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TUESDAY, SEPTEMBER 14
7:00 am Registration Open
7:30-8:30 Morning Coffee
8:25-8:30 Chairperson’s Opening Remarks
Robert McCormack, Ph.D., Head, Technology Innovation and Strategy, Veridex, LLC
8:30-9:00 Contemporary Issues in Circulating Tumor Cell Testing
Robert McCormack, Ph.D., Head, Technology Innovation and Strategy, Veridex, LLC
The introduction of the first automated system for detecting, enumerating and characterizing rare circulating tumor cells (CTC) in peripheral blood has unlocked the potential of CTC for both clinical and research applications at a global level. The ensuing five years since commercial introduction has resulted in hundreds of publications about CTCs and the development of multiple alternate CTC technologies. This presentation will emphasize both the potential of CTCs in drug discovery and development, as well as emphasize some of the contemporary issues surrounding CTC testing and a potential path forward.
9:00-9:30 Pharmaceutical Considerations for Employing CTCs in a Meaningful Way to Promote Drug Development
David R. Shalinsky, Ph.D., Associate Director, Translational Oncology, Pfizer Oncology Business Unit, Pfizer, Inc.
CTCs offer promise for tailoring therapy to individual patients but CTC assays will have to be improved and qualified to be incorporated in oncology drug development in a meaningful manner. Challenges include understanding: tumor hetereogeneity, definition(s) of CTCs, and employing reproducible assays with sufficient sensitivity for enumeration and molecular characterization. Developing practical, cost-effective assays is key. This talk will address these challenges in the context of oncology development (“Go, No Go decision-making”) and will provide insight into assay characteristics and utilities that could help stimulate the use of CTC assays in the pharmaceutical setting where established diagnostic approaches predominate and compete with exploratory CTC approaches.
9:30-10:00 Molecular Biomarker Analyses from Circulating Tumor Cells
Elizabeth Punnoose, Ph.D., Scientist, Development Oncology Diagnostics, Genentech, Inc.
Tumor tissue collection is essential for biomarker assessment but can be difficult in tumor types such as non small-cell lung cancer (NSCLC) where often no surgery is performed and diagnosis is done with biopsies yielding only very limited tissue quantities. Also, in cases where primary tissue is available, the samples may not be representative of patient’s current disease, i.e. in the case of hormone refractory prostate cancer (HRPC). In this presentation, we report on our efforts to evaluate Circulating Tumor Cells (CTC) for utility in tumor biomarker assessment. These efforts included evaluating multiple technologies for isolation and molecular analysis of CTCs from blood. Validation of these assays in patient blood is ongoing and early data suggests that biomarker assessment is indeed possible from CTCs. Using blood samples from metastatic, HER2+ breast cancer patients; we were able to evaluate the HER2 status from CTCs using immunofluorescence and/or FISH.
10:00-10:30 Circulating Tumor Cells: Phenotypic and Molecular Characterization and Potential Applications in Drug Development
Haifeng Bao, Ph.D., Research & Development, Translational Sciences, MedImmune
10:30-11:30 Networking Coffee Break with Poster and Exhibit Viewing
11:30-12:00 pm Multiparameter Analysis of Circulating Tumor Cells in the Blood of Cancer Patients using a Process which Only Depletes Normal Cells
Jeffrey J. Chalmers, Ph.D., Professor, Department of Chemical and Biomolecular Engineering, The Ohio State University
We have developed a process which utilizes a unbiased negative enrichment protocol that depletes the normal blood cells to give an enriched and relatively pure CTC cell suspension. In this presentation we demonstrate that our technique is capable of detecting a significant number of CTCs in the peripheral blood of Head and Neck Cancer and Breast Cancer patients with high levels of sensitivity. Since the outcome of our negative depletion, enrichment process is a cell suspension; the final product can be further analyzed. By performing multi-parameter microscopic analysis, we are able to find a significant number of circulating tumor cells which have down-regulated epithelial markers and upregulated mesenchymal markers and markers that have been suggested to be consisted with “cancer stem cells.”
12:00-12:30 In vivo High-Speed Photoacoustic Detection of Circulating Multiple Tumor Markers for Early Cancer Diagnosis and Personalized Therapy
Vladimir Zharov, Ph.D., Professor and Director, Philips Classic Laser & Nanomedicine Laboratories; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences
Recently we introduced a new platform of in vivo, noninvasive, photo-acoustic (PA) flow cytometry for detection of circuiting tumor cells (CTCs) targeted by conjugated nanoparticles directly in the bloodstream.1-2 This report summarizes new advances of this platform including multicolor high-pulse-repetition-rate laser arrays, ultra-fast signal acquisition algorithms, novel nanotechnology-based PA molecular contrast agents, and in vivo targeting of multiple markers in CTCs and tumor-associated nano- and microparticles. The study in vivo on tumor-bearing mouse models and spiked human blood samples demonstrates ultrahigh sensitivity of specificity for breast cancer CTCs and circulating particles that may be used for early cancer diagnosis and therapy selection when metastasis has not yet well developed and, hence well-timed therapy is more effective.
12:30-2:00 Lunch on Your Own
2:00-2:30 Circulating Mutant DNA as a Dynamic Cancer Biomarker
Luis Diaz, Ph.D., Assistant Professor, Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University
The recent advances in digital genomic have opened the doors to the clinical development of tumor-derived DNA as a biomarker for cancer screening, early detection, monitoring and measurement of early residual disease. The basis of this work is based on the well-accepted premise that cancer is defined by a discrete set of genetic alterations. This approach combines genomic sequencing with novel digital techniques to count tumor-derived DNA fragments in complex mixtures of DNA. The mutations found in cancers are never found in normal cell populations and detection of these mutations therefore confers exquisite specificity to the assay. Accordingly, he demonstrated that the level of mutations in the circulation [also known as circulating tumor DNA (ctDNA)] tracked with fluctuations in tumor burden in patients undergoing resective surgery for colorectal cancer. Most striking is the ability of ctDNA to accurately predict recurrence after surgery and monitor patients with undetectable CEA levels. This novel biomarker is based on personalized genomics that in essence provides a ‘viral load’ equivalent for patients with solid tumors.
2:30-3:00 Mutation Detection of Circulating Tumor Cells in Castration Resistant Prostate Cancer
Yuqiu Jiang, Ph.D., Principal Scientist, Molecular Technology Assessment, Veridex, LLC
Towards understanding molecular mechanisms of therapy response and drug resistance in patients, we sought to expand the utility of CellSearch technology to directly interrogate molecular markers in circulating tumor cells (CTCs). Here, we report a novel method, which combines CellSearch and WAVE® DHPLC technologies, for detecting gene mutations from peripheral-blood based on CTC enrichment. The androgen receptor gene mutation status was analyzed in 35 patients with castration resistant
prostate cancer. 19 missense and 2 silent mutations, 5 deletions, and 1 insertion were observed in these CTC enriched samples. This approach has the potential to open new perspectives in understanding CTCs.
3:00-3:30 A Novel Approach for Finding and Characterizing CTCs
David Nelson, Ph.D., President and CEO, Epic Sciences, Inc.
Circulating tumor cells (“CTCs”) hold the promise to provide a readily accessible real-time fluid biopsy of tumors. CTCs would be immediately useful to Pharma and Biotech in clinical trials as secondary endpoints through counting CTCs. Molecularly characterizing CTCs would also be useful for guiding inclusion/exclusion decisions and, ultimately, as companion diagnostics for targeted therapies. In addition, CTCs are expected to be useful as a prognostic tool as well as for screening and staging. The key is finding enough CTCs in enough patients to be useful.
3:30-4:30 Networking Refreshment Break with Poster and Exhibit Viewing
4:30-5:00 Advances in Circulating Tumor Cell Analysis: Analytical Validation Must Precede Clinical Application
Martin Fleisher, Ph.D., Chair, Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center
Detecting Circulating Tumor Cells (CTC) in peripheral blood of patients with cancer has become a clinically relevant and important prognostic biomarker and has been shown to be a predictive biomarker post-therapy. Currently, one analytical method, the Veridex CellTrack Analyzer, has been FDA approved for use in monitoring therapeutic response in patients with breast, prostate and colon cancer. This enrichment technique requires expression of EpCAM by CTCs. Other methods to enrich CTCs that rely on size, shape and phenotypic characteristics are: (a) flow cytometry that sorts cells by size and surface antigen expression; (b) microchips designed to capture CTCs as blood flows past EpCAM-coated microposts; (c) filters with pore size designed to retain CTCs but permits smaller cells to pass; (d) imaging techniques that rely on Fiber-Optic Array Scanning Technology (FAST) that identify CTCs based on fluorescent labels, and (e) negative enrichment that eliminates all cells from blood samples, except CTCs. The successful clinical application of these emerging CTC technologies depends on rigorous analytical validation. A validation protocol, consistent with CLIA regulator guidelines will be presented.
5:00-5:30 Significance and Characterization of Circulating Tumor Cells in Breast Cancer
Minetta C. Liu, M.D., Associate Professor, Medicine and Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Hospital
The ability to optimize treatment will improve with the development and validation of new prognostic and predictive factors that result from a greater understanding of tumor biology. As demonstrated in the setting of metastatic breast cancer, the enumeration and characterization of circulating tumor cells (CTCs) will be useful in this regard. Two prospective clinical trials using the automated CellSearch® technology suggest potential clinical utility when used in conjunction with radiographic imaging and clinical evaluations for patients with metastatic breast cancer. One study identified a strong correlation between baseline and/or first follow-up CTC enumeration and progression-free and overall survival. A second independent study validates the use of serial CTC enumeration as a reliable means of monitoring disease status in metastatic breast cancer. Therefore, CTC enumeration may be helpful in resolving discrepancies between imaging results and clinical findings or in guiding the timing of costly imaging studies in asymptomatic patients. Refinements of the current technology - or the development of improved technologies - are needed in order to increase the detection threshold of CTCs and to allow for further phenotypic and genotypic characterization of the collected cells. These advances may translate into use of CTC analysis in earlier stages of breast cancer for diagnosis and/or clinical management.
5:30 Close of Day