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The potential for non-invasive tests that provide equivalent research and diagnostic value as can be obtained from tissue biopsies is real, but not yet realized. Tissue biopsies allow for identification, phenotyping and molecular analysis of cancer and associated cells. The RareCyte platform has been designed to reflect tissue analyses in the identification, multi-parametric characterization and single cell molecular interrogation of rare cells in liquid biopsies and other sample types. Applications to be presented include genomic assessment of heterogeneity in individual breast cancer circulating tumor cells (CTCs) at multiple time points during treatment, development of a Companion Diagnostics-type assay to identify the presence of a drug target on CTCs, and identification of rare antigenspecific T cells. These examples demonstrate progress toward the fulfilling the promise of liquid biopsy.
- To understand how rare cell analysis, including “liquid biopsy”, can be incorporated into diagnostic pathology to extract clinically important information.
- To understand the value of phenotypic and molecular characterization of individual rare cells within liquid biopsies and other specimens.
Eric Kaldjian is Chief Medical Officer at RareCyte. He trained in anatomic pathology at the University of Michigan and subsequently at the National Cancer Institute. His pharmaceutical experience at Hoffmann- La Roche and at Parke-Davis/Pfizer encompassed discovery research through full clinical development positions with a focus on translational medicine. He has directed clinical genomics programs at Gene Logic, was Chief Scientific Officer at Transgenomic, and was Medical Director for Companion Diagnostics at Ventana Medical Systems before joining RareCyte, where he oversees scientific and medical applications of its rare cell detection technology. He is an associate member of the BioInterfaces Institute at the University of Michigan.
The learning objectives for today are to understand how rare cell analysis, including liquid biopsy, can be incorporated into diagnostic pathology to extract clinically important information, as well as to understand the value of phenotypic and molecular characterization of individual rare cells within liquid biopsies and other specimen types.
Evolution of Tumor Sampling
The approach to accessing tumors for analysis has evolved from highly invasive to increasingly less invasive. Yet at the same time that biopsy sample volume has decreased, the diagnostic information required from the sample has increased. With liquid biopsy, we have a non-invasive sampling method with very few cells. The challenge, then, is to extract information from these few cells.
History of Liquid Biopsy
First, a little bit of the past of liquid biopsy. The term "liquid biopsy" has quite rapidly entered the vocabulary of diagnostics. Its original meaning was to describe a way to access the cells of a tumor indirectly by capturing rare tumor cells that circulate in the blood and thus allow a real-time investigation of the cancer via blood sampling.
Before discussing the future, let's actually go even further back to its original origins. As many of you know, the origins of the field can be traced to nearly a century and a half ago in the famous report from Thomas Ashworth in the Australian Medical Journal. In this paper, he described a patient who had many tumors visible in the skin throughout the body. He investigated the blood to try to understand how so many tumors appeared. The tumors had cells with an unusual appearance and Ashworth saw similar cells in the blood, allowing him to infer a relationship between the tumor cells and the cells he found in the blood.
Here are the figures that he drew of the tissue and of the blood cells.
Below is a micrograph of a chordoma, which is likely what the tumor that Ashworth described as a "tumor of chorda dorsalis" in his paper actually was. You can see a similarity between the cells in the micrograph and in the drawings. Microscopic visualization of the cells is what actually allowed Ashworth to make his investigation and arrive at his seminal conclusion. That was the past.
First Generation Liquid Biopsy
The present has largely been influenced by the CellSearch® system. This can be considered the first generation of liquid biopsy. CellSearch® accomplished remarkable milestones for liquid biopsy, notably the prognostic significance of CTC counts in epithelial cancers.
Next Generation Liquid Biopsy
The future of liquid biopsy will involve expanding the breadth of diagnostic analyses to match what can be obtained with tissue biopsy. CellSearch® has robustly addressed the first level of tissue biopsy evaluation, namely identification and counting of circulating tumor cells.
A second level of evaluation is phenotypic characterization of malignant cells, as well as potentially immune cells in the tumor microenvironment.
A third level is the molecular analysis of individual cells. Here is an example of what next generation liquid biopsy will look like. These are unusual cells that were found in the blood of young woman. You can see in green that the cells are expressing cytokeratin. This woman had no history of cancer. She did, however, have a history of pregnancy. These are in fact fetal cells circulating in maternal blood. We know this because we isolated them individually and demonstrated on a single cell basis that they were male cells in a female host. After removal of individual cells, whole genome amplification, and