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Continuing Discussion about the "Liquid Biopsy"

Posted Jan 10 2011 12:00am

In response to my blog note of last Friday concerning liquid biopsies (see: Rapid Adoption of the Term "Liquid Biopsy" on the Web ), Dr. Ulysses Balis, head of the division of pathology informatics at the University of Michigan Medical School, submitted the following comment:

To add some historical perspective to this blog entry, the term "liquid biopsy" dates back to an informal discussion at Harvard's Center for Engineering in Medicine,....in thε fall of 2004, [when] Mehmet Toner, Ron Tompkins and I were discussing the implications of being able to detect as few as [one] malignant cell in 10^12 events in peripheral blood. It was Mehmet, in fact, who coined the term "Liquid Biopsy" at that time. This investigative effort progressed, with very consistent returns on identifying circulating malignant epithelial cells being possible by 2006, as we hoped that we would be able to demonstrate. We ultimately reported our findings in Nature in December of 2007. Since that time, continued exploration of the topic of CTCs has demonstrated that this cell contingent is a very real component of the pathogenesis of malignant neoplasms. Thus, they represent an ideal target for further investigation, in terms of CTCs being suitable as an early warning surrogate for both primary presentation of disease as well as identifying recurrence in the setting of patients in clinical remission.

In addition, Rod Forsman, Assistant Professor of Laboratory Medicine and Pathology at the Mayo Clinic, sent me that following message via LinkedIn at On 01/09/11:

Good catch. I just wanted to add that I worked with Norbert Tietz, Robert Rej, Ray Vanderlinde and others on an lipase project in 1974.  The results were presented at the "First International Enzyme Congress" shortly after. I remember the conversations at the meeting touted all the emerging enzyme assays as "liquid biopsies" or a similar sobriquet.

So we now have an reference to the use of the term liquid biopsy going back to 1974 at which time it was used to describe enzyme assays. By way of contrast, the Harvard researchers have stayed true to their original definition for liquid biopsy, defined as the isolation and identification of circulating tumor cells (CTCs) in a liquid medium, the serum.

It occurs to me personally that the use of the term to refer solely to biomarkers such as Her2 in serum potentially derived from CTCs may be a stretch (see: Genentech Scientists Zero in on “Liquid Biopsies” as a Way to Replace Tissue Biopsies in Breast Cancer) . I say this because, in my view, the term biopsy should be restricted to the sampling of cells or tissue. However, I did find one definition for biopsy that encompassed both tissue or liquids from the human body.

My best guess is that the term liquid biopsy has so much resonance from a marketing perspective that its use will broaden to include the analysis of biomarkers either with or without accompanying morphologic cellular analysis. Here's a quote from a press release from 2007 (see: Nephrocor Introduces Non-Invasive "Liquid Biopsy" Test to Fight Kidney Disease ):

"RenalVysion...permits the pathologist to distinguish important categories of renal and bladder lesions by integrating urine cytopathlogy and quantitative and qualitative urine chemistries. RenalVysion...is often referred to as a 'liquid biopsy' since it can assist physicians to monitor acute and chronic renal diseases. This test provides the clinician with critical information that can provide diagnostic insight and inform therapeutic decisions."

This 2007 use of the term by RenalVysion is very interesting and describes the use of urine cytopathology plus supporting "quantitative and qualitative urine chemistries" but presumably not the tumor biomarkers that may be expressed by the malignant cells in the urine.

In summary, we have what appears to be at least a 35-year-history of the use of the term liquid biopsy to refer to the following set of conditions: serum enzyme assays, malignant cells in urine plus accompanying urine "chemistries," serum CTCs, and tumor biomarkers expressed by serum CTCs. My prediction is that the term will continue to be used in a very broad way, perhaps referring to all of these different diagnostic scenarios.

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