Genetic Engineering & Biotechnology News

MAY15 2017

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Genetic Engineering & Biotechnology News | GENengnews.com | MAY 15, 2017 | 27 GEN What is the biggest obstacle that liquid biopsy must overcome before it wins widespread acceptance as a clinical diagnostic tool? Ms. Robinson The need for sufficient medi- cal evidence accrued from prospective clini- cal studies that can drive a change in the standard of care. Motivating clinicians to order and rely on the technology will re- quire physician education combined with robust clinical evidence that demonstrates the advantages of liquid biopsies for can- cer diagnosis, therapeutic decision-making, and monitoring disease progression and a patient's response to treatment. We need to capture the attention of busy physicians and provide them with the evidence that will con- vince them to change. Dr. Patel One of the biggest challenges is re- liably finding tumor DNA in the vast sea of healthy DNA. Clinicians must be convinced that liquid biopsies are as reliable as tissue genotyping and can help patients. The slow uptake of liquid biopsy use in the clinic illus- trates the need for more prospective clinical trials that can establish concordance and the real-world utility of liquid biopsy strategies. The ideal method for liquid biopsy ge- notyping would both detect and precisely quantify circulating tumor DNA. Unlike next-generation sequencing (NGS), which can primarily identify mutations that are present, Bio-Rad Laboratories' droplet digi- tal PCR (ddPCR) can provide both qualita- tive and quantitative information for cancer biomarkers. This is important to clinicians because recent studies at the Dana-Farber Cancer Institute have suggested the amount of mutation present is tied to specific out- comes, including relapse. Dr. Ionescu-Zanetti The key obstacle is clinical utility. We need to demonstrate that data obtained from a liquid biopsy provides new, actionable information to the clinician that leads to improved patient outcomes. The first step is demonstrating concordance to primary tumor data to show that the liq- uid biopsy approach works, and that work is happening now. We don't, however, see liquid biopsies replacing traditional biopsies anytime soon. The near-term use will be in situations where liquid biopsies can provide new information. For example, liquid biopsies could be used to identify subclonal mutations or the emer- gence of resistance mutations. Long term, the technology needs to progress to early- stage patient profiling—that's where we can really affect outcomes. Dr. Burke Pathologists say that "tissue is the issue." Genomics might point to a BRAF mutation, but in the case of colorectal can- cer, BRAF inhibitors don't work so well— not as well as they do in melanoma. This dependence on tissue is important, but also limiting. Dr. Manaresi Evidence of clinical utility will probably drive wider clinical adoption. Although studies have demonstrated that the enumeration of circulating tumor cells (CTCs) is a strong, independent predictor of overall and progression-free survival in metastatic breast, prostate, and colorectal cancer, evidence that treatment decisions based on the enumeration or molecular char- acterization of CTCs positively impact clini- cal outcome is still lacking. However, several studies, such as STIC Metabreast and DE- TECT III, are currently underway and might provide important new insights. In addition, the lack of standardized methods for genetic analyses of CTCs might also play a role. But this limitation could be overcome by recently developed technologies. Dr. Lin With any diagnostic or therapeutic, the key to success is improving patient out- comes. Too often, the temptation is to take a research-use product, one more suited for discovery, and attempt to validate and imple- ment it as a laboratory-developed test, which means trying to find clinical actionability and determine the outcome later. Instead, we need to be precise in our approach to preci- sion medicine. We need to start with the end in mind. Just as there is no one-size-fits-all approach to medicine, there is no one-size- fits-all approach to diagnostics. An under- standing of the differences between clinical diagnostic tools and research discovery tools is needed. Mr. Kazinski Liquid biopsy will most likely become part of standard diagnostic proce- dures. Patient monitoring for disease pro- gression, drug-resistance detection, or strati- fication of patients for a therapeutic regime are likely to be adopted earlier. Applications such as patient screening will probably take a bit longer. Clinical trial data showing the advantages of liquid biopsy regarding both survival time and quality of life of patients when com- pared to conventional methods will be one of the major acceptance drivers for adopting liquid biopsy in routine diagnostics. In ad- dition, regulatory approval and reimburse- ment of tests are essential for the success of this approach. Ms. Bramlett The clinical research commu- nity is gaining confidence in liquid biopsy results; continuing to build that confidence is critical. Researchers need to know that liquid biopsy results reflect tumor evolution. The recent availability of Oncomine cell- free DNA assays for next-generation sequenc- ing certainly helps move us in that direction. Making tools like these widely available helps foster the collaboration and sharing of results that can build confidence. And, through rig- orous analytical verification of cfDNA analy- sis methods, the clinical research community is gaining a clear understanding of the ad- vantages and limitations of cfDNA related to cost, false positive results, and a low limit of detection. GEN Do you think there is an advantage in the collection method of genetic material for liquid biopsy, that is, cell-free DNA (cfDNA) vs. circulating tumor cells (CTCs)? Ms. Robinson In contrast to cfDNA, which is released into the blood when cancer cells die and break apart, CTCs offer a window into the living tumor and the parts that may be resistant to therapy. CTCs can provide information not just on DNA but also on RNA and protein expression and tumor het- erogeneity. The problem has been difficulty in harvesting CTCs for analysis. Easy har- vest of CTCs is now available using Angle's Parsortix system. Consequently, there is no longer an advantage in the collection process for cfDNA. Furthermore, both CTCs and cfDNA can now be collected from the same patient sample. Dr. Patel Yes. cfDNA is 100 times more abundant in blood than CTCs, but is nor- mally fragmented. Technology advance- ments to detect cfDNA have been critical in validating this as a cancer biomarker. Small fragments that would have been difficult to examine and detect in the past can now be assessed with high accuracy and sensitivity. The sensitivity of ddPCR for plasma cfDNA is about 70%, and you can detect specific stretches of tumor DNA even at levels as low as 0.1% of total DNA in the blood. Dr. Ionescu-Zanetti We don't believe there is a one-size-fits-all solution. The right sample format will depend on the question being asked, the patient's cancer type, stage, etc. At Fluxion Biosciences, we have developed solutions for both approaches, and we think they will be complementary. CTCs have the advantage of being enrichable and capable of improving the signal-to-noise ratio, which we find beneficial in early-stage patients where tumor burden is low. cfDNA has the advantage of not requiring a cell isolation step, so the workflow is simpler. But each ap- proach has merits, and we don't expect to see one dominant approach. Dr. Burke CTCs make identification of tissue of origin more tangible—although that's not to say it's impossible with cfDNA. Dr. Manaresi The information ctDNA and CTCs provide are probably complementary rather than mutually exclusive. ctDNA can detect known mutations in disease-specific genes but does not allow reliable analysis of copy number aberration profiles and cannot detect loss of heterozygosis, which may be important in certain clinical settings. CTCs, on the other hand, may provide important information on the biology of metastasis and allow multi-omic profiling on a cell- by-cell basis and can in this way potentially provide an even more complete picture of tumor biology as compared to analyzing ctDNA alone. Dr. Lin Precision diagnostics means tailoring products to specific indications for specific diseases with unmet medical needs. There are some clinical situations where cfDNA is the most appropriate approach, and there are others where CTC is the better fit. CTCs provide a whole cell to analyze but are rare; they are also better suited to explore the func- tional effects of the cell, such as drug sensi- tivity and whole-omics profiling. However, cfDNA is often more abundant and better suited for early detection, therapy selection, Translational Medicine See Roundup on page 28

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