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A. Hoffmann
Moderator of
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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: 4
- Moderators:A. Hoffmann, L. Montuenga
- Coordinates: 9/07/2015, 14:15 - 15:45, 401-404
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MS02.01 - Free Circulating Tumor DNA (ID 1852)
14:20 - 14:40 | Author(s): P.C. Mack
- Abstract
Abstract not provided
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MS02.02 - Circulating Tumor Cells (ID 1853)
14:40 - 15:00 | Author(s): T. Sundaresan
- Abstract
Abstract:
In EGFR-mutant lung cancer, acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) develops after a median of 9-14 months. The T790M gatekeeper mutation is the most common mechanism of TKI resistance, detected in >50% of tissue biopsies done after the advent of resistance. The recent clinical development of third-generation, irreversible EGFR TKIs that have preliminarily demonstrated durable tumor responses in patients who have developed the EGFR T790M mutation has generated a need for novel methods of T790M detection. Repeating tumor biopsies at the time of acquired resistance to help select second-line therapies is recommended in the NCCN guidelines. However, tissue biopsies do not always supply sufficient material for current sequencing strategies and thus may require multiple invasive procedures for adequate genotyping. Blood-based methods are more readily repeated when necessary and avoid the risks and discomfort of invasive tissue biopsies. As there may be heterogenous mechanisms of acquired resistance, a tissue biopsy of a single site of disease also may not capture the full spectrum of resistance. Blood-based methods theoretically have the potential of more comprehensively illustrating the principal mechanisms of resistance within a patient. Although there are multiple non-invasive sources of tumor-derived genetic material, circulating tumor cells (CTCs) and plasma circulating tumor DNA (ctDNA) are two that have received particular attention for blood-based genotyping. CTCs are cells shed into the bloodstream from primary and metastatic tumors that can be captured through multiple microfluidic platforms. Despite their rarity in the blood there is ongoing development of increasingly sensitive methods of CTC isolation. ctDNA is also shed into the bloodstream from tumor deposits. While more abundant than CTCs, ctDNA analysis is complicated by a high background of plasma DNA shed from normal cells. Techniques for genotyping from these blood-based sources of tumor-derived genetic material have proliferated rapidly, but there have been few studies directly comparing them. In this presentation, I will describe an exploratory study comparing T790M genotyping, using either CTCs or ctDNA versus concurrent tumor biopsies in patients with non-small cell lung cancer progressing on first line EGFR inhibitors.
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MS02.03 - Blood-Based Proteomics Strategies for the Early Detection of Lung Cancer (ID 1854)
15:00 - 15:20 | Author(s): R. Pio
- Abstract
Abstract:
Blood-based proteomics strategies for the early detection of lung cancer. Since the advent of the new proteomics era, large-scale studies of protein profiling have been exploited to identify the distinctive molecular signatures in a wide array of biological systems spanning areas of basic biological research, various disease states, and biomarker discovery directed toward diagnostic and therapeutic applications. Recent advances in protein separation and identification techniques have significantly improved proteomics approaches, leading to enhancement of the depth and breadth of proteome coverage. Proteomic signatures specific for invasive lung cancer and preinvasive lesions have begun to emerge. In this presentation, we will provide a critical assessment of the state of recent advances in proteomic approaches to the discovery and validation of blood based biomarker signatures for the early detection of lung cancer. Mass spectrometry and immuno-based detection methods will be reviewed including commercially available blood tests to aid the early detection of lung cancer. Much of this progress was driven by increasing knowledge of tumor-related aberrations that affect nucleic acids at genomic, transcriptional, and posttranscriptional levels. Proteins are the functional end product of genes that ultimately control vital biological processes via their expression level and posttranslational modifications. Moreover, the number of proteins produced by cells far exceeds the number of genes because proteins vary in their stability compared with mRNA and are subjected to many levels of posttranscriptional and posttranslational regulations, such as splicing variants, fusions, and posttranslational modifications. Therefore, to advance our understanding of the biology of lung cancer and to obtain a more integrated view of the disease biology, it is critical to capture the full spectrum of the variations in protein expression patterns, their posttranslational modifications, and their functions in cancer cells. Thus, we hope to take advantage of the molecular complexity of the proteome to improve early detection strategies for lung cancer. Proteomic analysis of blood represents an appealing choice to researchers addressing the discovery of biomarkers because it can be quickly and easily obtained noninvasively in large quantities over time. Several recent studies have investigated the extent to which proteomic technologies can unravel the complexity of the plasma proteome. In this regard, the Human Proteome Organization completed a comprehensive collaborative study to characterize the human serum and plasma proteomes. The rapid proteomic profiling of blood in particular has generated great enthusiasm but has been minimally successful at providing robust signatures to translate to the clinic. The major preanalytical challenges are related to the lack of standardized sample collection and preparation techniques, leading to the introduction of analytical bias and the lack of reproducibility. The extreme complexity of biofluids, such as blood, serum, or plasma, and the low abundance of most of the specific protein markers are among other factors that reduce the sensitivity of detection by proteomic technologies. After the discovery of new biomarkers, the next critical steps are to validate and evaluate their performance in clinically relevant patient populations. Multiple levels of validation have to take place before confirming the clinical utility of the biomarker. This includes confirmation of detected changes in protein level by different techniques and correlation with biological outcomes of lung cancer such as early detection, chemosensitivity, or survival. These phases of clinical validation will evaluate a biomarker's performance in relevant clinical context and how it may affect clinical management of risk or disease. Selected readings: 1. Zeng GQ, Zhang PF, Deng X, Yu FL, Li C, Xu Y, Yi H, Li MY, Hu R, Zuo JH, et al. Identification of candidate biomarkers for early detection of human lung squamous cell cancer by quantitative proteomics. Molecular & cellular proteomics : MCP. 2012;11(6):M111 013946. 2. Massion PP, and Walker RC. Indeterminate pulmonary nodules: risk for having or for developing lung cancer? Cancer Prev Res (Phila). 2014;7(12):1173-8. 3. Hassanein M, Callison JC, Callaway-Lane C, Aldrich MC, Grogan EL, and Massion PP. The state of molecular biomarkers for the early detection of lung cancer. Cancer Prev Res (Phila). 2012;5(8):992-1006. 4. Kikuchi T, Hassanein M, Amann JM, Liu Q, Slebos RJ, Rahman SM, Kaufman JM, Zhang X, Hoeksema MD, Harris BK, et al. In-depth proteomic analysis of nonsmall cell lung cancer to discover molecular targets and candidate biomarkers. Molecular & cellular proteomics : MCP. 2012;11(10):916-32. 5. Skates SJ, Gillette MA, LaBaer J, Carr SA, Anderson L, Liebler DC, Ransohoff D, Rifai N, Kondratovich M, Tezak Z, et al. Statistical design for biospecimen cohort size in proteomics-based biomarker discovery and verification studies. Journal of proteome research. 2013;12(12):5383-94. 6. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, et al. Proteogenomic characterization of human colon and rectal cancer. Nature. 2014;513(7518):382-7. 7. Neal JW, Gainor JF, and Shaw AT. Developing biomarker-specific end points in lung cancer clinical trials. Nature reviews Clinical oncology. 2015;12(3):135-46.
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MS02.04 - Exhaled Breath (ID 1855)
15:20 - 15:40 | Author(s): N. Peled
- Abstract
Abstract not provided
