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H.I. Pass

Moderator of

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    MINI 12 - Biomarkers and Lung Nodule Management (ID 109)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 15
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      MINI12.01 - A Novel Serum 4-MicroRNA Signature for Lung Cancer Detection (ID 585)

      E. Nadal, A. Truini, A. Nakata, J. Lin, R. Reddy, A.C. Chang, N. Ramnath, N. Gotoh, G. Chen, D. Beer

      • Abstract
      • Presentation
      • Slides

      Background:
      Early detection of lung cancer using low-dose CT led to a 20% reduction in mortality. However, this strategy has several limitations including high false-positive rates, potential over-diagnosis, and the potential harm associated with radiation exposure. The aim of this study was to identify differentially-expressed miRNAs in the serum of non-small cell lung cancer (NSCLC) patients that might be a clinically-useful tool for lung cancer early detection.

      Methods:
      We performed miRNA expression profile analysis using TaqMan OpenArray Human panel in a discovery set of 70 serum samples obtained at lung tumor resection including lung adenocarcinoma (AD) and lung squamous carcinoma (SCC) and 22 non-cancer subjects (NC). To construct the diagnostic signature, the miRNA candidates were selected based upon the following criteria: miRNAs significantly up-regulated (adjusted t-test p < 0.001) in the NSCLC tissue and serum as compared to normal lung tissue and NC serum respectively, not overexpressed in circulating blood cells and with Area Under the Curve (AUC) > 0.840 for discriminating stage I LC from NC in the receiver-operating characteristic (ROC) plots. Selected serum miRNAs were then validated by quantitative PCR using an independent validation set of serum samples from LC patients (n=84) and NC (n=23).

      Results:
      Sixty miRNAs were significantly up-regulated and 31 were down-regulated in the serum from NSCLC patients versus NC (adjusted p<0.001). Four miRNAs (miR-193b, miR-301, miR-141 and miR-200b) were selected for validating their diagnostic value in an independent cohort. A diagnostic signature was obtained by logistic regression based upon the expression values of these 4 serum miRNAs in the discovery set. This miRNA signature generated an AUC of 0.985 (95% CI 0.961 – 1.000, p < 0.001) for detecting NSCLC (all stages) and of 0.989 (95% CI 0.967 – 1.000, p < 0.001) for detecting stage I NSCLC in the discovery set. In the test set, the diagnostic utility of this miRNA signature was validated and exhibited an AUC of 0.993 (95% CI 0.979 – 1.000, p < 0.001).

      Conclusion:
      We identified a serum 4-miRNA signature that discriminated with high accuracy lung cancer patients from NC. Further prospective validation of this miRNA signature is warranted using an independent cohort of serum samples from patients who participated in a lung cancer screening program.

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      MINI12.02 - Clinical Utility of Chromosomal Aneusomy in High Risk Individuals (ID 1299)

      A.E. Barón, S. Kako, W.J. Feser, D.T. Merrick, K. Garg, S. Malkoski, S. Pretzel, T. Byers, J.M. Siegfried, W.A. Franklin, Y.E. Miller, H.J. Wolf, M. Varella-Garcia

      • Abstract
      • Presentation
      • Slides

      Background:
      In the context of CT screening in current and former smokers at high risk for lung cancer, the false positive rate is high (26% at first NLST screening; 13% with Lung-RADS criteria applied to NLST) and indeterminate nodules are frequently discovered. Noninvasive biomarkers are urgently needed to reduce false positives with screening CT and to improve risk stratification in those with indeterminate nodules. The Colorado (CO) Lung SPORE program performed a retrospective longitudinal evaluation (Pepe Phase 3 validation) to assess the potential of chromosomal aneusomy detected in sputum via fluorescence in situ hybridization (CA-FISH) as a biomarker for early detection in four nested case-control studies. Two of the cohorts (ACRIN/NLST and PLuSS) enrolled current and former smokers to investigate use of low dose CT to diagnose lung cancer. The other two were Colorado cohorts in which pulmonary clinic patients (mostly current and former smokers) were enrolled to investigate biomarkers to predict lung cancer. One of these cohorts (CO High Risk) was a COPD population and the other, still in the accrual phase, comprises patients referred for care of indeterminate lung nodules (CO Nodule).

      Methods:
      The cohorts were grouped into a Screening cohort (ACRIN/NLST (49 cases, 96 controls) and PLuSS (48 cases, 89 controls)) and a High Risk cohort (CO High Risk (55 cases, 59 controls) and CO Nodule (13 cases, 10 controls)). The CA-FISH assay was a 4-target panel including genomic sequences encompassing the EGFR and MYC genes, and the 5p15 and centromere 6 regions or the FGFR1 and PIK3CA genes. At the subject level, the assay was scored on a 4-category scale representing normal, probably normal, probably abnormal and abnormal. Operating characteristics (with 95% CI) of the assay were estimated for each group of cohorts overall and separately for COPD patients: sensitivity, specificity, likelihood ratio+ (LR+) and likelihood ratio- (LR-).

      Results:
      Using the cutoff of abnormal vs. not abnormal for CA-FISH, sensitivity and specificity for Screening subjects are 0.20 (0.13, 0.30) and 0.84 (0.78, 0.89), respectively; and for High Risk subjects are 0.67 (0.55, 0.78) and 0.94 (0.85, 0.98), respectively. Likelihood ratios for Screening subjects are LR+: 1.36 (0.81, 2.28) and LR-: 0.93 (0.83, 1.05), and for High Risk subjects are LR+: 11.66 (4.44, 30.63), and LR-: 0.34 (0.24, 0.48). Similar results were observed when only COPD subjects were analyzed.

      Conclusion:
      The high LR+ of sputum CA-FISH indicates that this noninvasive biomarker could be a clinically useful adjunct to CT among patients in high risk settings. Whether this same high level of LR+ will be reproducible in patients at high risk because of their indeterminate nodules remains to be seen. If so, a hypothetical patient with indeterminate nodules and a pre-test (CA-FISH) lung cancer risk of 20% would have a post-test probability of lung cancer of 78% if the CA-FISH test were positive. In the screening setting, however, the low LR+ of CA-FISH limits its clinical utility. Prospective assessment of sputum CA-FISH is ongoing in the Nodule Cohort of the CO Lung SPORE.

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      MINI12.03 - Comprehensive Analysis of MicroRNA Expression Patterns in Lung Adenocacinoma Presenting with GGNs and Non-Tumorous Tissues (ID 701)

      Y. He, C. Zhou, S. Ren

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80% of primary lung cancer cases and approximately two thirds of them are diagnosed at an advanced stage . The poor prognosis of this disease is partially due to the lack of an effective means of early diagnosis. Discovery of an effective and reliable tool for early diagnosis of lung cancer would play a pivotal role in improving the prognosis of patients with lung cancer. Pulmonary ground-glass nodules (GGNs) are increasingly detected in clinical practice. GGNs are related to lung cancer, especially lung adnocacinoma . The subject of how to manage the pulmonary GGNs remains controversial. It is necessary to identify biological markers that can be used to screen high-risk patients in order to allow better lung adenocacinoma presenting with GGNs detection, earlier intervention and increase the likelihood of successful treatment. MicroRNAs are small non-coding RNAs of 18–24 nucleotides, typically excised from 60–110 nucleotide foldback RNA precursor structures . MicroRNAs have drawn significant attention in cancer research after it was linked to oncogenesis and tumor metastasis. Abnormal expression of microRNAs has been found in both haematopoietic and solid tumours by various genome-wide techniques. There is no report about the relationship between microRNA and pulmonary GGNs. It is necessary to identify biological markers that can be used to screen high-risk patients presenting GGNs in order to allow early lung adenocacinoma detection. Our study investigated microRNA expression with the intention to identify a panel of microRNAs for the diagnosis of lung adenocarcinoma presenting with GGNs.

      Methods:
      73 pairs of samples (tumorous and non-tumorous) were surgically resected from lung adnocacinoma patients presenting with GGNs from Shanghai Pulmonary Hospital between May 2012 and June 2014. After obtaining the approval of the patient consent, fresh tissues samples were taken during surgical resection, snap-frozen on dry ice and stored at−80◦C. MicroRNA expression of tumor and non-tumorous tissues was investigated in 3 participants by the next generation sequencing. Then, we analyzed the difference expression microRNA profiles which were identified by second generation sequencing in 73 pairs of lung adenocacinoma presenting with GGNs and adjacent non-tumorous tissues using a quantitative reverse-transcriptase polymerase chain reaction assay (qRT-PCR).

      Results:
      When we compared microRNA expression among lung cancer tissues versus corresponding noncancerous lung tissues via next-generation sequencing, 23 microRNAs had statistical differences in expression between groups. Five microRNAs (hsa−miR−548ar−5p, chr10_7330_star, chr17_10932_star, hsa−miR−148a−3p, hsa−miR−210−3p) exhibited higher expression in the adnocacinoma samples than that in the non-tumorous samples, eighteen microRNAs (hsa−miR−548x−5p, hsa−miR−144−3p, hsa-miR-106a-5p, hsa−miR−548ay−5p, hsa−miR−199a−3p, hsa−miR−378d, hsa−miR−4732−3p, hsa−miR−486−3p, chr7_5517, hsa−miR−1307−5p, chr17_10880, hsa−miR−127−3p, hsa−miR−411−5p, chr1_1402, chr16_10269, hsa−miR−138−5p, hsa−miR−212−3p, hsa−miR−33b−5p) demonstrated lower expression in adnocacinoma samples than that in the non-tumorous samples (P<0.05). Further validated by qRT-PCR, six microRNAs (chr17_10932_star, hsa−miR−148a−3p, hsa−miR−210−3p, chr1_1402, hsa−miR−378d, hsa−miR−138−5p) were statistically differentially expressed in tumorous compared with non-tumorous tissues.

      Conclusion:
      We found a microRNA panel that has considerable clinical value in diagnosing lung adenocacinoma presenting with GGNs. Thus, patients who would have otherwise missed the curative treatment window can benefit from optimal therapy.

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      MINI12.04 - Blinded Evaluation of the LuCED test to Detect Early Stage Lung Cancer (ID 869)

      M. Meyer, C. Presley, D. Wilbur, R. Katdare, J. Hayenga, T. Bell, J. Liang, A. Nelson

      • Abstract
      • Presentation
      • Slides

      Background:
      A previous, non-blinded study presented at the American Society of Cytopathology demonstrated performance of the LuCED[®] test for early detection of lung cancer and showed a sensitivity to cancer of 93.6% with 100% specificity based on 94 patients. Sensitivity was consistent across tumor histology, stage, size and location. Here, LuCED performance is presented where the pathologist was blinded to the case diagnosis. Data for this evaluation was produced as part of the CLIA validation of LuCED for use in the VisionGate Biosignatures Laboratory.

      Methods:
      Sputum from 42 patients was processed by LuCED: 23 patients had biopsy-confirmed lung cancer and 19 patients were normal. Sputum was collected from three spontaneous morning coughs, fixed and stained with hematoxylin, and enriched for epithelial cells using fluorescence activated cell sorting. Each enriched specimen was analyzed using the Cell-CT® platform that computes 3D digital images of single cells through tomographic reconstruction with isometric, sub-micron resolution. 3D morphometric biosignatures were automatically measured to produce a probabilistic score that identified abnormal cell candidates while a second score identified normal bronchial epithelial cells to determine specimen adequacy. Specimen adequacy was achieved when either abnormal cells were detected or 800 normal bronchial epithelial cells were enumerated by the classifier, whichever came first. Data was randomized by case and cell images of abnormal candidates were viewed using a CellGazer® workstation for blinded, cytopathologist confirmation. Cases were run until one of the following conditions was met: an abnormal cell was discovered, the specimen was exhausted, the criterion for specimen adequacy was reached. Example images of positive cells are shown in Figure 1. Figure 1



      Results:
      For cancer cases, lung cancer histology included adenocarcinoma (10 cases), squamous cancer (7), small cell lung cancer (3) and undifferentiated cancer (3); representing TNM stages I (5), II (10), IV (5), and unknown (3). Abnormal cells were found in all 23 cancer cases for 100% case sensitivity (lower 95% CI bound: 85.1%). Non-cancer lung diseases may produce reparative changes whose morphology can mimic cancer cell features. To stress test LuCED, patients with COPD, bronchitis, etc., were included in the normal group. 100,645 cells were processed from the 19 normal cases with 0.47% identified by the classifier for review using CellGazer. No abnormal cells were found. Case specificity is 100% (lower 95% CI bound: 82.4%).

      Conclusion:
      This interim blinded study of LuCED performance demonstrates highly sensitive (100%) and specific (100%) early lung cancer detection suggesting utility as a non-invasive screening test.

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      MINI12.05 - Discussant for MINI12.01, MINI12.02, MINI12.03, MINI12.04 (ID 3418)

      L. Montuenga

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI12.06 - Bioconductance Compared to 18FDG-PET in Evaluating CT-Detected Lung Lesions (ID 647)

      R. Yung, J. O'Driscoll, M. Garff, M.Y. Zeng

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer (LC) is the leading cause of cancer mortality. Computed tomographic (CT) screening detects LC at earlier stages but also results in finding many more smaller, benign nodules. Positron-Emission-Tomography (PET) is commonly used to evaluate suspicious lesions prior to invasive biopsies. However, PET accuracy is confounded by various factors including size, inflammation and tumor metabolic activity. Another potential biomarker of cancerous tissue is a non-invasive measure of transcutaneous bioconductance. This study compares Electro Pulmonary Nodule (EPN), a tissue bioconductance scan, to 18FDG-PET in evaluating CT detected suspicious lung lesions.

      Methods:
      Cohort- 27 patients with suspicious nodules evaluated with both PET and EPN scanning (IRB approved protocol) prior to biopsy or long-term radiologic follow-up. An EPN Scan measuring bioconductance was performed on bilateral anatomic skin sites and results were scored as either positive or negative dependent on a defined cut-off point. The PET results were interpreted as positive, negative or indeterminate.

      Results:
      There were 18 LCs (16 non-small cell LC, 2 small cell LC) and 9 benign lesions. PET results yielded 7 indeterminate readings. Excluding these 7, PET had 100% sensitivity (14/14 true positives) and 67% specificity (4/6 true negatives). EPN Scan evaluation of these 20 determinate PET cases had 86% sensitivity (12/14 true positives) with 83% specificity (5/6 true negatives). When evaluating the entire cohort of 27, the EPN results improved sensitivity and specificity to 89% (16/18 true positives) and 89%(8/9 true negatives), respectively. Table 1 describes the 7 lesions 18FDG-PET indeterminate lesions compared to EPN Scanning. Figure 1 In these 7 cases, the EPN Scan correctly classified all cases for 100% accuracy. Of note, 2 of the 4 cancers classified by PET as “indeterminate” were < 1 cm and were correctly categorized by the EPN Scan.



      Conclusion:
      While 18FDG-PET is often used as a clinical adjunct in the evaluation of suspicious CT detected pulmonary lesions, it has recognized limitations. In this feasibility study of measuring transcutaneous bioconductance as a pre-biopsy assessment, EPN Scan performed favorably versus PET, especially in evaluating smaller or PET-indeterminate lesions.

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      MINI12.07 - Exhaled Breath Analysis in Lung Cancer - One Stop Shop for Diagnosis, Staging and EGFR Analysis (ID 2431)

      N. Peled, O. Liran, M. Abud-Hawa, M. Ilouze, N. Gai-Mor, D. Shlomi, A. Ben-Nun, A. Onn, J. Bar, H. Haick

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer (LC) is the leading cause of cancer death in the United States with more than 158,000 estimated deaths in 2015. Early detection of LC has been well established as a significant key point in patients' survival and prognosis, yet unfortunately, the vast majority of new LC patients are being diagnosed at advanced disease stages. Exhaled breath analysis can serve as a non-invasive method in early detection of LC. The tumor's micro-environment releases various compounds to blood, some of which are then exhaled at breath as Volatile Organic Compounds (VOCs). This study evaluates the potential of exhaled breath analysis in LC detection and to further diagnose histology, EGFR mutational status and to discriminate early from advanced disease in a multinational study.

      Methods:
      Breath samples were taken from untreated LC patients and matching controls. Patients were enrolled in a large tertiary referral hospital in Israel. Analysis was performed by gold nanoparticle-based Artificial Olfactory System (NaNose®) and Pattern recognition methods were used to analyze the results obtained from the NaNose®. Histology, EGFR mutation status and staging was taken from patient's files.

      Results:
      A total of 174 patients participated in this study, and Inter-group analysis of 80 LC patients (64 advanced stage) and 31 matched controls showed a significant discrimination between disease and control. Among all patients, 83 were adenocarcinoma and 11 were squamous. EGFR mutations were detected in 24 patients. The comparisons resulted in: early LC versus control: p < 0.0001; accuracy 85.11%, advanced LC versus control: p < 0.0001; accuracy 82.11%, early LC versus advanced LC: p < 0.0001; accuracy 78.75%. Histology (Adenocarcinoma vs. Squamous cell carcinoma) and EGFR status was also significantly determined by the volatile signature.

      Conclusion:
      Breath analysis may support early detection of cancer as well as histological diagnoses, staging and mutational testing in lung cancer. This innovative method may pose as an important non-invasive tool for lung cancer early detection, thus promoting better prognosis and therapeutic possibilities for patients.

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      MINI12.08 - Validation of Autoantibody Panel for Early Detection of Lung Cancer in Chinese Population (ID 2529)

      S. Ren, S. Zhang, Z. Ma, H. Cai, X. Xu, J. Zhou, X. Liu, X. Hu, C. Zhou

      • Abstract
      • Presentation
      • Slides

      Background:
      Autoantibodies is an attractive diagnostic approach for early detection of malignant tumors. Our previous studies found a panel of 7 TAAs(p53, GAGE7, PGP9.5, CAGE, MAGE A1, SOX2, GBU4-5) was associated with lung cancer. We performed this large-scale, multi-center clinical trial to validate their ability to aid early diagnosis of lung cancer in Chinese population. Autoantibodies is an attractive diagnostic approach for early detection of malignant tumors. Our previous studies found a panel of 7 TAAs(p53, GAGE7, PGP9.5, CAGE, MAGE A1, SOX2, GBU4-5) was associated with lung cancer. We performed this large-scale, multi-center clinical trial to validate their ability to aid early diagnosis of lung cancer in Chinese population.

      Methods:
      The 7 TAAs were selected from 43 candidate TAAs from our previous studies, which were detected by ELISA in 1915 participants from 5 clinical centers in China. These samples including lung cancer (n = 818), benign lung diseases (n = 386), healthy volunteers (n = 415) and interference group (n = 296). The sensitivity and specificity from 7 TAAs and the traditional cancer biomarkers CEA, NSE and CYFRA21-1 were compared.

      Results:
      The sensitivity and specificity of autoantibody assay were 61% and 90% respectively, which were similar in different subgroups such as age, gender, smoker status and histological type. As for the enrolled patients with lung cancer, the sensitivities were 60% for patients with stage I/II, which were significantly higher than 27% ( p < 0.01)when using the combination of CEA, NSE and CYFRA21-1 to detect patients with lung cancer. While in patients with stage III/IV lung cancer, sensitivities were similar (63% vs. 56%, p > 0.05) and specificity was significantly improved (90% vs 71%, p < 0.01). The specificity was consistent in benign lung diseases and autoimmune diseases(interference group) and were 90% and 94% respectively and a concentration decrease of 7 TAAs were also observed after tumor resection.

      Conclusion:
      This study suggest that the 7 TAAs autoantibody panel can be used to aid diagnosis of lung cancer, and show a significantly improving sensitivity in patients with early stage lung cancer when comparing with the combination of CEA, NSE and CYFRA21-1.

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      MINI12.09 - Progress with an RCT of the Detection of Autoantibodies to Tumour Antigens in Lung Cancer Using the Early CDT-Lung Test in Scotland (ECLS) (ID 48)

      F. Sullivan, S. Schembri

      • Abstract
      • Presentation
      • Slides

      Background:
      Since the majority of lung cancer cases are detected at a late stage the prognosis remains poor at present. The National Lung Screening Trial (NLST) reported 20% reductions in lung cancer mortality in 2011, however as a primary screening modality CT is expensive and may lead to significant morbidity in individuals whose tests are false positives. The EarlyCDT-lung test detects autoantibodies to proteins in the earliest stages of the disease with a specificity of 93%. Research question Does using the EarlyCDT-Lung test reduce the incidence of patients with late-stage lung cancer (3 & 4) or unclassified presentation (U) at diagnosis, compared with standard practice?

      Methods:
      We are conducting an RCT of 12 000 participants in areas of Scotland within the most deprived quintile of the population whose mortality from lung cancer is high by international standards. Adults aged 50 to 75 who are at 1.2% risk over the next 2 years are eligible to participate. They should also be healthy enough to undergo curative interventions. We will undertake a comparison of the EarlyCDT-lung test and follow-up imaging at six monthly intervals for 2 years with standard clinical practice. The primary outcome is the difference, after 24 months, between the rates of patients with stage 3, 4 or unclassified lung cancer at diagnosis. Participants who develop lung cancer will be followed-up via electronic record-linkage to assess both time to diagnosis and stage of disease at diagnosis. The secondary outcomes are cost-effectiveness, and a range of psychological measurements. There is a nested qualitative study of the psychological effects test of results on participants.

      Results:
      In the first 14 months of recruitment 8 848 patients have been recruited and 9.0% of those tested have had a positive blood test with eight early cancers and 13 abnormalities undergoing further investigation detected to date in those who tested positive. Six of the eight cancers have been staged and four of these are early cancers. Provisional data reported to the trial team on those tested negative include three cancers. No data are currently available for the main trial comparison. From prior observational studies the test performance is expected to be: 40% sensitivity and 90% specificity these early data. Based on the study so far the current Positive Predictive Value of the test is 2.0%.

      Conclusion:
      The study will determine the EarlyCDT-Lung test’s clinical and cost effectiveness. It will also assess potential morbidity arising from the test and potential harms and benefits of a negative EarlyCDT-Lung test result. Early results in the test only arm of the trial are encouraging.

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      MINI12.10 - Discussant for MINI12.06, MINI12.07, MINI12.08, MINI12.09 (ID 3419)

      H.I. Pass

      • Abstract
      • Presentation

      Abstract not provided

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      MINI12.11 - Screening for Lung Cancer with the Early CDT-Lung and Computed Tomography (ID 204)

      J.R. Jett, D. Dyer, J. Kern, D. Rollins, M. Phillips

      • Abstract
      • Presentation
      • Slides

      Background:
      Early CDT-Lung, a serum based biomarker consisting of a panel of seven autoantibodies that develop in response to tumor associated antigens, has been shown to detect lung cancer in all stages of disease. We hypothesized that this biomarker when used in combination with a low-dose CT (LDCT) in screening of a high-risk population would increase the detection of early stage lung cancer.

      Methods:
      A prospective study of 1,600 subjects at high risk for lung cancer was designed. Eligibility criteria included persons 50-75 years of age, current or former smokers of ≥ 20 pack years and < 10 years since quit smoking. Those with a history of lung cancer in first degree relative(s) and any history of smoking were included. Exclusion criteria ware any history of cancer within 10 years (except skin cancer), any use of oxygen, and life expectancy of < 5 years. A direct mail campaign was conducted with study announcements sent to the homes of potentially high-risk individuals, who then contacted us for consideration of participating in this screening study. Those fitting inclusion criteria received the Early CDT-Lung blood test and a LDCT. A nodule of ≥ 3mm was considered as a positive scan. The Early CDT-Lung test was considered positive if any one of the seven autoantibodies was positive. All participants are to have yearly telephone follow-up for two years.

      Results:
      From May 2012 through November 2014, 815 individuals were enrolled and 814 completed the initial blood and LDCT screening tests. The cohort median age was 59 years with 55% female and 45% male gender distribution. The mean smoking history was 44 pack-years. Fifty-four per cent were current smokers while 46% were former smokers. Forty-six per cent of the LDCTs were negative for any lung nodule while 38% were positive. Incidental non-lung cancer findings were identified in 15% of the study group. The Early CDT-Lung biomarker was positive in 60 (7%) of participants, 23 males and 37 females. In those with a positive LDCT (n=313), the biomarker was positive in 25 (8%). As of January 30, 2015, there have been six confirmed lung cancers: two limited stage small cell, two Stage IB adenocarcinoma (ACA), and two Stage IA (one ACA and one squamous cell). The Early CDT-Lung blood test was positive in two of the four Stage IA/B lung cancers and negative in the two small cell cancers.There are 35 Early CDT-Lung biomarker positive individuals whose LDCT had no nodule. These individuals are being followed with yearly LDCT for two years. The study is continuing to accrue with a goal of 1,600. (NCT01700257)

      Conclusion:
      The Early CDT-Lung biomarker was positive in 7% of our high-risk population. The biomarker was positive in two of six lung cancers, specifically in two of four Stage I lung cancers. Accrual to the study and follow-up of 35 biomarker positive but LDCT negative participants continues.

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      MINI12.12 - Validation of Blood-Based Biomarker for Classification of Patients with Indeterminate Pulmonary Nodules (ID 559)

      J.L. Tomic, R.L. Lagier, H.I. Pass, W.N. Rom, T.R. Pollard, C.E. Birse

      • Abstract
      • Presentation
      • Slides

      Background:
      The United States Preventive Services Task Force recommends annual CT-screening for lung cancer in high risk adults but also acknowledges that one disadvantage of CT-screening is the large number of false positive results. Circulating biomarkers may provide a noninvasive, cost-effective means of addressing this disadvantage by assisting with classification of patients with indeterminate pulmonary nodules. Here, we describe the development and testing of a blood-based 5-analyte panel to classify these patients.

      Methods:
      A 5-analyte panel was developed in a training study comprising stage I NSCLC patients (n=95) and healthy smoker controls (n=186). The ability of the biomarker to resolve patients with benign nodules from those with malignant lesions was investigated in two validation studies: (1) Prostate, Lung, Colorectal, Ovarian (PLCO), a CXR-based screening trial, cases n=56, controls n=56; (2) Conversant Bio (CB), cases n=22, controls n=22.

      Results:
      In the training study, the 5-marker classifier (TFPI, OPN, CEA, CYFRA, SCC) resolved malignant cases with 72% sensitivity and 90% specificity (AUC=0.90). In the PLCO validation study, the biomarker distinguished pre-diagnostic cases with an AUC=0.65. In the CB study, a clinical model developed integrating nodule size, nodule location and gender, classified subjects with an AUC=0.79. When added to the clinical model, the biomarker significantly improved overall accuracy (P=0.016; AUC=0.86).

      Conclusion:
      A blood-based biomarker has been developed that accurately classifies patients with indeterminate nodules. Adding this biomarker to currently employed clinical and imaging-based evaluations of pulmonary nodules, may prove valuable in assessing malignant risk.

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      MINI12.13 - Early Detection of Lung Cancer Using DNA Methylation in Plasma and Sputum (ID 1691)

      A. Hulbert, A. Stark, C. Chen, I. Jusue-Torres, K. Rodgers, B. Lee, C. Griffin, A. Yang, K. Sugimoto, Z. Lu, J. Wrangle, P.B. Illei, R. Battafarano, D. Molena, S. Yang, P. Huang, T. Wang, S. Baylin, R. Brown, M. Brock, J. Herman

      • Abstract
      • Slides

      Background:
      Lung cancer is the worldwide leading cause of cancer-related mortality. Almost 85% of lung cancer cases are diagnosed at late stages with a five-year-survival probability at the time of diagnosis of 16.8%. The National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality using low-dose computed tomography (CT) screening, but there was also a 96.4% false positive rate. Lung cancer screening might be improved through cancer specific biomarkers detected in body fluids such as plasma or sputum. Previous studies using DNA methylation failed to achieve adequate sensitivity because of use of infrequently methylated genes and detection techniques unable to detect the small amounts of DNA yielded from blood and sputum. We sought to improve the diagnostic accuracy using gene promoter methylation in blood and sputum through the use of Methylation On Beads (MOB) and a highly lung-cancer specific panel of genes for detection of lung cancer.

      Methods:
      We conducted a prospective case-control study obtaining cases and controls from the Lung Cancer Spore. Cases had pathological confirmation of Non-Small Cell Lung Cancer (NSCLC) lesion stage IA or IB. Controls were defined as patients with pathological confirmation of non-cancerous lesion in the surgical specimens. Plasma, sputum and CT scans were obtained pre-operatively. We quantified methylation levels and the amplification cycle threshold from sputum and plasma samples by using MOB and quantitative methylation specific real-time PCR lung cancer-related genes previously identified from The Cancer Genome Atlas (TCGA). This panel of genes include: CDO1, TAC1, HOXA7, HOXA9, SOX17 and ZFP42.

      Results:
      A total of 210 subjects fulfilled inclusion criteria, including 150 patients with NSCLC and 60 patients with non-cancerous lesions. All six genes were methylated in significantly more people with cancer than without cancer in both plasma and sputum (p<0.001) with the exception of HOXA9 in sputum, which was methylated in more than 90% of people with cancer and more than 90% of people without cancer. After adjusting by age and pack·year, the methylated genes that were significantly associated with risk of lung cancer stage IA & IB from blood samples were: CDO1 (p=0.009), TAC1 (<0.001), HOXA9 (p=0.005), SOX17 (<0.001) & ZFP42 (p=0.003) and from sputum samples were: CDO1 (p=0.066), TAC1 (p=0.007), ZFP42 (p=0.009). Sensitivity and specificity for lung cancer diagnosis using the 3 best genes in plasma was 91% and 68% respectively and for sputum 91% and 88%. Area under the curve for 3 best genes in plasma was 0.78 95% confidence interval (CI) (0.69-0.87) (p<0.001) and for the best 3 genes in sputum 0.88 95% CI (0.77-0.99) (p<0.001).

      Conclusion:
      This study shows that its is possible to obtain high diagnostic accuracy for Lung Cancer in early stages using a panel of methylated promoter genes in Plasma and Sputum, by using Methylation-on-beads. These epigenetic biomarkers could potentially be used to identify patients with high risk of lung cancer development. reducing unnecessary tests and increasing the chance to diagnose lung cancer at earlier stages

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      MINI12.14 - Exhaled microRNAs as Potential Biomarkers of Lung Cancer Case versus Control Status (ID 2948)

      M. Shi, W. Han, J. Lin, S.D. Spivack

      • Abstract
      • Presentation
      • Slides

      Background:
      There is a need for non-invasive airway-based biomarkers in lung carcinogenesis for both risk assessment of the ex-smoker, and earlier diagnosis. Exhaled breath condensate (EBC) contains airway molecules, presumably in part from bronchial and alveolar epithelial cellular origins. Our previous study showed microRNAs could qualitatively be detected in EBC. Here both qualitative and quantitative multivariate analysis were applied to look for microRNA candidates in EBC from a new sample of lung cancer patients and controls.

      Methods:
      MicroRNA expression profiling using RNA-specific RT-qPCR was performed in EBC from 41 patients and 41 contols with clinical and microRNA expression data. The panel of microRNAs was assembled based on literature-derived reports of blood or lung microRNAs which segregate with case-control status, combined with our own lung tissue-based discovery effort using microRNA-seq on lung tumor-non-tumor pairs. The assembled panel for this effort included n=19 tumor-non-tumor differentiating microRNAs (miR-9, 18a, 20a, 31, 130b, 142, 146, 182, 183, 196a, 200a, 200c, 205, 210, 212, 221, 224, 330 and 708) chosen from the literature and our own lung tissue-based discovery data. Small nuclear RNA U1 was a housekeeping gene in the study based on its universality. Qualitative and quantitative (miRNA qPCR data normalized to internal reference U1 small ncRNA) analyses were considered. Multivariate analyses considered clinical information, including age, smoking status, underlying lung disease (COPD or not).

      Results:
      By univariate analyses, between cases (all histologies) and controls, qualitative/binary data showed miR-221 (p=0.030; OR=3.11) and miR-708 (p=0.016; OR=3.04) were significantly different. The case-adenocarcinoma subgroup (n=13) also differed from the controls in miR 708 frequency (p=0.034, OR=4.71). Examples of multivariate analyses (qualitative/binary data, case – all histologies) are shown in the Table: ontrols.

      miRNA Odds Ratio lower bound of CI upper bound of CI p-value
      miR.221 3.339 0.994 12.482 0.059
      age 1.084 1.026 1.158 0.008
      smoking 1vs0 1.467 0.304 8.372 0.642
      smoking 2vs0 2.211 0.411 14.436 0.371
      Underlying lung dz (COPD vs no COPD) 3.400 1.184 10.349 0.026
      miR.708 5.041 1.651 17.603 0.007
      age 1.093 1.031 1.172 0.006
      smoking former vs never 1.378 0.273 8.145 0.704
      smoking current vs never 2.144 0.386 14.269 0.397
      Underlying lung dz (COPD vs no COPD) 4.437 1.448 15.047 0.012
      Similar multivariate models were obtained for miR 221 and miR708 in the cancer-adenocarcinoma subgroup. No clear case-control discriminant exhaled microRNAs were found in the analogous quantitative data (delta CT) analyses, by univariate or multivariate analyses.

      Conclusion:
      From the qualitative analysis, two possible miRNA biomarkers of case status (miR-221 and miR-708) were obtained. Previous work had suggested miR 221 as a discriminant microRNA in lung cancer case versus control setting. Quantitative data was not informative. We are working on expanding and refining the miR panel, and larger sample size to partition covariates such age, underlying lung disease, and other factors. Our goal is to test this non-invasive biomarker approach to lung cancer risk assessment.

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      MINI12.15 - Discussant for MINI12.11, MINI12.12, MINI12.13, MINI12.14 (ID 3478)

      A. Spira

      • Abstract
      • Presentation

      Abstract not provided

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    PLEN 01 - Lung Cancer Prevention and Screening (ID 50)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 4
    • +

      Introduction (ID 2097)

      • Abstract

      Abstract not provided

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      PLEN01.01 - Lung Cancer Screening (ID 2038)

      C. Berg

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Screening of high risk individuals for lung cancer was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial (NLST) comparing low-dose helical computerized tomography (LDCT) to chest x-ray [1]. Implementation of lung cancer screening will be a serious challenge. Since the time of the IASLC meeting in Sydney in 2013 additional information from the NLST has provided guidance on many aspects of screening and informed public health policy in the United States. The United States Preventive Services Task Force (USPSTF) in December 2013 and the Centers for Medicare and Medicaid Services in February 2015 released decisions favorable to lung cancer screening [2, 3]. The USPSTF recommended it at a Grade B level which means under the terms of the Affordable Care Act (ACA), many insurance companies must reimburse without a deductible. The recommendations followed the NLST criteria but extended the age for screening to cover 55 to 80. CMS also followed NLST extending screening to age 77. The coverage includes a counseling and shared decision making visit with a written order for the procedure. Requirements also included radiologist credentials, image acquisition standards and participation in a CMS registry. The American College of Radiology Lung Cancer Screening Registry has been approved. Coverage decisions acknowledged the known drawbacks of high false-positive rates, overdiagnosis potential, radiation risk, psychosocial consequences, effect on smoking behavior and incidental findings. More efficient screening strategies may use different criteria than the NLST excluding those at lower risk while including those outside NLST criteria that are at identifiable high risk. Several risk prediction models exist. The PLCO~m2012~ model is the best-validated. Selected risk factors included age, race, ethnicity, education, body mass index, self-reported chronic obstructive pulmonary disease, personal and family history of lung cancer, and smoking variables. A risk threshold of 1.5% over 6 years was chosen as below this threshold there was no reliable evidence of screening benefit and much higher numbers needed to screen. Comparing this risk model threshold to the USPSTF criteria in the PLCO CXR arm demonstrates that the PLCO~m2012~ risk model approach is more efficient [4]. Table The American College of Radiology developed the Lung-RADS nodule classification system [5]. When applied retrospectively to NLST data (26,455 baseline scans and 48,671 incidence scans), Lung-RADS 1.0 substantially reduced the false-positive rate (12.8% versus 26.6% at baseline and 5.3% versus 21.8% at incidence scans respectively). However, the trade-off was reduced sensitivity compared to NLST criteria: 84.9% vs. 93.5% at baseline and 78.6% versus 93.8% for incidence scans [6]. Retrospective subset analyses while imperfect are useful, providing some information about potential variations in effectiveness in subgroups. Analysis of performance within the NLST was conducted by age, gender and smoking status with additional detail comparing those less than 65 and ≥ 65 [7]. The mortality risk ratios by age, < 65 and ≥ 65, were 0.82 and 0.87; gender, males and females, 0.92 and 0.73, and by smoking status, current versus former, 0.81 and 0.91. Reassuringly, ninety day postsurgical mortality rates in those less than and ≥ 65 were 1.8% and 1.0% respectively. An estimate of overdiagnosis within the NLST has been done [8]. Using follow-up data extended from that in the primary manuscript, a total of 1089 lung cancers occurred in the LDCT arm compared with 969 in the CXR arm, resulting in 120 additional lung cancer cases in the LDCT arm. Two estimates of the upper bound of overdiagnosis were calculated, 18.5% of the cases detected during screening and 11% of the cases overall. More follow-up would be helpful to determine the extent of continued catch-up in cases in the CXR arm. Current smokers in the Lung Screening Study portion of the NLST were evaluated for smoking cessation and results also analyzed by findings on LDCT [9]. Those with normal scans did show a decline in smoking prevalence that continued for the seven years of assessment. Those with abnormal scans had higher cessations rates; the more abnormal the scan the higher the rates. All lung cancer screening programs should incorporate proven smoking cessation strategies. The cost-effectiveness analysis from the NLST utilized data from medical record abstraction covering in exhaustive detail medical interventions delivered as a consequence of screening [10]. As compared with no screening, screening with low-dose CT cost an additional $1,631 per person and provided an additional 0.0316 life-years per person and 0.0201 Quality Adjusted Live Years (QALY) per person. The corresponding Incremental Cost Effectiveness Ratios were $52,000 per life-year gained and $81,000 per QALY gained but varied widely by underlying risk group. Information from the NLST continues to refine our understanding of lung cancer screening. This should prove invaluable in ensuring that screening is done at a high level to achieve optimal mortality reductions as programs are expanded. References 1. The National Lung Screening Trial Research Team. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N Engl J Med 2011; 365: 395-409. 2. Moyer VA. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Int Med 2014; 160: 330-338. 3. Centers for Medicare and Medicaid Services. Decision Memo for Screening for Lung Cancer with Low Dose Computed Tomography (LDCT) (CAG-00439N). http://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=274 (accessed February 22, 2015). 4.Tammemagi MC, Church TR, Hocking WG et al. Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts. PLoS Medicine 2014; 11: e10001764. 5. American College of Radiology ACR-STR Practice Guideline for the Performance and Reporting of Lung Cancer Screening Thoracic Computed Tomography http://www.acr.org/~/media/ACR/Documents/PGTS/guidelines/LungScreening.pdf (accessed February 22, 2015). 6. Pinsky PF, Gierada DS, Black W et al. Performance of Lung-RADS in the National Lung Screening Trial. Ann Intern Med [Epub ahead of print 10 February 2015] doi:10.7326/M14-2086. 7. Pinsky PF, Gierada DS, Hocking W et al. National Lung Screening Trial Findings by Age: Medicare-Eligible Versus Under-65 Population. Ann Intern Med 2014; 161: 627-633. 8. Patz EF, Pinsky P, Gatsonis CG et al. Overdiagnosis in Low-Dose Computed Tomography Screening for Lung Cancer. JAMA Intern Med 2014: 174: 269-274. 9. Tammemagi MC, Berg CD, Riley TL et al. Impact of Lung Cancer Screening Results on Smoking Cessation. J Natl Cancer Inst 2014;106: dju084. 10. Black WC, Gareen IF, Soneji SS et al. Cost-Effectiveness of CT Screening in the National Lung Screening Trial. N Engl J Med 2014; 371: 1793-1802. TABLE Comparison of PLCO~M2012~, NLST and USPSTF [4]

      PLCO~M2012 ~vs. NLST PLCO~M2012~ vs. USPTF
      PLCO~M2012~ NLST PLCO~M2012 ~ USPSTF
      Selection criteria >1.3455%[1] Age 55-74, current/former smoker ≥30 PY ≥ 1.51%1 Age 55-80, current/former smoker ≥30 PY
      Validation cohort 14,144 PLCO trial screening arm smokers 14,144 PLCO trial screening arm smokers who met NLST criteria 37,327 PLCO trial screening arm smokers 37,327 PLCO trial screening arm smokers who met USPSTF criteria
      Sensitivity, % (95% CI) 83.0 71.1 80.1 (76.8–83.0) 71.2 (67.6–74.6)
      Specificity, % (95% CI) 62.9 62.7 66.2 (65.7–66.7) 62.7 (62.2–63.1)
      Positive Predictive Value, % (95% CI) 4.0 3.4 4.2 (3.9–4.6) 3.4 (3.1–3.7)
      [1] Estimated lung cancer risk over six years

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      PLEN01.02 - Epidemiology of Lung Cancer/Smoking in the World (ID 2039)

      D. Christiani

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Lung cancer remains the most common cancer in the world. Worldwide, the leading cause of cancer mortality in men and the second leading cause in women. 1.8 million new cases were diagnosed in 2012. About 58% of lung cancer cases occurred in low and middle income countries. Although by far not the only known or suspected lung carcinogen, cigarette smoking remains the principal cause of lung cancer and is estimated to be responsible for 85% of all types of this cancer. The major risk factors and risk modifiers for lung cancer include: Cigarette Smoking Secondhand Smoke (SHS) Air Pollution Radon Occupational Exposures (e.g., asbestos, silica, Chromium, radon) Lung Cancer Susceptibility Genes Aspirin/NSAIDs Use (protective) Dietary vitamin D (protective) HRT – possibly protective. I will cover updates on our understanding of the major risk factors for lung cancer in the USA and globally. Smoking Smoking causes an estimated 170,000 cancer deaths in the U.S. every year (American Cancer Society) and the incidence among women is rising. Lung cancer now surpasses breast cancer as the number one cause of death among women. Globally, cigarette consumption has changed over the decades, with China now the number one consumer (44%) of cigarettes in the world, while the USA is consumes about 5%. In the USA, “Second Hand Smoke” is the third leading cause of lung cancer and responsible for an estimated 3,000 lung cancer deaths every year. Globally, the number of SHS related cancer deaths is unknown, but surely rising. SHS is also referred as ‘environmental tobacco smoke (ETS)’, ‘passive smoking’ or ‘involuntary smoking’. IARC has deemed SHS is “carcinogenic to humans”, with an increased risk of 20% for women and of 30% for men among never smokers who are exposed to SHS (i.e., environmental tobacco smoke) from their spouse. Ambient Air Pollution IARC has classified outdoor air pollution - as a whole - as “carcinogenic to humans (Group 1)”. Outdoor air pollution has been shown to cause lung cancer and bladder cancer, pointing to the role of overlapping carcinogen exposure to compounds such as polycylic aromatic compounds (PAC). The most recent data from the Global Burden of Disease (GBD) Project indicate that in 2010, 3.2 million deaths worldwide resulted from air pollution alone, including 223,000 from lung cancer. Radon Radon is an odorless, colorless, radioactive gas that causes lung cancer. IARC classifies radon and its progeny as “carcinogenic to humans” (Class I), and the US EPA lists radon as the second leading cause of lung cancer in the US and the number one cause of lung cancer among non-smokers. Originally described as a risk factor in underground miners (among both smokers and non-smokers, with synergistic interaction with smoking), the U.S. EPA estimates that 1 of 15 homes in the US (as many as 1 of 3 homes in some states)-about 7 million homes-have high radon levels. Occupational Exposures: Asbestos In North America, and most other high income countries, asbestos has been the most prevalent occupational lung carcinogen exposure. All forms of asbestos have been classified as a known human carcinogen (by the U.S. Department of Health and Human Services, EPA, and the IARC). About 125 million people in the world are exposed to asbestos at the workplace. According to WHO estimates, more than 107,000 deaths each year are attributable to occupational exposure to asbestos. Exposure to asbestos, including chrysotile, causes cancer of the lung, larynx and ovaries, and also mesothelioma. Co-exposure to tobacco smoke and asbestos fibers substantially increases the risk for lung cancer (multiplicative interaction). Heritable Factors: Common Genetic Variants GWAS provide novel insights into the development of LC. Genetic factors are increasingly recognized to be important in the etiology of LC: 15q25.1 (CHRNA5-CHRNA3-CHRNB4) 5p15.33 (TERT-CLPTM1) 6p21.33 (BAT3-MSH5) Follow up studies that pool data international as part of a large consortium (International Lung Cancer Consortium - ILCCO) have identified other common variants at multiple loci influencing LC risk, and these include BRACA1. Studies of pleiotropy are well underway. Additionally, GWAS studies globally, such as one from China, have identified unique, population-specific, risk loci. COPD and Lung Cancer risk COPD and LC are the 4[the] and 7[th] leading causes of death worldwide. The coexistence of COPD is an important marker of future risk of LC among smokers. Epidemiologic studies have shown that 50-70% of LC patients have co-existing impaired lung function or COPD. And, not surprisingly, 90% of combined LC and COPD cases are attributable to cigarette smoking. Recently, we have found that the co-existence of COPD with lung cancer also negatively influences survival among patients with all stages. Conclusion Lung cancer remains the number one cancer threat to the world’s populations. Lung cancer epidemiology continues to evolve and as we understand more about the origins and behavior of lung cancer, the more opportunities we will have for prevention and control of this deadly disease.

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      PLEN01.03 - Smoking by Lung Cancer Patients: Clinical, Biologic and Behavioral Considerations (ID 2040)

      G. Warren

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Smoking is the largest preventable risk factor for the development of lung cancer. Continued smoking by cancer patients and survivors causes adverse outcomes including an increase in overall mortality, cancer specific mortality, risk for second primary cancer, and associated increases in cancer treatment toxicity. Significant evidence demonstrates the biologic mechanisms of cancer initiation and progression caused by cigarette smoke, but relatively few studies have evaluated the effects of smoking on cancer biology and therapeutic response to cytotoxic agents. Most oncologists believe smoking causes adverse outcomes and that smoking cessation treatment should be a standard part of cancer care. However, most oncologists do not regularly provide cessation support to cancer patients. Moreover, tobacco assessments and cessation support are not regularly incorporated into clinical trials design or analysis. Recently released guidelines from several national and international organizations advocate for addressing tobacco use by cancer patients. This session will discuss the clinical and biologic effects of smoking on cancer, present the current state of tobacco assessments and cessation in clinical practice and research, and discuss methods to improve access to cessation support for cancer patients. Discussion will further detail deficits in the current understanding of the effects of smoking on cancer treatment outcomes and highlight areas of needed improvement.

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    PRC 01 - Press Conference 1 (ID 196)

    • Event: WCLC 2015
    • Type: Press Conference
    • Track: Other
    • Presentations: 5
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      Q&A (ID 3618)

      • Abstract

      Abstract not provided

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      PRC01.01 - Introduction to WCLC, preview of Opening Ceremonies & Daily Theme - Dr. Fred R. Hirsch, IASLC CEO, Congress President, Professor of Medicine and Pathology, University of Colorado (ID 3614)

      F.R. Hirsch

      • Abstract
      • Slides

      Abstract not provided

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      PRC01.02 - Summary of the IASLC Third CT Screening Workshop - Dr. John Field, Chair, Screening Advisory Committee, IASLC (ID 3615)

      J.K. Field

      • Abstract

      Abstract not provided

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      PRC01.03 - Summary of Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session - Dr. ChunXue Bai, Session Chair (ID 3616)

      C. Bai

      • Abstract

      Abstract not provided

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      PRC01.04 - Advocacy and Patient Advocates - Janet Freeman-Daily, Lung Cancer Patient & Advocate (ID 3617)

      J. Freeman-Daily

      • Abstract

      Abstract not provided



Author of

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    GR 02 - Difficult Mesothelioma Cases (ID 15)

    • Event: WCLC 2015
    • Type: Grand Rounds
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      GR02.01 - Case 1: A 70 Year Old with a Biphasic Stage I MPM (ID 1832)

      H.I. Pass

      • Abstract
      • Presentation
      • Slides

      Abstract:
      A 70 year old retired insulator presented to the emergency room with progressive shortness of breath limiting his ability to complete his daily 5 mile runs. Physical examination reveals minimal breath sounds and dullness to percussion on the right side. The patient denies chest pain or weight loss. There is no history of cardiac disease and he is a never smoker. Family histroy reveals a brother with cured uveal melanoma. Chest radiography reveals a completely opacified right hemithorax. WBC is 7000, platelet count 245,000, and his HgB is 13.2 gms. A thoracentesis reveals 3.5 liters of serosanguinous fluid, and post thoracentesis radiograph reveals complete expansion. Fluid is sent for culture and cytology, and the patient is discharged to home with a 2 day supply analgesics. The culture report at 5 days reveals no growth and the cytology reveals atypical mesothelial hyperpplasia. Two months after his thoracentesis he returns to see his PCP with similar complaints of shortness of breath with exertion without chest pain. 1. What is the proper further management of this patient? 2. What is unusual about his family history, and what are the possible implications?

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    MINI 12 - Biomarkers and Lung Nodule Management (ID 109)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 2
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      MINI12.10 - Discussant for MINI12.06, MINI12.07, MINI12.08, MINI12.09 (ID 3419)

      H.I. Pass

      • Abstract
      • Presentation

      Abstract not provided

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      MINI12.12 - Validation of Blood-Based Biomarker for Classification of Patients with Indeterminate Pulmonary Nodules (ID 559)

      H.I. Pass

      • Abstract
      • Presentation
      • Slides

      Background:
      The United States Preventive Services Task Force recommends annual CT-screening for lung cancer in high risk adults but also acknowledges that one disadvantage of CT-screening is the large number of false positive results. Circulating biomarkers may provide a noninvasive, cost-effective means of addressing this disadvantage by assisting with classification of patients with indeterminate pulmonary nodules. Here, we describe the development and testing of a blood-based 5-analyte panel to classify these patients.

      Methods:
      A 5-analyte panel was developed in a training study comprising stage I NSCLC patients (n=95) and healthy smoker controls (n=186). The ability of the biomarker to resolve patients with benign nodules from those with malignant lesions was investigated in two validation studies: (1) Prostate, Lung, Colorectal, Ovarian (PLCO), a CXR-based screening trial, cases n=56, controls n=56; (2) Conversant Bio (CB), cases n=22, controls n=22.

      Results:
      In the training study, the 5-marker classifier (TFPI, OPN, CEA, CYFRA, SCC) resolved malignant cases with 72% sensitivity and 90% specificity (AUC=0.90). In the PLCO validation study, the biomarker distinguished pre-diagnostic cases with an AUC=0.65. In the CB study, a clinical model developed integrating nodule size, nodule location and gender, classified subjects with an AUC=0.79. When added to the clinical model, the biomarker significantly improved overall accuracy (P=0.016; AUC=0.86).

      Conclusion:
      A blood-based biomarker has been developed that accurately classifies patients with indeterminate nodules. Adding this biomarker to currently employed clinical and imaging-based evaluations of pulmonary nodules, may prove valuable in assessing malignant risk.

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    MINI 19 - Surgical Topics in Localized NSCLC (ID 138)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      MINI19.14 - Survival After Sub-Lobar Resection for Early Stage Lung Cancer: Methodological Obstacles in Comparing the Efficacy to Lobectomy (ID 1583)

      H.I. Pass

      • Abstract
      • Presentation
      • Slides

      Background:
      Surgery is the treatment of choice for early stage lung cancer (LC). While lobectomy (L) is the historic standard, whether long term outcomes of sub-lobar resection (SL) are comparable is still under debate. The only randomized trial was conducted 20 years ago; 5 subsequent meta-analyses showed inconclusive or conflicting results. We present a comprehensive review of the literature on 5 year-survival after SL compared to L for early stage LC.

      Methods:
      A priori inclusion criteria were: 1) observational studies, 2) L compared to SL for early stage LC, 3) at least CT staging, 4) 5-year survival reported. A Medline search through January 2015 resulted in 32 studies, representing 24 distinct datasets. The absolute difference in 5-year survival was calculated and plotted for each study.

      Results:
      There were 4,702 cases treated with L, 2,323 treated with SL. Of 20 studies reporting the reason for SL, 11 indicated that SL was performed because of comorbidities, or impaired cardiopulmonary function. Among all 24 studies, 4 showed no difference in 5-year survival, 13 favored L, and 7 favored SL (Figure 1). Of the two studies using propensity scores, one favored L and the other SL. No meta-estimate could be calculated due to high statistical heterogeneity. Of 21 studies reporting recurrence rate (Figure 2), 11 favored L and 10 favored SL. Figure 1



      Conclusion:
      Studies comparing 5-year survival rates of SL to L are heterogeneous, and traditional meta-analytic summary estimates of survival and recurrence could not be calculated. SL survival is often similar to L survival, despite the fact that SL is performed in patients with comorbidities or impaired cardiopulmonary function. New approaches to comparing L to SL survival are needed.

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI38.15 - Discussant for MINI38.11, MINI38.12, MINI38.13, MINI38.14 (ID 3558)

      H.I. Pass

      • Abstract
      • Presentation

      Abstract not provided

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    MS 24 - CT Screening: Minimize Harm/Cost and Risk Assessment (ID 42)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
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      MS24.04 - Biomarkers in Selection for CT Screening/Management of Nodules (ID 1957)

      H.I. Pass

      • Abstract
      • Presentation

      Abstract:
      The complexity of biomarker discovery is amplified by the multitude of platforms on which the biomarker is discovered (mutational sequencing, fluorescence in situ hybridization (FISH), single-nucleotide polymorphisms (SNPs), copy-number variation (CNV) of chromosomes, immunohistochemistry, epigenetics including methylation studies, or microRNA ), and by the material used (tissue, plasma, serum, urine, breath, sputum, effusion). The aim is to define these biomarkers in a way whereby their use is contingent on maximal accuracy, which depends on the ability of biomarker researchers to not only put forth markers with the greatest sensitivity and specificity, but also to be able to validate these biomarkers in a methodologic algorithm that will satisfy regulatory bodies including the Food and Drug Administration (FDA) in the United States as well as other agencies abroad. This lecture will concentrate on novel biomarkers for lung cancer being investigated by the Lung Group and industrial members of the Early Detection Research Network. These biomarkers include autoantibodies, MRM proteomics, micro and lncRNAs, SomaMers, and airway transcriptomics.

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    ORAL 26 - Clinical Trials 2 (ID 127)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL26.01 - Initial Analyses of the IASLC Malignant Pleural Mesothelioma (MPM) Database: Implications for the 8th Edition AJCC and UICC Staging Manuals (ID 1734)

      H.I. Pass

      • Abstract
      • Presentation

      Background:
      This report is on behalf of the Mesothelioma Domain (MD) of the IASLC International Staging and Prognostic Factors Committee (ISC). The ISC MD previously developed the largest international staging database in MPM and analyzed outcomes and prognostic factors. (JTO 2012:1631-1639 and 2014:856-864).These results indicated the need for more granular TNM data to inform revisions of the staging system for the upcoming 8th edition of the AJCC/UICC staging manuals. We report analyses of this new MPM database.

      Methods:
      The MD established a new data dictionary with more detailed information about TNM descriptors and permitting electronic data capture. Minimum case submission requirements: complete clinical and/or post-surgical TNM stage with anatomical descriptors to support stage designation, accurate survival information, no conflict between descriptors and reported stage, and node positivity recorded by individual station. Overall survival analyzed by Kaplan-Meier and significance of individual T,N, and M descriptors evaluated by logrank and Cox regression.

      Results:
      3,519 cases treated 1995-2014 were submitted from 31 centers or consortia. 1,069 cases were excluded due to timing of presentation (244), missing dates (196), conflicting or incomplete stage information (615) or incorrect cell type (14). Geographic source for remaining 2,450 cases was: Europe 33%, North America 36%, Turkey 12%, Asia 10%, Australia 9%. Stage available: clinical (cTNM) only 34%; post-surgical (pTNM) only 33%; both 34%. A total of 1,982 cases (81%) underwent surgery (43% EPP, 23% PD, 8% partial pleurectomy, 26% exploration without resection). 5 year overall survival (OS) for any N, M0 showed no difference for T1a versus T1b or for post-surgical T2 versus T3. 5 year OS for any T, M0 showed no difference for N1 versus N2 (Table 1). Median and 5 year OS by stages I-IV were similar to those reported from original database. Table 1. Median overall survival times (MST), 2-year, and 5-year overall survival rates for pre-treatment and post-surgical stage categories. Figure 1



      Conclusion:
      While additional analyses are ongoing, these initial results suggest some changes in the current MPM staging system are warranted, especially regarding T categories.

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    ORAL 35 - Surgical Approaches in Localized Lung Cancer (ID 155)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      ORAL35.05 - The Role of Surgical Mediastinal Resection in CT Screen-Detected Lung Cancer Patients (ID 960)

      H.I. Pass

      • Abstract
      • Presentation
      • Slides

      Background:
      Comparison of long-term survival of patients with clinical Stage I non-small-cell lung cancer (NSCLC) with and without mediastinal lymph node resection (MLNR) in the International Early Lung Cancer Action Program, a large prospective cohort in a low-dose CT screening program.

      Methods:
      All instances of thoracic surgery for first solitary primary non-small-cell lung cancer prompted by low-dose CT screening, performed under an IRB approved common protocol at each of the participating institutions since 1992 to 2014, are included. Follow-up time was calculated from diagnosis to death from lung cancer, last contact, or December 31, 2014, whichever came first. Univariate logistic regression analysis of the demographic, CT, and surgical findings for those with and without MLNR was performed. Kaplan-Meier (K-M) survival rates and Cox regression analysis was performed using all significant univariate variables.

      Results:
      The 10-year Kaplan-Meier (K-M) NSCLC-specific survival rate for the 225 patients manifesting as a subsolid nodule was 100%, regardless of whether they had MLNR (N = 169) or not (N = 56). For the 373 NSCLC patients manifesting as a solid nodule, for those who had MLNR (N = 285) and those who did not (N = 88), the K-M NSCLC-survival rate was not significantly different (86 % vs. 93%, P = 0.23). The rate was 95% vs. 96% (P = 0.86) for those whose pathologic tumor diameter was <= 10 mm; 83% vs. 94% (P = 0.19) for 11-20 mm, and 79% vs. 86% (P = 0.67) for 21-20 mm. Cox regression analysis comparing MLNR with no MLNR showed that survival rates were not significantly different (P = 0.33), but significantly survival decreased when the tumor diameter was above 20 mm (HR= 5.1, 95% CI: 1.6-15.7).

      Conclusion:
      Lymph node evaluation is not necessary for resection of subsolid nodules in patients with screen-detected lung cancer.

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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 2
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      P1.08-003 - Minimal Asbestos Exposure in Germline BAP1 Heterozygous Mice Is Associated with Deregulated Inflammatory Response and Increased Risk of MM (ID 1483)

      H.I. Pass

      • Abstract
      • Slides

      Background:
      Germline BAP1 mutations predispose to several cancers, in particular malignant mesothelioma. Mesothelioma is an aggressive malignancy generally associated to professional exposure to asbestos. However, to date we found that none of the mesothelioma patients carrying germline BAP1 mutations were professionally exposed to asbestos. We hypothesized that germline BAP1 mutations might influence the asbestos-induced inflammatory response that is linked to asbestos carcinogenesis, thereby increasing the risk of developing mesothelioma after even minimal exposure.

      Methods:
      We experimentally tested in a BAP1[+/-] murine model whether germline BAP1 heterozygosity would result in alterations of the asbestos-induced inflammatory response, and whether low doses of asbestos might be sufficient to cause MM.

      Results:
      Germline BAP1 heterozygosity is associated with a significantly altered peritoneal inflammatory response upon exposure to asbestos fibers and to an increased risk of MM following exposure to even minimal amounts of asbestos that rarely cause MM in wild type animals.

      Conclusion:
      Our findings support our hypothesis that germline BAP1 heterozygosity increases susceptibility to the carcinogenic effects of low doses of asbestos. Based on these results, we suggest that prevention programs of MM in individuals carrying germline BAP1 mutations should focus on reducing exposure to even minimal indoor and/or naturally occurring outdoor sources of carcinogenic fibers, levels that are within the acceptable “safe” limits for the population at large.

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      P1.08-014 - The Small Molecule Inhibitor, LCRF004, Is Effective in Targeting the RON/MST1R Pathway in Malignant Pleural Mesothelioma (ID 1311)

      H.I. Pass

      • Abstract
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer. We have previously identified RON as frequently activated in MPM patient samples and cell lines. RON is a member of the MET proto-oncogene family and is bound by macrophage stimulating protein (MSP). High positivity for total RON by IHC was an independent predictor of favourable prognosis. Additionally, elevated expression levels of MSP correlated with better survival. The aim of this study was to further examine the MSP-RON signalling axis in MPM using a RON inhibitor, LCRF004.

      Methods:
      MPM cell lines and a normal mesothelial cell line were screened for the expression of RON and MSP at the protein (Western) and mRNA (RT-PCR) level. Downstream mediators affected by MSP stimulation and LCRF004 were identified using a proteome profiler array. The effect of LCRF004 and MSP were examined using proliferation (BrdU ELISA), viability (High Content Analysis), migration (xCELLigence), apoptosis and cell cycle (HCA) assays. A xenograft study was also completed.

      Results:
      Treatment with LCRF004 resulted in a significant decrease in proliferation, viability and migration in vitro and reduced tumour growth in vivo (p<0.05, compared with vehicle control). In addition, LCRF004 significantly increased apoptosis. In terms of cell cycle, drug treatment decreased cells in 2n, whilst increasing cells in the G0/G1 phase. Experiments are on going to further characterise the mechanism of action of LCRF004.

      Conclusion:
      The in vivo and in vitro data generated in this study, indicates that the MSP-RON signalling axis is a potential target in MPM. Targeting the RTK domain of the RON receptor with a small molecule inhibitor is an effective interventional strategy in MPM.

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    P2.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 225)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P2.08-002 - Germline BAP1 Mutation Is Associated with a Significant Increased Survival and Multiple Cancer in Mesothelioma Patients (ID 961)

      H.I. Pass

      • Abstract

      Background:
      Because the diagnosis is often made at a late stage, malignant mesothelioma (MM) prognosis is very poor, with a median survival of 6-12 months and a five-year survival of less than 5%. We found that germline BAP1 mutation is associated with a new cancer syndrome, including rare malignancies such as MM and uveal carcinoma (UV), and other cancers. We noted that some MM cases that we followed from BAP1 mutated families had prolonged survival. We carried out a pooled analysis of BAP1 mutated MM patients to test the hypothesis that they had a better survival compared to sporadic MM.

      Methods:
      : We included all published BAP1 germline mutated MMs with available data on BAP1 status, site of MM, age at diagnosis, gender, and age at death or status at end of follow-up, in addition to the BAP1 mutated MM cases from families that we are following. Twenty-three BAP1 MM patients were included. Using the Kaplan-Meier method and Wilcoxon test, we compared survival among BAP1 mutated MM patients with that of all MMs (N = 10 556) recorded in the US SEER data from 1973 to 2010.

      Results:
      In our BAP1 cohort, ten patients had peritoneal MM, ten pleural MM, and three MM in both locations. Thirteen patients had one or more malignancies in addition to MM. Actuarial median survival for the MM patients with germline BAP1 mutations was five years, as compared with less than one year in the SEER MM control group. Five-year survival was 47%, 95%CI [24-67%], as compared with 6.7% [6.2-7.3%] in the SEER MM control group. The small size of our BAP1 cohort did not allow for significant statistical comparisons. However, patients with peritoneal MM (median survival of 10 years, P=0.0571), or with a second malignancy in addition to MM (median survival of 10 years, P=0.0716), survived for a longer time compared to patients who only had pleural MM, or MM patients without a second malignancy, respectively. Figure 1



      Conclusion:
      MM patients with germline BAP1 mutations have an overall seven-fold increased survival, independently of sex and age. This better prognosis was associated with multiple cancer and/or peritoneal MM. Appropriate genetic counseling and clinical management should be considered for MM patients who are also BAP1 mutation carriers.