Liquid Biopsy: Physicians, Patients, Beware!

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Liquid Biopsy: "Hottest Topic in Medicine"

Hello and welcome. I'm Dr. George Lundberg and this is At Large at Medscape.

I first heard the words "molecular pathology" from my professor of pathology as a medical student in Alabama in about 1955. I heard them again only rarely for the next 40-50 years. But now, because of giant leaps in technology, mostly gene-oriented, it is the hottest topic in medicine. The concept of liquid biopsy -- using blood as the cancer sample -- serves as a metaphor for the entire field.

Medscape approached me, on behalf of Editor-in-Chief Eric Topol, to craft a column on liquid biopsy. I agreed, with the proviso that I would include a full disclosure of my considerable conflicts of interest.

I am a consulting professor of pathology and health research policy at the Stanford University School of Medicine. Stanford is a major player in the field of genomics and personalized medicine.[1] I am also the chief medical officer of CollabRx, a San Francisco company that provides cloud-based data analytics and focuses on applied oncogenomics. CollabRx has a particular interest in interpreting the results of liquid biopsies.[2]

The central idea is that not only hematologic malignancies such as leukemia, lymphoma, and myeloma but also many epithelial malignancies, and maybe some sarcomas, shed tumor cells into the circulating blood -- and not only a few cells, and not only late. Some shed before a primary cancer has become diagnosable, and many before a metastatic locus or recurrence has become detectable by any other known technique. Some of these blood-borne cancer cells take hold in locations other than their primary site. Some call that metastases -- and many don't. Call that a mystery. Sometimes these epithelial malignant cells transform into mesenchymal cell types when transported in blood and then revert into epithelial cells. Some floating cancer cells may find their way back home to re-establish themselves in the primary site, nesting nowhere else on their sojourn. Think salmon returning to their origin to spawn. Some cancer cells, growing away from the primary, may take root and proliferate into actual metastases only after the primary has been removed. Wild thoughts.

Should These Lab Results Be Available?

The concept of positive therapeutic and prognostic value of early diagnosis is an oncologic mantra. How about so early as to be before any local primary can be found by any current methodology? Liquid biopsy offers that possibility. One of the least understood and standardized areas in all of oncology is how to responsibly follow a patient after a best-practice effort at curative therapy for a well-defined malignancy, and before any metastases are recognized. Recommendations and practices are all over the lot and often not informed by good data. Liquid biopsy offers possible posttherapeutic surveillance for recurrence. Many malignancies mutate over time; liquid biopsy can track those mutation changes. Malignancies develop drug resistance. Liquid biopsy could detect those developments.

Companies such as California-based Cynvenio and Guardant provide gene sequencing for known cancer mutation profiles of cell-free circulating cancer-derived DNA as well as circulating cancer cells in blood specimens. The ultimate trick is to assess clinical actionability of specific cancer genetic profiles in DNA, derived from malignant cells, and match them with approved and/or investigational drugs and clinical trials best suited for each patient. That is a CollabRx offering.

Switching gears in this scary, brave new world, Secretary of Health and Human Services Kathleen Sebelius recently decreed that American patients must have direct access to their lab results.[3] These liquid biopsy findings are simply lab results -- super-fancy and super-complex, but just lab results. Are we, as a society that embraced direct-to-consumer marketing of drugs and devices, ready for direct-to-consumer marketing of lab tests (simple or complicated) that deal with the most difficult topics: cancer or not, recurrent or not, metastatic or not? I have a libertarian streak, but I am not so sure about this one. Once the American medical marketing machine gets ramped up, it can run roughshod over an easily fooled public.

In this really early field of liquid biopsy for cancer, my advice is: Go gung ho, clinical, translational, and laboratory researchers. Have at it, full speed ahead. Collect reams of data, including outcomes, and promptly report them. It's very exciting -- even amazing.

But for me and you, as a physician and as a patient, caveat emptor, medicus, et aeger. Let the buyer, the physician, and the patient beware. There is so much more that we do not yet know than that we do know. This field is barely an infant, but it's a robust and promising infant.

That's my opinion. I'm Dr. George Lundberg, at large for Medscape.


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