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N. Peled
Moderator of
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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: 8
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- Abstract
Background:
Currently, a blood test for lung cancer does not exist. Low-dose spiral computed tomography (CT) has been proposed as an early detection screening tool. However, despite its high sensitivity, the specificity of CT in lung cancer detection is poor. In addition, the necessity for repeated CT scans to determine growth rates over time can expose patients to potentially harmful radiation. Therefore, a minimally-invasive biomarker-based test that could further characterize CT-positive patients based on risk of malignancy would greatly enhance its clinical efficacy.
Methods:
From 2009 through 2013, six hospitals enrolled 1148 patients with lung cancer, 889 blood donors as healthy participants and 36 patients with other lung diseases. The lung cancer associated biomarker panels were identified from the pretreated serum samples and subsequently analyzed in three randomly determined subgroups, the discovery cohort (40 patients with lung cancer, and 45 healthy participants), test cohort (204 patients with lung cancer, and 120 healthy participants), and validation cohort (904 patients with lung cancer, 724 healthy participants, and 36 patients with other lung diseases). Finally the panel of biomarkers were used to predict 12 prospective patients with a suspicious pulmonary nodule by CT images.
Results:
The discovery cohort demonstrated that 4 serum biomarkers (C-reactive protein, prolactin, hepatocyte growth factor, and NY-ESO-1 autoantibody) were significantly higher in patients with lung cancer compared to healthy controls. The 4-biomarker panel was independently investigated in the test cohort and validation cohort. The test characteristics were area under the curve (AUC) of 0.835 (95% CI 0.79-0.873, sensitivity 70.1%, specificity 88.3%) in the test cohort, and 0.818 (95% CI 0.798-0.836, sensitivity 70.0%, specificity 79.6%) in the expanded validation cohort. The 4 biomarkers had no discriminatory power for detecting other benign lung diseases. The performance of the panels in patients with stage I-II lung cancer was AUC of 0.774 (95% CI 0.746-0.801) in the combined test and validation cohorts. Remarkably, analysis model generated by the biomarkers correctly predicted 7 out of 9 prospective patients having lung cancer, and 2 out of 3 patients as benign, which were further verified by the pathologist.
Conclusion:
This study identified four diagnostic biomarkers in serum samples with the potential to distinguish patients with lung cancer from healthy controls. This panel of serum proteins is valuable in suggesting the diagnosis of patients with an indeterminate pulmonary lesion, and potentially in predicting individuals at high risk for lung cancer. Further research is necessary to understand whether these have clinical implications for early detection of lung cancer.
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ORAL39.02 - Early Detection of Lung Cancer by a FISH-Based Sputum Test (ID 711)
16:56 - 17:07 | Author(s): W.R. Burfeind Jr., G. Soo Hoo, R. Batra, Y. Schwarz, N. Peled, T. Kaplan, G. Fink
- Abstract
- Presentation
Background:
Early detection represents an important opportunity for decreasing lung cancer mortality. Lung cancer screening with low-dose CT scanning is plagued by a high false-positive rate and non-invasive adjuncts that improve diagnostic accuracy or serve as a pre-screen may be helpful. This study evaluated the performance of a sputum based lung cancer detection (LCD) test that utilizes fluorescence in-situ hybridization (FISH) to detect chromosomal alterations at the 3p22.1 and 10q22.3 loci caused by a cancerous process.
Methods:
At 5 international centers, between March 2012 and July 2014, induced sputum samples were collected from 173 subjects with 8-30 mm solitary pulmonary nodules, where imaging and other subject characteristics mandated biopsy. At least 50 lower respiratory tract cells were required for analysis. The LCD Test, performed at one of 3 reference labs, enabled a combined analysis of sputum cytology and Target-FISH analysis on the same cell using an FDA approved imaging analysis system (BioView Duet™). The LCD test was considered positive if at least 7.5% of the target cells had an abnormal FISH pattern. The results of the LCD were then compared to the clinical pathology. Subjects with an initial non-surgical negative biopsy result were followed for up to 2 years to determine their final diagnosis.
Results:
There were 116 subjects who met the inclusion criteria, had a pathologic diagnosis of lung cancer if the nodule was malignant, and produced adequate sputum for analysis. Seventy-two subjects were diagnosed with lung cancer from the initial biopsy, 7 had definitive negative surgical biopsies, and 37 subjects were classified as indeterminate due to non-surgical negative biopsies. Initial positive concordance was 86.1% (62/72) and initial negative concordance was 71.4% (5/7). From the initial 37 indeterminate negative subjects, additional clinical analyses during the follow up period enabled a definitive classification for 23 subjects: 11 were diagnosed with lung cancer and 12 were reclassified as definitive negative. From this group the LCD test had a positive concordance of 81.8% (9/11) and a negative concordance of 91.7% (11/12). Overall, sensitivity was 85.5% (71/83), specificity was 84.2% (16/19), positive predictive value was 95.9%, and negative predictive value was 57.1%. Fourteen indeterminate negative subjects are still being clinically monitored. The test performance for nodules of 8-20mm was as good as the results for 21-30mm nodules.
Conclusion:
In a cohort of patients with a high risk of lung cancer, the LCD test had a high positive predictive value. A positive LCD test could potentially lead to an earlier intervention in a nodule that might otherwise have been monitored for growth. An adequate cancer resection might then be accomplished by segmental resection rather than lobectomy in smaller lesions. The LCD test may be useful as a decision support tool at critical points in the management of solitary pulmonary nodules detected by screening CT scans in subjects at high risk for lung cancer.
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ORAL39.03 - Clinical Utility of a Blood Based Circulating Tumour DNA Signature for the Diagnosis of Lung Cancer (ID 2457)
17:07 - 17:18 | Author(s): E. Lim, M. Freidin, D. Freidina, M. Leung, A. Rice, A.M. Fernandez, A. Nicholson
- Abstract
- Presentation
Background:
Lung cancer is conventionally diagnosed by confirmatory tissue biopsy, an invasive procedure that involves waiting time, costs and complications. The development push for a blood based liquid biopsy is a less invasive, more readily acceptable means to expedite the diagnosis and management of cancer. Circulating tumour DNA is promising in this regard as cancer specific genetic mutations are not usually found in the circulation of healthy individuals. The aim of our study is to report the performance of a three gene signature in for the diagnosis of cancer.
Methods:
Pre-operative blood samples were obtained from patients undergoing surgery for known or suspected lung cancer and 1ml aliquots of plasma were extracted from 9ml of EDTA preserved blood. DNA was extracted from the plasma using the QIAamp DNA blood mini kit. High resolution melt analysis was undertaken to identify mutations in hotspots of the TP53, KRAS and EGFR genes in the ctDNA from plasma as well as matching FFPE tissue. A positive test result was defined as a mutation identified in the plasma ctDNA and compared against the reference clinical histopathology report of the resected lung abnormality. Clinical test performance was quantified and reported conventionally using sensitivity and specificity.
Results:
Pre-operative blood was analysed in a blinded manner from 223 patients undergoing surgery at our institution, and the pathology reports were issued blinded to the blood test results. In total, 116 (52%) had primary lung cancer, 64 (29%) had secondary cancer, 6 (3%) had primary thoracic (not lung) cancer and 35 (16%) did not have any evidence of cancer. Of the 186 patients with confirmed cancer, a mutation was identified in the FFPE sections of the primary tumour of 113 (61%) and in the plasma ctDNA in 127 (68%) with substantial agreement of 85% and a kappa statistic of 0.70 (P<0.001). The clinical test performance for the blood based diagnostic signature was a sensitivity of 68% (95% CI 61-75), specificity of 91% (77 to 98), positive predictive value 98% (93-100) and a negative predictive value of 35% (25 to 46) when compared to conventional clinical histopathology reporting of the resected tissue.
Conclusion:
There is substantial agreement between the detection of ctDNA and FFPE tumour tissue mutations. We postulate higher mutation levels detected in the plasma is due to heterogeneity of tumour and FFPE sections in comparison to a global (plasma based ctDNA) estimate of mutation burden. Our results suggest blood based ctDNA analysis of cancer mutations is a specific, non-invasive test for the diagnosis of cancer. A positive test strongly rules in the diagnosis but a negative test does not have sufficient discriminatory ability to exclude the diagnosis of cancer.
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ORAL39.04 - Discussant for ORAL39.01, ORAL39.02, ORAL39.03 (ID 3437)
17:18 - 17:28 | Author(s): A. Vachani
- Abstract
- Presentation
Abstract not provided
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- Abstract
Background:
Current clinical diagnostic methods lack the specificity in detecting lung cancer patients. The issue is critical for stage I & II patients as there are no available biomarkers to indicate which high-risk patients should undergo adjuvant therapy. There is considerable evidence that microRNA plays a very important role in lung carcinogenesis. We postulated that the expression pattern of multiple microRNAs (miRNAs) could aid clinicians in detecting cancer patients thus reducing the mortality of lung cancer.
Methods:
Differential expressed miRNAs were analyzed by miRNA microarrays in 15 paired non-small-cell lung cancer (NSCLC) tumors and distant normal tissues. The identified miRNAs were further validated by qRT-PCR using snap-frozen lung tissue samples collected from independent 22 patients with NSCLC. Classification analyses of miRNA expression data were performed by the Bayesian Compound Covariate predictor (BCCP). The expression levels of miR-141-5p, miR-301a-3p and miR-1244 were also analyzed by qRT-PCR in serum samples collected from 60 patients with lung cancer and 50 healthy controls.
Results:
A total of 41 miRNAs was identified with significantly elevated levels in patients with lung cancer by profiling microRNA array, of which 12 miRNAs were further validated in the independent sample cohort. Multiplexing analysis with the panel of 12 miRNAs generated the highest discriminatory power in separating NSCLC from normal tissues with an AUC of 0.915 (95% CI = 0.894-1.000; P <0.001). Leave-one-out cross-validation revealed the 85% sensitivity and 95% specificity at a cutoff score of 0.5. In addition, serum miR-1244 was significantly upregulated in an independent trial and could distinguish NSCLC from controls with 77.6% sensitivity and 78.7% specificity.
Conclusion:
Our 12-miRNA classifier might have potential clinical utility in discriminating NSCLC from healthy population.
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ORAL39.06 - Whole Blood microRNA Expression May Not Be Useful for Screening Non-Small Cell Lung Cancer (ID 2547)
17:39 - 17:50 | Author(s): R. Mallick, S.K. Patnaik, E. Kannisto, A. Vachani, S. Yendamuri
- Abstract
- Presentation
Background:
Five studies have shown that microRNA levels in whole blood can be used to diagnose lung cancer. We conducted a large bi-institutional study to validate this finding.
Methods:
PAXgene[TM] Blood miRNA System (Qiagen®) was used for peripheral venous blood collection and total RNA isolation for 85 pathologic stage IA-IIIB non-small cell lung cancer cases and 76 clinically-relevant controls who either had a high risk of developing lung cancer because of smoking and age >50 y, or had a benign pulmonary nodule. Cases and controls were accrued at two institutions in the United States, Roswell Park Cancer Institute, Buffalo and University of Pennsylvania, Philadelphia. MiRCURY™ microarrays (Exiqon®) with locked nucleic acid hybridization probes were used to quantify microRNAs in RNA isolates. Quantification was also performed using Taqman™ microRNA reverse transcription (RT)-PCR assays (ABI®) for five microRNAs whose lung cancer-diagnostic biomarker utility had been suggested by the five published studies.
Results:
Cases (n=85) and controls (n=76) were similar for age, gender, race, and blood hemoglobin and leukocyte but not platelet levels (Table 1). Of the 1936 human mature microRNAs detectable with the microarray platform, 586 (30%) were identified as expressed and reliably quantified among the study's subjects. However, none of the microRNAs was differentially expressed between cases and controls (P >0.05 in test using empirical Bayes-moderated t statistics and false discovery rate <5%). In classification analysis using the whole blood microRNA profiles with leave-one-out internal cross-validation, accuracy was 48% and 50% with the support vector machines and top-scoring pair methods, respectively. With RT-PCR assays, cases and controls did not differ for any of the five microRNAs whose biomarker potential had been suggested by previous studies.Table 1. Characteristics of study groups; *Fisher's exact test for categorical variables, and t test for others; #blood values for 84 cases and 30 controls.
Cases Controls P* 85 76 Mean age, y (range, SD) 64 (41-83, 8) 61 (45-83, 9) 0.07 %male 49 51 0.87 %white 90 93 0.57 RPCI 42 32 0.43 U. Pennsylvania 43 44 Adenocarcinoma 43 Squamous cell 33 Other non-small cell 9 High-risk control 58 Nodule control 18 Leukocytes (x1000/µl; mean, SD)# 8.2 (2.6) 7.8 (2.1) 0.37 Platelets (x1000/µl; mean, SD)# 291.8 (114.3) 238.2 (50.2) 0.01 Hemoglobin (g/dl; mean, SD)# 13.4 (1.8) 13.9 (1.4) 0.15
Conclusion:
This study suggests that whole blood microRNA expression profiles may not be useful for developing biomarkers for use in non-invasive blood-based assays for generic screening of non-small lung cancer. Further studies are required to examine if whole blood microRNA diagnostic biomarkers may exist for use with specific types of lung cancer or non-cancer control conditions.
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ORAL39.07 - A Bronchial Genomic Classifier Measured in Airway Epithelial Cells Improves Diagnostic Sensitivity of Bronchoscopy for Lung Cancer (ID 2215)
17:50 - 18:01 | Author(s): A. Vachani, D. Whitney, A.C. Gower, K. Porta-Smith, J.S. Ferguson, J. Brody, G. Silvestri, M. Lenburg, A. Spira
- Abstract
- Presentation
Background:
Bronchoscopy is often used for the diagnosis of lung cancer however its sensitivity is imperfect, especially for small and peripheral lesions. Adjunctive methods to improve the sensitivity of cancer detection would reduce the need for more invasive follow-up procedures when bronchoscopy is non-diagnostic. It has previously been shown that gene expression of cytologically-normal bronchial airway epithelial cells is altered in smokers with lung cancer. In this study we evaluated the performance of a bronchial genomic classifier to predict malignancy in an independent cohort of suspect lung cancer patients.
Methods:
A bronchial genomic classifier consisting of the expression of 23 genes measured in the airway epithelium was evaluated in a previously published, independent cohort (n=163) of current and former undergoing bronchoscopy for suspect lung cancer. In cases where bronchoscopy was non-diagnostic for malignancy, the performance of the classifier was evaluated using ROC-AUC, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
Results:
In the test set, bronchoscopy led to a diagnosis in 40 of 78 patients with cancer (sensitivity=51%, 95% CI 40-63%). The combination of the classifier with bronchoscopy improved the sensitivity to 96% (95% CI 89-99%; p <0.001); see Table. The prediction accuracy of the classifier was similar in lesions <3cm, as well as across cancer stage and histology. Among the 123 patients with a non-diagnostic bronchoscopy, 38 were ultimately diagnosed with lung cancer (prevalence of 31%). In this group of patients, the classifier had an AUC of 0.81 (95% CI, 0.73-0.88), accurately identifying 35 of the 38 lung cancer patients (sensitivity=92%; 95% CI, 78-98%), and 45 of 85 patients with benign lesions (specificity=53%; 95% CI, 42-63%). Of the 48 patients with a negative classifier result, 45 were diagnosed with benign lesions (NPV=94%, 95% CI 83-99%).Table. Performance of bronchoscopy, classifier, and the combined procedures in the test set
a) The performance of the classifier was evaluated for patients in whom bronchoscopy did not result in a finding of lung cancer (n=123).Category Bronchoscopy Classifier[a] Combined Total, N 163 123 163 Lung Cancer, N 78 38 78 Benign Lesion, N 85 85 85 Sens. (95% CI) 51% (40-62%) 92% (78-98%) 96% (89-99%) Spec. (95% CI) 100% (95-100%) 53% (42-63%) 53% (42-63%) NPV (95% CI) 69% (60-77%) 94% (83-99%) 94% (83-98%) PPV (95% CI) 100% (90-100%) 47% (36-58%) 65% (56-73%)
Conclusion:
A gene expression classifier measured in bronchial epithelial cells is able to accurately identify those at low risk for lung cancer in patients who have undergone bronchoscopy with non-diagnostic results. Due to the high sensitivity and NPV of the classifier, it could potentially inform clinical decisions regarding the need for further invasive testing for lung cancer in patients whose bronchoscopy is non diagnostic.
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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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Author of
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MINI 04 - Clinical Care of Lung Cancer (ID 102)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Gaspar, V. Westeel
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2c-3c
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MINI04.09 - The Impact of Next-Generation Sequencing on Clinical Decisions in Lung Cancer (ID 2978)
17:30 - 17:35 | Author(s): N. Peled
- Abstract
- Presentation
Background:
In the last decade, important advances have been made in understanding genetic and molecular mechanisms of Non-Small Cell Lung Cancer (NSCLC) tumor development. This has led to the creation of innovative, targeted drugs that significantly prolong survival in advanced patients. Recent data shows that 63% of NSCLC tumors harbor at least one activating driver mutation, including treatable mutations such as RET, HER2 and ROS1 gene mutations, besides the regularly screened ALK and EGFR genes that account for 23% of the patients. Clinical cancer genomic profiling tests based on Next Generation Sequencing (NGS) technologies are capable to reveal clinically actionable genetic alterations in up to three times the number of actionable alterations detected by current diagnostic tests. However, there is no data regarding the true impact of these tests on clinical decisions in lung cancer. In this study, our objective is to evaluate the impact of NGS-based genetic profiling tests on treatment strategy in NSCLC patients in the real life setting, considering the additional diagnostic tests performed. Based on clinical experience from Israel, NGS-based tests actively change treatment plans, but the effect size is unknown and merits further investigation.
Methods:
In this retrospective study, data is collected from patient files at the Thoracic Cancer Unit of Davidoff Cancer Center, Rabin Medical Center, Israel. The current study population is 78 NSCLC patients who performed NGS-based genetic profiling tests.
Results:
Out of 78 patients, 58 patient files have already been reviewed and 6 were excluded. Treatment decision change rate after NGS testing was 33% (17 out of 52 patients were treated with a targeted therapy - 24% of the current study population). Interestingly, 9 patients became EGFR and ALK positive by NGS after the previous standard local molecular testing was negative. Based on the RECIST criteria of response evaluation, 41% of the patients had a partial response after switching to targeted therapy, 23% had a complete response, 18% experienced progressive disease and 18% were not evaluated yet. Survival rates will be calculated further in the study based on data availability.
Conclusion:
The use of NGS for tumor classification and treatment planning holds a great potential for improving patient life quality and survival. In this study, we aimed to determine its clinical impact in the real life setting in the treatment of lung cancer. Our partial results show that in addition to performing standard molecular testing for NSCLC, almost a quarter of the patients can be identified having an actionable driver mutation and switched to targeted therapy. Most of these patients showed a positive response to treatment. Although this topic needs to be further assessed in large randomized controlled trials, these positive results emphasize the importance of upfront multiplex testing or suggest such technology as a reflex test in places where the primary kits are done first in sake of cost-benefit.
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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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MINI12.07 - 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
- 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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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.14 - The Role of Breath Sampling in Monitoring Response to Treatment in Lung Cancer (ID 2551)
18:00 - 18:05 | Author(s): N. Peled
- Abstract
- Presentation
Background:
The current available method to monitor response to treatment in lung cancer patient is by Computerized Tomography (CT) scans. However, time intervals between consecutive CT scans might be too long to allow early identification of treatment failure. The aim of this study is to examine the use of breath sampling as a tool for monitoring response to anti-cancerous treatment in patients with advanced lung cancer.
Methods:
In a prospective study, repeated exhaled breath samples were collected from patients with advanced lung cancer before and under systemic therapy. VOCs[1] profiles were determined by GC-MS[2] and nanomaterial-based array of sensors and correlated with response to therapy, assessed by CT scans as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). [1] Volatile Organic Compounds [2] gas-chromatography/mass-spectrometry
Results:
One hundred forty three breath samples were collected from 39 patients with stage III/IV lung cancer. GC-MS anaylsis identified 3 VOCs as significantly indicating PR/SD samples. One of them was also significantly discriminated between PR/SD and PD. Further, the NA-NOSE signals were able to alarm per a change in tumor response across therapy, i.e. indicating lack of further response to therapy, or developement of resistance to therapy. PR/SD was detected in a sensitivity of 93%, specificity of 85% and accuracy of 89% and ppositive/negative predictive values (PPV; NPV) of 86% and 92% respectively. PD was detected with 100% specificity and 92% accuracy, but the sensitivity was only 28%. The PPV and NPV were 100% and 91%, respectively. The achieved results indicate high reliability in predicting a progression of the disease and detecting patient's lack of response to treatment (i.e., PD).
Conclusion:
Breath analysis may serve as a serogate marker for response to systemic therapy in lung cancer. Such a monitoring tool can provide the oncologist with a quick and simple method to identify patient's response to anti-cancerous treatment in shorter intervals than currently available by CT scans.
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MS 02 - Are Non-Tissue Biomarkers Ready for the Clinic? (Presentation recordings currently in editing process) (ID 20)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:A. Hoffmann, L. Montuenga
- Coordinates: 9/07/2015, 14:15 - 15:45, 401-404
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MS02.04 - Exhaled Breath (ID 1855)
15:20 - 15:40 | Author(s): N. Peled
- Abstract
Abstract not provided
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ORAL 09 - CT Screening - New Data and Risk Assessment (ID 95)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:J. Mulshine, J.K. Field
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL09.04 - Discussant for ORAL09.01, ORAL09.02, ORAL09.03 (ID 3532)
11:18 - 11:28 | Author(s): N. Peled
- Abstract
- Presentation
Abstract not provided
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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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ORAL39.02 - Early Detection of Lung Cancer by a FISH-Based Sputum Test (ID 711)
16:56 - 17:07 | Author(s): N. Peled
- Abstract
- Presentation
Background:
Early detection represents an important opportunity for decreasing lung cancer mortality. Lung cancer screening with low-dose CT scanning is plagued by a high false-positive rate and non-invasive adjuncts that improve diagnostic accuracy or serve as a pre-screen may be helpful. This study evaluated the performance of a sputum based lung cancer detection (LCD) test that utilizes fluorescence in-situ hybridization (FISH) to detect chromosomal alterations at the 3p22.1 and 10q22.3 loci caused by a cancerous process.
Methods:
At 5 international centers, between March 2012 and July 2014, induced sputum samples were collected from 173 subjects with 8-30 mm solitary pulmonary nodules, where imaging and other subject characteristics mandated biopsy. At least 50 lower respiratory tract cells were required for analysis. The LCD Test, performed at one of 3 reference labs, enabled a combined analysis of sputum cytology and Target-FISH analysis on the same cell using an FDA approved imaging analysis system (BioView Duet™). The LCD test was considered positive if at least 7.5% of the target cells had an abnormal FISH pattern. The results of the LCD were then compared to the clinical pathology. Subjects with an initial non-surgical negative biopsy result were followed for up to 2 years to determine their final diagnosis.
Results:
There were 116 subjects who met the inclusion criteria, had a pathologic diagnosis of lung cancer if the nodule was malignant, and produced adequate sputum for analysis. Seventy-two subjects were diagnosed with lung cancer from the initial biopsy, 7 had definitive negative surgical biopsies, and 37 subjects were classified as indeterminate due to non-surgical negative biopsies. Initial positive concordance was 86.1% (62/72) and initial negative concordance was 71.4% (5/7). From the initial 37 indeterminate negative subjects, additional clinical analyses during the follow up period enabled a definitive classification for 23 subjects: 11 were diagnosed with lung cancer and 12 were reclassified as definitive negative. From this group the LCD test had a positive concordance of 81.8% (9/11) and a negative concordance of 91.7% (11/12). Overall, sensitivity was 85.5% (71/83), specificity was 84.2% (16/19), positive predictive value was 95.9%, and negative predictive value was 57.1%. Fourteen indeterminate negative subjects are still being clinically monitored. The test performance for nodules of 8-20mm was as good as the results for 21-30mm nodules.
Conclusion:
In a cohort of patients with a high risk of lung cancer, the LCD test had a high positive predictive value. A positive LCD test could potentially lead to an earlier intervention in a nodule that might otherwise have been monitored for growth. An adequate cancer resection might then be accomplished by segmental resection rather than lobectomy in smaller lesions. The LCD test may be useful as a decision support tool at critical points in the management of solitary pulmonary nodules detected by screening CT scans in subjects at high risk for lung cancer.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-067 - Mitochondrial Respiration Capacity and Sensitivity to Glycolysis Blockade in Lung Cancer (ID 2360)
09:30 - 09:30 | Author(s): N. Peled
- Abstract
Background:
One of the metabolic perturbations in cancer cells is the Warburg effect; glycolysis is preferred over oxidative phosphorylation (OXPHOS), even in the presence of oxygen. The precise mitochondrial alterations that underlie the increased dependence of cancer cells on aerobic glycolysis for energy generation may serve as an escape mechanism from apoptosis. Here, we aimed to profile the mitochondrial activity in different lung cancer cell lines in reference to their glycolytic activity and to their sensitivity to metabolic modifications.
Methods:
The metabolic profile of A549 and H358 cell lines were tested before and after glycolysis blockade (glucose starvation, 2DG) and mitochondrial induction (FCCP). Glycolysis inhibition and mitochondrial activity were assessed by western-blot quantification of key enzymes involved in the glycolysis pathway (e.g. Hexokinase I/II, glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase 2) and of mitochondrial coded proteins (e.g. ND1, ATP6 synthase). The oxygen consumption rates (OCR) and extra cellular acidification rate (ECAR) were measured by XF[e]24 extracellular flux analyzer. Further, mitochondrial index was compared to the cells' sensitivity to glycolysis inhibition.
Results:
A549 cells were highly affected by glucose inhibition/starvation accompanied by ineffective mitochondrial compensation. On the other hand, H358 cells recovered completely from glucose starvation through mitochondrial hyper-activation (Fig 1); At the basal level (when no material was applied), A549 cells that were starved had a decrease of 68% in the ECAR, as compared to non-treated cells. Their recovery was limited after glucose injection (23 vs.41 mpH/min). In comparison, H358 cells had a 43% decrease in their glycolysis rate with a full recovery after glucose injection (44-46 mpH/min; pre & post respectively). Mitochondrial respiration was very low for A549 cells under starvation, while significantly increased in H358 cells (223 vs.143 pmol/min, *Pv<0.0001). Respectively, the expression level of mitochondrial coded proteins was higher in the cells that demonstrated higher mitochondrial capacity (Fig 2). Figure 1
Conclusion:
Cells with high mitochondrial capacity may tolerate glucose starvation/ blockade, while a limited mitochondrial reserve exposes the cells to higher sensitivity to glycolysis stress. This might suggest a potential therapeutic avenue with a companion predictive test.
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P1.06 - Poster Session/ Screening and Early Detection (ID 218)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.06-009 - Volatolomic Signatures to Assess Sensitivity to FGFR Tyrosine Kinase Inhibitors (ID 1711)
09:30 - 09:30 | Author(s): N. Peled
- Abstract
Background:
Targeted therapy is transforming the treatment of lung cancer. Such therapies are critically dependent on companion diagnostics that can predict the response to therapy. An ideal test is one that is quick, inexpensive, and non-invasive. In this regard, artificial intelligence nanosensor-based devices that profile volatolomic signatures (through volatile organic compounds (VOCs) analysis) have shown exciting potential. Numerous studies have shown cancer cells produce characteristic patterns of VOCs as a byproduct of their metabolism. These patterns can be used to diagnose patients with cancer using exhaled-breath samples. Here we asked whether the VOC patterns emanating from cancer cells could also be used to guide targeted therapy. In particular, we investigated whether lung cancer cell lines known to be sensitive to FGFR tyrosine kinase inhibitors (TKIs) can be distinguished from cell lines known to be resistant using an array of cross reactive, highly sensitive chemiresistors composed of gold nanoparticles (GNP) and carbon nanotubes (CNTs) coated with various recognition layers previously shown to be highly effective at profiling VOCs.
Methods:
Fourteen sensitive cell lines having an IC~50~ ≤ 50 nM for Ponatinib and AZD4547 (nonspecific and specific FGFR TKIs, respectively) and 21 resistant cell lines representing small cell and non-small cell lung cancers were cultured in complete media (RPMI 1640, 10% fetal bovine serum, and penicillin/streptomycin) under standard conditions to 50% to 75% confluency. SKC Tenax® TA Adsorbent resin was used to collect the VOCs from the head space of each cell line over a period of 60 to 72 hours. Triplicate measures were collected on each sample along with biological replicates. VOCs were also collected at the same time from control plates containing media only. After thermal desorption, the VOC pattern of each sample was characterized using a chemiresistor array of 36 sensors and 4 features per sensor. A statistical pattern recognition analysis was then conducted using a discriminant function analysis (DFA) algorithm to identify the most informative sensors and features.
Results:
We found that sensitive cell lines could be distinguished from resistant cell lines using only 4 sensors and one feature from each (GNP+dodecanethiol, CNT+PAH, GNP+thiol and CNT+β dextrin). Leave-one-out cross validation indicated a sensitivity of 88% for the FGFR TKI-sensitive cell lines with 100% specificity and 92% accuracy. The area under the receiver-operating characteristic curve was 70% and Wilcoxon p-value of 0.06.
Conclusion:
Profiling the VOCs emanating from lung cancer cells shows excellent diagnostic potential as a means of gauging initial sensitivity to FGFR1 TKIs. Consequently, this study suggests that the electronic nose devices currently being developed to profile exhaled breath for cancer detection could also play an important role in predicting responses to targeted therapies. Although cell lines are useful for identifying the VOC pattern that predicts the cancer cell response to therapy, they do not necessarily reflect the complexity that occurs in vivo due to interactions with the microenvironment. Therefore, future studies are needed to confirm if these results can be extended to project efficacy in patients assigned to FGFR TKI therapy.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-047 - Mitochondrial Activation- A Potential Therapy in Lung Cancer (ID 2359)
09:30 - 09:30 | Author(s): N. Peled
- Abstract
Background:
Lung cancer is the leading cause of cancer related deaths in the United States with an overall 5- year survival rate of all stages of~ 17%. Radiation therapy plays a key role in lung cancer treatment. However, many lung cancer patients show resistance to radiation. There is a growing body of evidence indicating that mitochondria may be the primary targets for cancer therapeutics: The unique metabolism of most solid tumors, including lung cancer, stems from remodeling mitochondrial functions to produce a glycolytic phenotype and a strong resistance to apoptosis (Warburg effect). Cancer specific remodeling can be reversed by a small molecule named dichloroacetate (DCA) which promote mitochondrial activation by increasing the influx of pyruvate. Sodium oxamate- another molecule that interferes with cells metabolism, inhibits the formation of the lactate-the end product of glycolysis. Here, we tested whether mitochondrial induction (using DCA and sodium oxamate) may increase the sensitivity of non-small cell lung cancer (NSCLC) cells to radiation through this mechanism. Moreover we tested whether sodium oxamate, increases the effect of DCA on radiation.
Methods:
Two representative NSCLC cell lines (A549 and H1299) were tested for their sensitivity to radiation with and without pre-exposure to DCA and sodium oxamate. The treatment efficacy was evaluated using a clonogenic survival assay. An extracellular flux analyzer was used to assess the effect of DCA on cellular oxygen consumption as a surrogate marker for mitochondrial activity.
Results:
We found that DCA increases the oxygen consumption rate in both A549 and H1299 cells by 60 % (p = 0.0037) and 20 % (p = 0.0039), respectively. Pre-exposure to DCA one hour before radiation increased the cytotoxic death rate 4-fold in A549 cells (55 to 13 %, p = 0.004) and 2-fold in H1299 cells (35 to 17 %, p = 0.28) respectively, compared to radiation alone. Sodium Oxamate radisosensitized H1299 cells as well. Double treatment with DCA and Sodium Oxamate enhances the radiosensitivity of H1299 cells.
Conclusion:
Mitochondrial activation may serve as a radio-sensitizer in the treatment of non-small cell lung cancer. Inhibition of the end stage of glycolysis increases the effect of mitochondrial activation on radiation.
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P2.06 - Poster Session/ Screening and Early Detection (ID 219)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.06-009 - Oral Glucose Tolerance Test as a Diagnostic Tool in Lung Cancer (ID 1040)
09:30 - 09:30 | Author(s): N. Peled
- Abstract
Background:
Previous studies have demonstrated that volatile organic compounds (VOCs) in exhaled breath can distinguish between healthy and affected individuals, and can even discern between SCLC and NSCLC and within the subtypes of lung cancer (LC) and its mutations status. The current study assessed the differences in glucose metabolism on the volatile signature in LC through an oral glucose tolerance test (OGTT).
Methods:
This cohort included forty participants (22 control participants whom are at high risk for LC, 18 study participants whom have active, naïve lung cancer). Pre-OGTT and Post-OGTT blood glucose levels and exhaled breath samples were measured with a lay period of 90 minutes. A proton transfer reaction mass spectrometer (PTR MS) detected and measured the VOCs. The data was then analyzed using a series of feature selection methods to identify relevant inputs for multilayer perceptron (MLP) models to distinguish LC patients from controls, with and without the consideration of the glucose effect.
Results:
The feature selection method “infogain” revealed a combination of 14 masses (m/e) that were different between the two groups without considering the glucose effect. All the average values of these masses were higher in the LC group except for m/e 52, which was higher in the high-risk group. These 14 masses enable us to distinguish between the two groups with an average accuracy of 91.67% for three internal validation tests of a MLP (threshold set at 0.45). The analysis of the effect of glucose revealed that several m/e increased more for the control group whereas others increased more for the LC group. Moreover, three feature selections, each with a different combination of 4 masses, allowed the design of three MLPs that yielded 90% for K-fold cross-validation accuracy. Figure 1
Conclusion:
This study showed that breath analysis could discriminate between the high-risk and LC group. Furthermore, it demonstrated that glucose metabolism leaves a unique VOC pattern in the LC group. These findings may assist in the development of a non-invasive screening method for lung cancer.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-041 - Identification of the Functional Significance of Mutations in Lung Cancer Using the Novel Precision Cancer Analysis System (ID 1000)
09:30 - 09:30 | Author(s): N. Peled
- Abstract
Background:
Mounting evidence indicates that growth of pathologically identical lung cancers in each individual patient is fueled by different sets of driving mutations. The need to identify these drivers stems from the recognized necessity for tailoring therapy and scheduling future surveillance. This personalized medical approach has been shown to result in better treatment outcomes. We present a novel Precision Cancer Analysis system (PCAS) capable of identifying activated signaling pathways by means of a transfected cell-based fluorescent reporter assay yielding a quantitative output of particular pathway activation levels. Being a functional platform PCAS reveals activated pathways regardless of the type of mutation behind it, i.e. whether it is already a known mutation or a variant of unknown significance (VOUS) mutation.
Methods:
In 10 patients with lung cancer next generation sequencing (NGS) was employed to sequence a set of 37 genes relevant in lung carcinogenesis. These genes were sequenced with 90 -100 % coverage. According to the prevalence of mutations in the analyzed cohort 3 major genes were selected for the current study: EGFR, PIK3CA and KRAS. These genes were then mapped to their major signaling pathways, and the reporters that best account for their activation were selected. Four major signaling pathways were found to be relevant for these genes‐ MAPK, STAT, NFkB and AKT.
Results:
In analyzed samples of 10 patients 14 mutations were identified, among them 3 in the tested genes: 2 in KRAS and 1 complex mutation in EGFR. The remaining mutations were found in STK11, CDKN2A, NF1, RB1 and TP53 genes. Of mutations found in KRAS 1 was known mutation (K117N) and 1 was VOUS (G60R). The former caused activation via MAPK/ERK but not via AKT pathway. The latter, never so far reported in cancer, significantly activated both pathways: MAPK/ERK and AKT. Interestingly the VOUS KRAS mutation was identified in carcinoid, whereas 2 carcinoid samples from other individuals displayed no mutations in the 37-gene panel. Additionally, 1 VOUS in RB1 and 2 mutations in STK11 were found to be associated with cancer cells aggressiveness evidenced by vessel and nerve tissue invasion. Measuring the functional mechanism behind known mutations and VOUS provides another layer of critical information to the physician.
Conclusion:
The study produced a comprehensive delineation of the oncogenic activity of each patients’ individual mutations demonstrating the ability of the PCAS to: Accurately deliver comparable actionable information as found by NGS Functionally characterize mutations annotated as VOUS. Monitor oncogenic activity of signaling pathways induced by different mutations and mutation-combinations enabling informed treatment decisions.
