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J.M. Siegfried
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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
- Moderators:J.M. Siegfried, H.I. Pass
- Coordinates: 9/07/2015, 16:45 - 18:15, 401-404
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MINI12.01 - A Novel Serum 4-MicroRNA Signature for Lung Cancer Detection (ID 585)
16:45 - 16:50 | Author(s): E. Nadal, A. Truini, A. Nakata, J. Lin, R. Reddy, A.C. Chang, N. Ramnath, N. Gotoh, G. Chen, D. Beer
- Abstract
- Presentation
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)
16:50 - 16:55 | Author(s): 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
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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- Abstract
- Presentation
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)
17:00 - 17:05 | Author(s): M. Meyer, C. Presley, D. Wilbur, R. Katdare, J. Hayenga, T. Bell, J. Liang, A. Nelson
- Abstract
- Presentation
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)
17:05 - 17:15 | Author(s): L. Montuenga
- Abstract
- Presentation
Abstract not provided
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MINI12.06 - Bioconductance Compared to 18FDG-PET in Evaluating CT-Detected Lung Lesions (ID 647)
17:15 - 17:20 | Author(s): R. Yung, J. O'Driscoll, M. Garff, M.Y. Zeng
- Abstract
- Presentation
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)
17:20 - 17:25 | Author(s): 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
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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- Abstract
- Presentation
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)
17:30 - 17:35 | Author(s): F. Sullivan, S. Schembri
- Abstract
- Presentation
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)
17:35 - 17:45 | Author(s): 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)
17:45 - 17:50 | Author(s): J.R. Jett, D. Dyer, J. Kern, D. Rollins, M. Phillips
- Abstract
- Presentation
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)
17:50 - 17:55 | Author(s): J.L. Tomic, R.L. Lagier, H.I. Pass, W.N. Rom, T.R. Pollard, C.E. Birse
- Abstract
- Presentation
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)
17:55 - 18:00 | Author(s): 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
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)
18:00 - 18:05 | Author(s): M. Shi, W. Han, J. Lin, S.D. Spivack
- Abstract
- Presentation
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.
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.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
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)
18:05 - 18:15 | Author(s): A. Spira
- Abstract
- Presentation
Abstract not provided
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Author 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: 1
- Moderators:J.M. Siegfried, H.I. Pass
- Coordinates: 9/07/2015, 16:45 - 18:15, 401-404
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MINI12.02 - Clinical Utility of Chromosomal Aneusomy in High Risk Individuals (ID 1299)
16:50 - 16:55 | Author(s): J.M. Siegfried
- Abstract
- Presentation
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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ORAL 39 - Potential Biomarkers for CT Screening (ID 149)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
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ORAL39.08 - Discussant for ORAL39.05, ORAL39.06, ORAL39.07 (ID 3438)
18:01 - 18:11 | Author(s): J.M. Siegfried
- Abstract
- Presentation
Abstract not provided
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