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S. Lu
Moderator of
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MO01 - Lung Cancer Biology - Techniques and Platforms (ID 90)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 10
- Moderators:S. Lu, P. Waring
- Coordinates: 10/28/2013, 10:30 - 12:00, Bayside 204 A+B, Level 2
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MO01.01 - Next generation sequencing of circulating tumour cells captured by antibody-independent enrichment and matched primary tumours/metastases in patients with non-small cell lung cancer (ID 3311)
10:30 - 12:00 | Author(s): Y. Teng, J.Y. Chua, M. Loh, S. Ow, A. Wong, T. Agasthian, J.K.C. Tam, B. Pang, R. Soong, R. Soo
- Abstract
Background
Circulating tumour cells (CTCs) are considered the seeds of metastasis, and characterization of CTCs promises novel insights into metastasis, new targets for intervention, and less-invasive samples for assessing tumour status. CTCs however are rare in circulation and thus highly sensitive tools are required for their reliable capture and analysis. Antibody-based platforms using candidate gene-based approaches have begun to provide insights into CTCs. However tumour heterogeneity and the dependence of these methods on antigen expression has made antibody-independent methods of interest. The Clearbridge ClearCell System is a microfluidic-based platform that enables antibody-independent capture and retrieval of CTCs based on differences in the biomechanical characteristics of blood cells and CTCs. Next Generation Sequencing (NGS) has emerged as a tool to perform massive parallel sequencing of genomic regions with high efficiency and accuracy. The aim of this study was to perform NGS analysis of CTCs captured by antibody-independent methods, and their matched primary tumour or metastases samples, in patients with NSCLC.Methods
Three matched CTC and primary tumour samples and three matched CTC and metastases samples were obtained from patients with NSCLC. Whole blood samples were also obtained from the patients for germline DNA. Five patients had adenocarcinoma and none of the patients had received targeted therapy prior to biospy of the metastatic lesions. CTCs were captured and retrieved from 2ml whole blood using the Clearbridge ClearCell System near the time of tumour sampling. DNA was extracted from CTCs, tumour tissue, and whole blood using the Qiagen QiaAMP DNA Micro Kit, DNAeasy Blood and Tissue kit , and Biorobot EZ1 workstation respectively. NGS was performed on the Ion Torrent PGM Sequencer using the AmpliSeq Comprehensive Cancer Panel targeted to 409 genes prominent in cancer. DNA variants were identified using Ion Torrent Software Suite v3.4, and pathway analysis was performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID).Results
After subtraction of DNA variants found in whole blood, the average number of variants in CTC, primary tumour and metastases samples was 283 (range: 110-470), 433 (70-1002), and 242 (81-166) respectively. The concordance in variants between CTC and primary tumour samples was 22% (15-29%) and between CTC and metastases samples was 29% (20-38%). Genes frequently mutated in matched CTCs and primary tumours/metastases included NOTCH2, AKT1, and RET. Pathway analysis of genes with DNA variants revealed an enrichment of genes involved in mTOR signalling in both CTC/primary and CTC/metastases samples. In CTC/metastases samples, pathways including the JAK-STAT and B-cell receptor pathways were additionally enriched.Conclusion
Our results have highlighted a high level of genetic variability between CTCs and their matched tumours, reflective of high tumour heterogeneity. Preliminary analysis has identified genes and pathways with alterations in CTCs that could be potential targets for systemic treatment. -
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MO01.03 - Transitioning To Next Gen Testing Of Lung Carcinoma (ID 2891)
10:30 - 12:00 | Author(s): W.A. Franklin, J. Haney, D.T. Merrick, K.L. Jones, K. Gowan, A. Van Bokoven, P. Bunn, Y. Miller, D. Aisner
- Abstract
Background
The feasibility of multigene testing in a clinical setting has been demonstrated by the Lung Cancer Mutation Consortium (LCMC) which has evaluated over 1000 cases from multiple institutions in a CLIA environment. The initial platforms used by the LCMC were SNaPshot and Ion Torrent, allele specific tests. More recently the sequencing by synthesis method (Illumina) used for whole genome sequencing has been scaled for sequencing of a limited number of targeted genes. In this study we compare the performance characteristics of Next Generation testing on the MiSeq platform with the older allele specific SNaPshot platform and evaluate the applicability of Miseq-based testing to a clinical, CLIA regulated setting.Methods
Two Illumina kits, the TruSeq and TruSight evaluating 221 hotspots in 48 gene and 175 exons in 26 genes, respectively, were compared. To assess analytical sensitivity, cell lines with known mutations and SNPs were titered into liver DNA known to be wild-type for the selected mutations, at tumor cell concentrations ranging from 3% to 50%. In addition, 24 formalin-fixed paraffin-embedded lung tumors that had previously been evaluated by SNaPshot or direct sequencing were tested to compare sensitivities and specificities of methods. Paraffin embedded human tumor tissue samples were enriched for tumor cells by coring of paraffin block or macrodissection using a pneumatic cell collector. DNA was extracted by proteinase K digestion and column chromatography, end repaired and phosphorylated. Libraries were prepared from each sample by ligating index adapters that allow for mixing of samples and binding adapters that link DNA fragments to flow cell. Combined libraries were added to flow cells at an appropriate concentration, clusters generated, and sequencing reaction commenced. Results were evaluated by software developed by Illumina or locally at the University of Colorado.Results
Spiking studies indicated that analytic sensitivity for Miseq at loading quantities of 100 to 300 ng (TruSeq) was ~5% for known KRAS and TP53 mutations and several synonymous polymorphisms in other covered genes, comparable to SNaPshot. For clinical samples, average depth of coverage was 5700 (+/- 2267). Unfiltered results using Illumina software supplied with the Miseq instrument showed an average of 88 heterozygous SNPs, 12 insertions and 17 deletions (uncurated for relevance). All of the mutations that were previously found by SNaPshot were also detected by Miseq TruSeq and TruSight protocols (100% concordance). Variants representing known polymorphisms, synonymous changes and variants identified in the context of low coverage were excluded. Data analysis using locally developed software indicated the presence of 1-9 SNPs in each sample that were not predicted by SNaPshot testing, attributable to the wider coverage of the Miseq platforms. None of the additional mutations represented treatable targets with currently available drugs.Conclusion
Next-generation testing is feasible in a CLIA environment using the Miseq platform. However, rigorous software validation is necessary before this platform can be adopted by a busy clinical laboratory. Software limitations currently being addressed include long turnaround time, inadequate vetting of new and recurrent SNPs for clinical significance and limited software development resources. -
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MO01.04 - Comparison of Microarray and RNA Sequencing Platforms for Profiling MicroRNAs in Formalin-Fixed, Paraffin-Embedded Non-Small Cell Lung Cancer Specimens (ID 3145)
10:30 - 12:00 | Author(s): D. Buitrago, K. Kadota, V.W. Rusch, S.K. Patnaik, P.S. Adusumilli
- Abstract
Background
MicroRNAs are useful biomarkers for various disease states, and their preservation in formalin-fixed, paraffin-embedded (FFPE) tissue makes them particularly useful for clinicogenetic studies. Although global microRNA expression in FFPE samples is routinely measured with microarrays, the utility of RNA sequencing for such profiling has yet to be established. In this study, to appraise the suitability of RNA sequencing, microRNAs in RNA from lung cancer FFPE samples were quantified by both a microarray and a sequencing platform.Methods
The affinity spin column–based Roche High Pure FFPE RNA kit was used to extract total RNA from 8 resected stage I lung adenocarcinoma FFPE tumor specimens (~3 mm[3]) with ≥50% tumor content. RNA was quantified by RiboGreen fluorometric and absorbance spectrometric analysis at 260 nm, and its quality was examined by electrophoresis on an RNA Pico chip in an Agilent Bioanalyzer 2100. MicroRNAs in 120 ng of RNA were profiled using the 8x60K Agilent Human miRNA Microarray (release 16.0) platform. MicroRNAs were also quantified by use of the Illumina HiSeq 2000 sequencing system (1x 50 bp reads), with multiplexed sequencing libraries prepared using 1 ug of RNA with the Illumina Truseq Small RNA Preparation Kit (version 2.0). Microarray data were processed using the AgiMicroRna Bioconductor package in R. Sequencing data were demultiplexed using CASAVA software and were mapped against mature human microRNAs in the miRBase database (version 16) using STAR aligner software. Absolute microRNA count values were then normalized among samples by use of the edgeR Bioconductor package.Results
Results of RiboGreen fluorometric analysis suggested that an average of 16 ug (range, 6-35 ug; SD, 8 ug) of RNA was obtained from the FFPE specimens. Significant degradation of RNA was observed, as expected, with Bioanalyzer RNA integrity number values between 1.9 and 2.5. An average of 1.3 million sequencing reads (range, 9.1-16.9 million; SD, 3.5 million) were obtained, but only 1.4% (range, 0.4%-2.1%; SD, 1.4%) of them mapped to known microRNAs. Of the 1205 human microRNAs detectable with the microarray platform, 302 were identified as expressed in the 8-sample set, and 593 were identified as expressed in the sequencing platform. For the 177 microRNAs detected by both microarray and sequencing methods, the interplatform Spearman correlation coefficient was >0.5 for only 51 of them. Reverse-transcription PCR assays are being performed to identify the platform that yields the most accurate microRNA profile.Conclusion
MicroRNA profiling by RNA sequencing and microarray techniques produced different results. The RNA sequencing method described here does not appear to be suitable for profiling microRNAs in RNA from FFPE samples. It is possible that depletion of ribosomal RNA fragments from FFPE RNA samples may improve the quality of data obtained from RNA sequencing. -
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MO01.05 - DISCUSSANT (ID 3900)
10:30 - 12:00 | Author(s): S. Fox
- Abstract
Abstract not provided
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- Abstract
- Presentation
Background
EGFR mutation-positive Non-Small Cell Lung Cancer (NSCLC) patients who show an initial dramatic response to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy almost always acquire resistance due to secondary resistance mutations on EGFR or other mechanisms. Strategies to overcome such acquired resistance have therefore become critical to improve TKI-based targeted therapy. One strategy is the development of therapeutic agents to be used in combination with EGFR-TKI to treat EGFR mutation-positive relapsed patients. Although several candidate drugs targeting putative resistance pathways in NSCLC cells have been attempted in combination with EGFR-TKI, a systematic screening has not been reported. We seek to screen a small molecule library for compounds that would specifically enhance the cytotoxic effect of TKIs on EGFR mutation-positive tumor cells bearing acquired resistance mutations.Methods
We have used MTS assay to screen a library containing about 1000 FDA approved drugs, 600 bioactive compounds, and 400 natural products, to identify compounds that when used in combination with 1µM Gefitnib, can result in significantly more toxicity to Gefitnib-resistant NSCLC cell line H1975 than either Gefitnib or the compound alone. The EGFR on H1975 contains both a TKI-sensitive mutation L858R and a resistant mutation T790M.Results
The screening identified one candidate compound 18G06, an experimental natural product that belongs to a family of drugs currently used for heart disease. The compound has an IC50 of 270nM on H1975, and acts synergistically with Gifitnib to affect cell apoptosis, suggesting that the drug can overcome Gefitnib resistance in H1975. Test of 4 other known drugs in this family showed that they all have sub-microM IC50 values against H1975, but only Drug D had synergistic effect with Gefitnib, while other three drugs showed only additive effects. In addition, 18G06 or Drug D can overcome Gefitnib resistance of H1650 cells, a resistant NSCLC cell line with TKI-sensitive exon19 microdeletion and a TKI-resistant PTEN deletion. However, these two drugs, when used alone or with Gefitnib, had little effect on A549 cells, a resistant NSCLC line with wildtype EGFR. Biochemical evidence suggested that the improved Gefitnib sensitivities of H1975 and H1960 were correlated with specific synergistic inhibition of the ERK signaling pathway during combination treatment. Finally, combination therapy with Drug D and Gefitnib inhibited the growth of tumors formed by inoculated H1975 cells in nude mice to a greater extent than did treatment with either drug alone.Conclusion
We identified two specific members of a family of therapeutics for heart disease that, when each combined with Gefitinib, have synthetic lethality effect on H1975 and H1960. The FDA-approved Drug D can be readily tested in clinical trials with Gefitnib to potentially reverse TKI-resistance of EGFR mutation-positive patients in targeted therapy.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO01.07 - Inhibition of the IGF-1R signaling pathway potentiates responses to ALK inhibitors in both ALK TKI naive and ALK TKI resistant lung cancer (ID 1660)
10:30 - 12:00 | Author(s): C.M. Lovly, N.T. McDonald, Y.H. Chen, H. Jin, D. Lim, Y. Suehara, L. Wang, D.H. Johnson, L. Horn, M. Ladanyi, W. Pao
- Abstract
- Presentation
Background
Oncogenic fusions involving the gene encoding the anaplastic lymphoma kinase (ALK) define a new clinically relevant molecular subset of lung cancer. The majority of patients with ALK+ lung cancer are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy, however, the efficacy of these ALK inhibitors is limited by the development of acquired resistance. Additional strategies using rationally selected therapeutic agents/combinations of agents are needed to both delay and overcome acquired resistance to ALK inhibition. Based upon an intriguing clinical observation from a patient with ALK+ lung cancer who had an ‘exceptional response’ to an IGF-1R monoclonal antibody (MAb), we report a novel therapeutic synergism between ALK inhibitors and IGF-1R inhibitors.Methods
A series of experimental approaches including cell culture models, in vitro assays, and a study of patient tumor samples prior to and at the time of acquired resistance to ALK TKI therapy were employed to test the hypothesis that IGF-1R can be targeted therapeutically to enhance anti-tumor responses in ALK+ NSCLC.Results
Across multiple different ALK+ lung cancer cell lines, including a novel ALK+ cell line developed from a patient prior to ALK TKI therapy, IGF-1R inhibitors (TKIs and MAbs) sensitized ALK+ lung cancer cells to the effects of ALK blockade as assessed by standard cell viability assays. Similar to IGF-1R, ALK fusions co-immunoprecipitated with the adaptor protein, IRS-1, and treatment with ALK inhibitors decreased IRS-1 protein levels. Furthermore, siRNA mediated knock-down of IRS-1 impaired the proliferation of ALK+ lung cancer cells and enhanced the anti-tumor effects of ALK inhibitors. The IGF-1R pathway was activated in cell culture models of ALK TKI resistance, and combined ALK/IGF-1R inhibition in the resistant cells blocked reactivation of downstream signaling and markedly improved therapeutic efficacy in vitro. Finally, IGF-1R and IRS-1 levels were increased in biopsy samples from a patient with advanced ALK+ lung cancer post crizotinib therapy.Conclusion
Collectively, these data support a role for the IGF-1R/IRS-1 signaling pathway in both the ALK TKI sensitive and ALK TKI resistant states and suggest that this rationally selected combination of inhibitors may be an effective strategy to attempt to delay or overcome acquired resistance to therapeutic ALK inhibition. Intriguingly, the ‘second generation’ ALK TKI, LDK-378, which has demonstrated an overall response rate of 70% in patients with both crizotinib naïve and crizotinib resistant ALK+ lung cancer, can inhibit both ALK and IGF-1R in vitro. We speculate, based on these data, that this surprising response rate may be due to LDK-378’s ability to simultaneously inhibit both targets.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO01.08 - Identifying Strategies For The Treatment Of Acquired EGFR Tyrosine Kinase Inhibitor Resistance (ID 3187)
10:30 - 12:00 | Author(s): C. Hasovits, A. Hudson, R. Harvie, S. Clarke, N. Pavlakis, V. Howell
- Abstract
- Presentation
Background
The management of non-small cell lung cancer (NSCLC) is becoming increasingly personalised with the identification of oncogenic drivers of cancer cell growth which are able to be targeted therapeutically. The paradigm of advanced non-squamous NSCLC treatment now incorporates assessment of epidermal growth factor (EGFR) mutations and treatment with EGFR tyrosine kinase inhibitors (TKIs) in cases where sensitising mutations are found, which results in significant prolongation of progression-free survival compared to empirical chemotherapy. However, the emergence of acquired resistance to EGFR TKIs is almost universal and the two most common mechanisms of resistance include the acquisition of a second mutation in EGFR, the T790M mutation, and c-MET amplification. Approximately one-quarter of cases of resistance are yet to be defined mechanistically and furthermore, optimal subsequent treatment remains unknown. Further research is required to understand the molecular origins of the development of acquired resistance in order to develop rational treatment strategies that incorporate both targeted and cytotoxic therapies. This study is evaluating, using in vitro models, pathways involved in the development of acquired resistance to EGFR TKI and chemotherapy and evaluating critical differences according to EGFR mutation status.Methods
A panel of human NSCLC cell lines with varying clinically relevant molecular characteristics is being assessed and used to develop resistance to various cytotoxic agents and EGFR TKIs, through chronic low dose exposure, as outlined in the table below:
Assessments of proliferation, cytotoxicity and key signalling pathways are being conducted to evaluate mechanisms of chemotherapeutic and targeted therapy resistance.Cell Line Mutation Status EGFR TKI Sensitivity Resistant Cell Line Generated HCC827 EGFR Exon 19 deletion Sensitive Erlotinib; Cisplatin; Paclitaxel; Pemetrexed H1975 EGFR Exon 21 Point Mutation (L858R) and T790M mutation Resistant Cisplatin; Paclitaxel; Pemetrexed H1299 EGFR Wild-Type Resistant Cisplatin; Paclitaxel; Pemetrexed A549 EGFR Wild-Type and KRAS Mutation Resistant Cisplatin; Paclitaxel; Pemetrexed, HDAC-inhibitor Results
Chronic low dose exposure has been successful in generating resistant cell lines to both chemotherapeutic agents and the EGFR TKI erlotinib. Cross-resistance to taxol in cisplatin-resistant cell lines has been observed, along with evidence of epithelial-to-mesenchymal transition in the development of EGFR TKI resistance. Antibody arrays of key signalling pathways are being conducted to confirm critical pathways of interest.Conclusion
The panel of human NSCLC cell lines with parental lines harbouring various EGFR sensitising and resistance mutations and generated lines resistant to cytotoxic agents and EGFR TKI are a useful in vitro model to understand key pathways involved in the emergence of therapeutic resistance and to understand how both sensitising and resistant EGFR mutations influence response to cytotoxic agents. This will guide treatment strategies selected for evaluation in vivo that may influence future treatment selection for patients.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO01.09 - A novel murine xenograft model using samples obtained by EBUS-TBNA (ID 773)
10:30 - 12:00 | Author(s): T. Nakajima, W. Geddie, Y. Wang, M. Li, N. Pham, T. Anayama, H. Wada, K. Hirohashi, H.M. Ko, G.D.C. Santos, S. Boerner, M. Cypel, G.E. Darling, T. Waddell, S. Keshavjee, I. Yoshino, M. Tsao, K. Yasufuku
- Abstract
- Presentation
Background
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive approach for lymph node staging in patients with lung cancer. Although EBUS-TBNA has been utilized for various molecular testing, intrinsic characteristics of different lesions produce variability in the amount of cellular material that can be obtained. In some samples, the quantity of tumor recovered may be limited for subsequent testing. To overcome this problem, we evaluated the feasibility of establishing a murine tumor xenograft model using EBUS-TBNA samples for advanced translational research.Methods
After confirmation of adequate sampling for cytopathological diagnosis during EBUS-TBNA, one additional pass was performed for this study (NCT01487603). The aspirate was stored in cell preservative solution (RPMI1640 with 10% FBS) for inoculation of the tumor for the xenograft model. The sample was transported to the laboratory on ice, then mixed with Matrigel and centrifuged. The pellet which contained tumor fragments was implanted to the subcutaneous pocket on the right flank of a NSG (NOD scid gamma) mouse. Once we confirmed the engraftment of the tumor, we passed the tumor to another mouse until 3 passages were completed. The success rate of tumor xenograft establishment was examined along with histopathology and the cellularity and cytopathologial diagnosis of the primary EBUS-TBNA samples.Results
From December 2011 to June 2012, 19 patients were enrolled in this study. The cytopathological diagnoses were as follows; 12 adenocarcinoma, 3 squamous cell carcinoma, 1 large cell carcinoma NOS, and 3 small cell carcinomas. 8 out of 19 cases (42.1%) showed tumor formation. The mean duration between inoculation and tumor formation was 62.38 days (13-144 days). All engrafted tumors could be passed to the second mouse. The histological types of the engrafted tumors were 3 adenocarcinoma (3/12: 25%), 2 squamous cell carcinoma (2/3: 67%), 1 large cell carcinoma (1/1: 100%), and 2 small cell carcinomas (2/3: 67%). The tumor cellularity of primary EBUS-TBNA samples was sufficient for diagnosis and there was no correlation between engraftment and the degree of blood/lymphocyte contamination or percentage of necrosis.Conclusion
EBUS-TBNA samples can be used for establishment of tumor xenograft model in immunodeficient mice. EBUS-TBNA allows minimally invasive sampling of metastatic lymph nodes in patients with advanced lung cancer which opens up possibilities for translational research. We need to continuously seek better ways to improve and standardize procurement and processing of samples obtained by minimally invasive techniques in order to optimize diagnosis and molecular analysis for improved patient care. Figure 1Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO01.10 - Integrated molecular characterization of Patient-Derived Tumorgrafts as innovative model for clinical management of Non-Small Cell Lung Cancer (ID 2919)
10:30 - 12:00 | Author(s): F. Tabbo', F. Guerrera, A. Nottegar, L. Bessone, P. Bartocci, E. Ercole, F. Di Giacomo, K. Messana, M. Gaudiano, M. Todaro, R. Machiorlatti, I. Landra, S. Urigu, L. Delsedime, M. Chilosi, G. Inghirami, E. Ruffini
- Abstract
- Presentation
Background
Lung cancer is the leading cause of death for cancer. Although impressive diagnosis and therapeutic achievements have been recently obtained, critical issues remain open. It is now believed that the generation of reliable preclinical models will provide the basis for new discoveries and to validate the clinical efficacy of known and novel compounds.Methods
From 2010 to 2013, we have generated a biorepository of 190 frozen tumor samples and matched normal lung tissues, peripheral blood mononucleate cell collections, serum and plasma samples from patients who had undergone surgery with curative intentions (stage Ia, Ib, IIa mainly). This data set has been enriched with 480 additional archival tumors. The entire library, encompassing all major histotypes [adenocarcinomas (ADC), squamous cell carcinoma (SCC) and large cell carcinoma (LCC)], covers the heterogeneous landscape of NSCLC. All tumors were characterized by immunohistochemistry (IHC) (TTF1, SPA, MUC5AC, CK5, CDX2, VILLIN, p53, p63, p16, ABCA3 and SOX2) and molecular analyses (EGFR, KRAS, BRAF and PI3K mutations). Considering that the pathogenetic role of many lesions is only in part elucidated, and that many lung cancers lack targetable mutations, we generated patient-derived tumorgrafts (PDTs), engrafting fresh and/or frozen tumor fragments in highly immunocompromised mice (NSG). Successfully grown tumors were propagated up to the third generation (T3). Primary versus PDT features were studied by histology, IHC and molecular profiling [Single Nucletoide Polimorphism (SNP), WES, RNA sequencing (RNAseq)] and HTP proteomic analyses.Results
A known distribution of mutations within the first 300 ADCs samples (17% EGFR; 35% KRAS; 2% PI3K; 1% BRAF) was observed. 26 PDT lines (9 adenocarcinoma, 14 squamous, 2 sarcomatoid, 1 mixed) have been propagated, showing that the time growth average required from engraftment was significantly longer for the ADC-lines than SCC-lines (ADC-lines 20 weeks vs SCC-lines 11 weeks). We demonstrated the strong correspondence of primary cancers and PDT tumors, highlighting primary tumor’s specific features or biomarkers. The SNP analysis has revealed the occurrence of stress engrafment events (i.e. loss of heterozigosity LOH) at the first PDT passage; these alterations, once acquired remain relatively stable along later passages. Preliminary data from proteomic profiling are demonstrating stable Phospho-Tyrosine-Kinase profiles in primary tumors compared to PDTs, reinforcing the idea that this PDT tumors aren’t drifted so far from primary cancer architecture.Conclusion
To improve bio-molecular stratification, pathological classification and clinical treatments of lung cancers, a multiparametric approach is needed; this should depict a complete and integrated cancer network in each cancer patient. Nonetheless, reliable preclinical models are required to define the best treatment choices and to overcome the boundaries between basic knowledge and the clinical requirements.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO01.11 - DISCUSSANT (ID 3901)
10:30 - 12:00 | Author(s): P. Mack
- Abstract
- Presentation
Abstract not provided
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Author of
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CALC - Chinese Alliance Against Lung Cancer Session (ID 79)
- Event: WCLC 2013
- Type: Other Sessions
- Track: Other Topics
- Presentations: 1
- Moderators:C. Bai, Y. Wu, D.C. Lam
- Coordinates: 10/27/2013, 07:30 - 12:00, Parkside Auditorium, Level 1
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CALC.11 - MicroRNA Biomarkers in Lung Cancer (ID 3878)
07:30 - 12:00 | Author(s): S. Lu
- Abstract
Abstract
ABSTRACT Rationale: Effective treatment for lung cancer requires accuracy in sub-classification of carcinoma subtypes. Objectives: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). Methods: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung tissues. Quantitative reverse-transcriptase PCR was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung tissues to evaluate 7 microRNA candidates discovered from microarrays. Two microRNA panels were constructed based on a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and SQ from AC in 207 bronchial brushing specimens. Measurements and Main Results: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375, AUC 0.991 and 0.982 for training and validation dataset, respectively) and in differentiating SQ from AC (miR-205 and miR-34a, AUC 0.977 and 0.982 for training and validation dataset, respectively) in FFPE surgical lung tissues. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC 0.947) and SQ from AC (AUC 0.962) in bronchial brushing specimens. Conclusion: We found 2 microRNA panels that accurately discriminated between the 3 subtypes of lung carcinoma in bronchial brushing specimens. The microRNA panels could have considerable clinical value in differential diagnosis and play an important role in determining optimal treatment strategies based on the lung carcinoma subtype.
