional factors other than smoking that predispose Maori to this disease. In the current study demographic and the well-established clinical risk variables for lung cancer were compared between New Zealand Maori and Europeans residing in the greater Auckland region and who were diagnosed between January 2004-January 2015.
Methods:
A retrospective review of patient clinical notes for those identified as being of NZ Maori ethnicity who were diagnosed with lung cancer (n=473) between January 2004 and January 2015 and treated within the greater Auckland region. Data extracted included histological type, smoking history, spirometry and basic demographics. This data was then compared with an established cohort of NZ European patients n= 417, with similar recruitment criteria over the period 2004-2008.
Results:
Despite comparable smoking exposure histories, NZ Maori patients were diagnosed on average 6 years younger than NZ European lung cancer patients (P<0.0001). At diagnosis, current smoking rate was 2 fold greater in NZ Maori compared to NZ Europeans (69% vs 36%, P<0.0001). Although NZ Maori patients had similar rates of COPD (≈64%), they had a trend towards less GOLD 1 (mild stage disease, P=0.08) and significantly greater airflow obstruction (worse COPD, FEV~1~%predicted 64% vs 73% in NZ Europeans, P<0.001). At lower smoking exposure (≤10 pk yrs), COPD rates in Maori with lung cancer were 2 fold greater than in NZ Europeans (64% vs 32% respectively, P<0.05). NZ Maori lung cancer patients had a lower prevalence of adenocarcinoma than in NZ Europeans (32% vs 43%, P=0.002) and a higher proportion of more aggressive lung cancer subtypes (squamous, non-small cell and small cell cancers) than NZ Europeans (61% vs 52%, P<0.0007).
Conclusion:
These results show that lung cancer in NZ Maori is associated with younger age at diagnosis, worse lung function and more aggressive histological subtypes compared to NZ Europeans. These results suggest that NZ Maori may have a greater inherent susceptibility to lung cancer compared to NZ Europeans. This greater susceptibility to lung cancer in Maori, along with socio-cultural factors, may contribute to their considerably greater mortality. These results suggest that for the future management of lung cancer, prevention measures (such as smoking cessation and tobacco control), risk assessment (such as lung function testing) and early diagnostic approaches (such as computed tomography screening) should be prioritised in high risk groups, particularly those with NZ Maori ancestry.
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P3.06 - Poster Session/ Screening and Early Detection (ID 220)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.06-002 - Favourable Stage-Shift Limited to Screening Participants with COPD in a Biomarker Sub-Study of the National Lung Screening Trial (NLST) (ID 873)
09:30 - 17:00 | Author(s): R. Young
- Abstract
Background:
Based on a 20% reduction in lung cancer deaths in participants of the National Lung Screening Trial (NLST), CT screening for lung cancer is now widely recommended in the US. However concerns remain regarding the cost-benefits of screening due to overall low detection rates, over-diagnosis and high false-positive rates. Using the spirometric data available from the ACRIN-biomarker sub-study of the NLST (n=18,714), we examined the effect of Chronic Obstrucitve Pulmonary Disease (COPD) status on lung cancer detection in the NLST screening participants. Specifically we compared lung cancer incidence, histology and stage shift in those with and without COPD based on baseline pre-bronchodilator spirometry.
Methods:
Baseline spirometry results were available for 18,475 (99%) of the total cohort of 18,714, (6,436 with COPD and 12,039 with no COPD). Spirometry results were available for 758 (99%) of the 768 histology-confirmed lung cancer cases diagnosed over the 7 year follow-up period. After lung cancer cases were sub-grouped by spirometry-defined COPD (GOLD 1-4, n=401) and no baseline COPD (n=357) it was possible to compare the number of cancers, histology and stage according to screening arm. Differences in lung cancer incidence rates were compared by incident rate ratios, while prevalence, histology and stage shift, were compared by chi-square frequency tables.
Results:
In this NLST-ACRIN Biomarker sub-study, we found the demographic variables were comparable to those from the full NLST study. Regardless of screening interval, we found the lung cancer incidence was 2 fold greater in those with COPD compared to no COPD (P<0.0001). In those with COPD, we found a signficant reduction in adenocarcinomas and bronchioloalveolar carcinomas. After stratification by COPD status, when comparing CT versus CXR screening arms, we found no excess lung cancers and comparable lung cancer histology. However, a clinically significant stage shift favouring increased early stage (+17) and reduced late stage cancers (-23) was found (P=0.05). In contrast, in cancer cases with no COPD, we found an 18% excess of lung cancers in the CT arm (+29) which were of a BAC/AC histology. After correction for this overdiagnosis from these excess cancers, the stage shift no longer favoured early stage over late stage. Figure 1
Conclusion:
These data suggest that in those with COPD at baseline, CT screening (vs CXR) was associated with no excess cancers, no histology shift but a clinically significant stage shift favouring early over late stage cancers. In those with no COPD, CT was associated with excess cancers and a marginal stage shift.
