Originally published 6/2/2018
The term “liquid biopsy” is appearing with increasing frequency in published literature. The fact that it’s more common than ever does not mean we’ve finally replaced a needle extraction of tissue. However, a blood or urine sample is a far less invasive way to gather a large quantity of information to profile a patient’s prostate cancer (PCa), thanks to numerous biological clues that tumor cells release into the bloodstream.
The clues occur in the form of biomarkers that identify the nature and characteristics of cancer cells. There are different kinds of biomarkers that can be obtained from bodily liquids (primarily blood, but some tumor components can be identified from urine, saliva and spinal fluid). These include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), tumor-educated platelets (TEP), microRNA (miRNA), and tumor-derived exosomes.
The most important consideration in diagnosing cancer is how to treat it. That means gaining the best characterization of a person’s cancer in order to match the best treatment for it. Fact: one patient’s Gleason 4+3 PCa will not be identical with another patient’s Gleason 4+3 PCa. This is because of differences at a molecular level that can lead to aggressive tumor behavior. Perhaps “liquid biomarker analysis” would be a more accurate phrase than “liquid biopsy.”
We now recognize the key role that collecting tumor markers and play. Plus, we now have tools to extract and identify them. However, in many cases this still relies on tissue samples—but tumor profiling through liquid biomarkers is finding its place. It’s less expensive and easier to collect samples, special expertise is not needed for collection, and there are almost no risks associated with drawing blood. As Underwood, et al. (2019) put it, “This technology could supplement existing clinical tools by improving detection of recurrent cancer, monitoring treatment, and guiding therapy.”[i] Although our 2018 blog was posted in the happy anticipation that the heyday of “liquid biopsy” was just around the corner, a little more patience is required. In the case of PCa, the day is still coming when access to liquid biomarkers, together with multiparametric MRI and Artificial Intelligence tools, will be the primary route to diagnosis and disease management.
Heroic searches have long been the subject of myths and legends. Most of them never existed, like the golden fleece, Atlantis, and the ability to turn base metal into gold. Some, like lost aviatrix Amelia Earhart or Jimmy Hoffa’s body, were very real but have eluded discovery so far.
Today, medical researchers are working to discover an alternative to the invasive needle biopsy of the prostate. Unlike the abovementioned historic quests, “liquid biopsies” are already in development (for prostate and other cancers), and they do not require physical insertion of a hollow needle in order to capture tumor tissue. A liquid biopsy means analyzing a patient’s blood sample for prostate cancer (PCa) tumor cells, or for genomic biomarkers such as specific tumor cell-free DNA and RNA. Currently, there are such blood tests in clinical tests with PCa patients who have post-treatment recurrence, or who have advanced or metastatic disease. At this stage, these analyses have a three-fold aim:
- Learn more about the diverse genomic profiles of a patient’s mutated cells
- Track how well advanced PCa is responding to treatment
- Adapt the treatment protocol to target drugs to new strains as they appear.[ii]
Clearly, the liquid biopsies have the advantage of being able to be used successively without having to put a patient through an uncomfortable repeat and often-risky needle biopsy.
Meanwhile the hunt continues for a liquid biopsy that would reliably diagnose prostate cancer in a never-diagnosed patient whose PSA is rising. Success surely lies in the not-too-distant future, so I thought I’d describe some signposts along the road.
Liquid biopsy using circulating tumor cells
Solid tumors like PCa shed breakaway cancer cells into the bloodstream, where they circulate. Thus, they are called circulating tumor cells, or CTCs. If some of these cells manage to implant and begin growing into a tumor in another site, this is called metastasis (spread). These satellite tumors may begin to mutate differently than the parent tumor, and they also produce CTCs.
For examination of CTCs, a blood specimen is placed onto a glass slide and stained with a special dye that distinguished normal blood cells from CTCs. “A machine then scans the slide to analyze various features of the CTCs, including size and shape. It works like facial recognition software used at airport security. The software can quickly identify a CTC by examining these features.”[iii] Thus, a basic CTC liquid biopsy simply quantifies the burden of disease in a patient by the proportion of CTCs.
Next generation sequencing
There are new advances that improve the sensitivity of liquid biopsy for patients with existing PCa. Not only can the CTCs themselves be subject to genomic analysis, but also other genetic materials that tumors shed into the bloodstream. These include snippets of tumor DNA as well as “exosomes, a grab bag of genetic debris, including DNA, RNA, and metabolites found in the blood.”[iv] Ritch, et al. (2017) point out, “Circulating cell-free tumor DNA (ctDNA) is highly abundant in the bloodstream of [metastatic castration resistant prostate cancer] patients and appears to provide an accurate snapshot of real-time tumor genomics.”[v]
Waiting requires patience
One factor that will add time to the quest for a primary liquid biopsy for as-yet-undiagnosed men is the process of correlating needle biopsy tissue biomarkers with blood-based biomarkers. The U.S. Food and Drug Administration, for example, will need research-demonstrated results with large populations and repeat findings. There is hope. According to one report, “…many studies show concordance or agreement between tissue biopsy results and those seen in liquid biopsies in advanced cancers, when DNA concentration and tumor burden are high.”[vi] The next step will be achieving the same agreement of results with primary, not advanced, tumor cancers – including prostate cancer.
I believe the “Holy Grail” of a liquid biopsy for general prostate cancer testing is close at hand. When it is achieved, it will help encourage PSA screening, since it will remove the objection that prostate needle biopsy is overused and over detects insignificant PCa.
Though we lack a crystal ball to predict exactly when we will have a liquid biopsy, the evidence shows it’s near at hand.
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.
[i] Underwood J, Quadri R, Kalva S, Shah H et al. Liquid biopsy for cancer: review and implications for the radiologist. Radiology. Vol. 294, No. 1. Published online Nov. 19, 2012.
[ii] Suh YS, Joung JY, Kim SH, Seo HK et al. Establishment and Application of Prostate Cancer Circulating Tumor Cells in the Era of Precision Medicine. Biomed Res Int. 2017;2017:7206307.
[iii] Stallard, Jim. “Liquid biopsy shows promise for guiding prostate cancer treatment.” On Cancer, Memorial Sloan Kettering Cancer Center, Jan. 7, 2016.
[iv] Jenks, Susan. “Liquid Biopsies for Circulating Tumor Cells: A New Prognostic Tool?” Cancer Therapy Advisor, Aug. 14, 2017.
[v] Ritch E, Wyatt AW. Predicting therapy response and resistance in metastatic prostate cancer with circulating tumor DNA. Urol Oncol. 2017 Dec 13. pii: S1078-1439(17)30605-1.
[vi] Jenks, Ibid.