Clinical OMICS

JAN-FEB 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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Page 12 of 51 January/February 2018 Clinical OMICs 11 A ssays for non-invasive monitor- ing of cancer have made great strides recently in the area of preci- sion medicine. Tests are now available encompassing a plethora of options including evaluation of single vari- ants, multiple variants across multi- ple genes, whole genes specific to a particular cancer, or a comprehensive "pan–cancer" panel. As liquid biopsy tests are developed, we need to ask: what do these tests mean, what is the purpose they serve, how effective are they, do they appropriately help aid decision making for the oncologist, and are they truly beneficial to the patient? For a liquid biopsy, one needs to obtain DNA from the blood that is rep- resentative of the cancer. One source is circulating tumor cells (CTCs), which can be isolated and used to extract DNA for the purposes of testing. A much easier source of DNA is to iso- late the cell-free DNA (cfDNA) that is released from these cancer cells as they breakdown. The question is whether the two sources are comparable in terms of specificity (how much of what is extracted in the cfDNA is truly representative of the tumor), yield and quality. Both CTCs and cfDNA have been demonstrated to be equally via- ble for a liquid biopsy assay depend- ing on the needs of the end user. But what should we be looking for as we develop the content to be evaluated? Should the content be cancer type specific or pan-cancer? Do we look at the complete gene such as EGFR specific to lung cancer, or should we include a couple of other variants in other genes such as KRAS or NRAS? Should we include all tumor sup- pressors and oncogenes (pan–cancer panel)? Should we restrict ourselves to variants that have a targeted therapy or an actively recruiting clinical trial (actionable variant) or are prognostic or indicative of sensitively or resistance to particular drugs (predictive variants)? Or should we look to early detection focusing on diagnostic variants? In other words, is less more or more less for a liquid biopsy test—what should be the driver to delineate the content? As researchers, we always want to build the most comprehensive test, but does it truly serve the oncol- ogist and ultimately the patient? In other words, what does the sensitivity of the assay need to be for an oncolo- gist for treatment and management of the disease? As cfDNA is a combination of nor- mal DNA, mutated tumor DNA and non-mutated tumor DNA, the chal- lenge is to find the needle (i.e., the variant of clinical relevance) in the haystack. The technology used deter- mines the lowest allelic frequency of a variant that can be specifically and reproducibly picked up in the mix, ranging from 0.01% – 1%. What does finding a variant at 0.01% allelic frequency mean to the oncolo- gist in terms of follow-up treatment and management for the patient? Will an oncologist have the confidence to alter treatment options for their patient based on finding a variant of clinical relevance at an allelic fre- quency of 0.1%? Do the variants iden- tified in cfDNA need to be confirmed by an orthogonal method to rule out false positives? In addition, depending on which portion of the tumor sheds, given tumor heterogeneity and what is actually present in the cfDNA pool extracted, variants of clinical relevance possibly missed being identified. The false negative rate, therefore, needs to be addressed. This is where concor- dance with matched tumor biopsies plays a significant role in enabling accurate reporting in the diagnostic lab as well as in facilitating decision making for the oncologist. If only it were that simple and straightforward. One can confirm vari- ants identified, track variants in com- parison to matched tumor biopsies, but this does not rule out the emer- gence of new mutations of resistance or prognosis, bringing us full circle as to the clinical utility of liquid biopsy for cancer. These assays are not yet ready for diagnosis or early detection of cancer; they do however serve as effective tools to monitor recurrence, resistance, metastasis, and minimal residual disease. Current Applications for Liquid Biopsy OP-ED Honey Reddi, Ph.D. Clinical Lab Director, The Jackson Laboratory Tonivaver / Getty Images

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