A Wave of Testing Advances or Just a Drop in the Bucket?

Hello again everyone and welcome back! Thanks for joining last time in my discussion of social media as an inexhaustible force in professional development. This month…something different…

Yes, indeed, this month’s piece from me to you is a well-deserved break from your regularly scheduled pandemic reading. Consider this your COVID content caesura. Whatever will we discuss without the virus at the forefront of all of our media channels? What then could possibly hold our attention, satisfy our craving for knowledge and professional development, and quench our thirst for lab-driven news?

Liquid biopsies. Obviously. Get it? Thirst? Quench? Yea? I’m sorry, let’s just jump in…

Image 1. This is totally what happens during liquid biopsies, can you guys not visually see DNA? You might need better centrifuges/brighter bulbs—talk about your 10,000 ft. diagnosis, right? (Stock image: Cancer.org)

In my recent social media scroll-binging (which is absolutely normal nowadays, don’t judge) a small story about a published article in JAMA appeared nestled gently between powerful protest content, pandemic virology, and 2020 politics. The article, which was just a small summary of a study in Science that combined liquid biopsy testing with PET-CT imaging to screen and guide interventions for a variety of cancers detected among over 10,000 recruited patients. Detected cancers included anything from solid masses to lymphoma and were found from thyroids to the ovaries. Translation: earlier, more comprehensive detection of malignant neoplasms of all sorts ….*drum-roll, please* ….BY BLOOD TEST! If you’re not impressed with this outright, then don’t fret. This kind of lab testing technology is some Penn & Teller level medical lab science, and I’m very excited about it! I could do a whole talk on this, a professional one, a TEDx one even…scroll to timestamp 4:50:00—of course I’m gonna plug the TEDx talk here. You know me.

Image 2. Remember your A-B-P’s: Always be promoting. Like the TEDx talk I gave, where I talked a bit about liquid biopsies; I don’t know if told you that I did that … (Source: TEDx)

What’s a liquid biopsy anyway?

That’s a great question, I’m glad you asked. Basically, think of it as the pinnacle of precision medicine—the gate key for all diagnoses and prognoses for an individualized treatment regimen based on the principles of known mutagens and detectable proteins and particles. Put plainly, a simple blood test that tests your blood (or other body fluid) for specific biomarkers to clue us in on the presence of an insidious malignancy. What kind of markers? Circulating tumor cells, micro-amounts of relevant RNA, vesicles, modified platelets, and other parts of cells, specific proteins—the list is growing. New concept, right? Not exactly, we’ve known about circulating tumor cells for at least 70 years now (nope, not a typo) but we haven’t been able to accurately hunt for them. We’ve had a concept of this sort of testing since the 70’s but have had a hard time implementing its clinical utility.

Image 3. A clinical lab. Somewhere. Circa 1975. To be a fly on the wall when they decided to skip gas biopsies and jump straight from solid tissue to liquid—what a concept! (Source: Univ. Texas at Austin, College of Health Sciences, historical photo of flu drug development at Memorial Sloan Kettering, NY)

Until the present day. Much like PCR, NGS, MALI-ToF, specialized mass spectrometry, and other awesome tools in our clinical arsenal, the ability is surpassing the paradigm. Whoa—philosophy check: are we moving too fast? Is this a reckless exercise? Should we do more research? No, no, and yes (obviously, always). Liquid biopsies have had pre-Wright brother success in getting airborne, so I’m recruiting all you readers out there to get excited with me and garner interest. Previous limitations might have meant we needed histological diagnosis first—I see you, everyone on the AP side… but these papers I’m showing you all today say basically three things: (1) our technology for liquid biopsy is getting better, (2) we might not need any previous test/section and could use liquid biopsy as a screening tool, (3) combined with imaging studies, this could be highly predictive and clinically useful.

The published study said what…?

Okay, let me show you the papers in the order I saw them: the JAMA article was just a primer in their Biotech Innovations magazine, a summary of an interesting development in liquid biopsies. They referenced the recent study in Science and discussed how 26 of the 10,000 women aged 65-75 were confirmed from liquid biopsy (LB) to imaging with PET-CT and, ultimately, biopsy to conclude. It said that the “blood test combined with the PET-CT had a 99.6% specificity and a 15.6% sensitivity…” with more being detected by LB at follow up. If those numbers triggered you as much as they did me, then of course you would have done what I did and followed the breadcrumbs.

Image 4. (LEFT) the three-tiered method of testing in the Detect-A Science paper and (RIGHT) the nearly 99% specificity of the CancerSEEK liquid biopsy modality in the second referenced Science article.

Que the Science study. In it, the authors presented their three-step testing process, using “Detect-A” LB for baselines. Ultimately 26 cancers in 10 organs were detected by just the blood test; this was out of a total of 96 cancers detected overall in the 10,000 participants either through liquid biopsy, current standards, or other investigative work ups. They did the math and showed that despite a sensitivity of 15.7% for the combined LB and PET-CT, the positive predictive value rose from 5.9% to 40.6% when you combined those two modalities. But the other statistics weren’t as impressive. Back to the JAMA article! The very last line said, “a newer version of the test that has a 99% sensitivity without confirmatory steps is in development…” Okay, now we’re cooking with gas—or testing with liquids—whatever: that’s the holy grail of CP testing 99% sensitivity, 99% specificity! Do tell!

Much ado about liquid—this was less impressive. This last line referenced a Science paper used “CancerSEEK” LB in 1,000 patients with sensitivities from 70-98%, but fantastic 99% specificity. Different panel, different cancers this time. Interesting to note, was that, applied to the specific incidence in the US population for the particular cancers detected by CancerSEEK, the sensitivity was around 55%. And, they managed to keep the cost relatively low at under $500 per test. (Sorry, if a red light just went on while you read this, CMS is probably recording now…) Well, this left me wanting. I’ve read so little about LB’s in recent years, is no one working on them? Well no, I was just busy, there’s tons of stuff out there, silly.

In just the past year alone, the American Journal of Clinical Pathology published 10 pieces on liquid biopsy cases, education, and utility for all kinds of malignancies from cytology to hemepath! AJCP—that’s us guys, it’s happening right here, right now! I told you we’ve got to do a PR run on this stuff and get it out there.

Is this the future? Are we in it now?

I’m happy to report that yes! This is indeed the future, well at least as thought of by the folks that conceptualized liquid biopsies 70 years ago. No hover-cars, or hover-boards, or hover-anything really (not without a lot of tech and work) but we’re closer to small advances in medical diagnostics!

Image 5. Maybe a better conceptual map of what liquid biopsies do. (Source: Gene Quantification)

Nature writer Catherine Alix-Panabieres put it very well when she wrote an Outlook piece this past March. On the one hand, liquid biopsies are a growing clinically useful tool in the synergy of addressing cancer in individualized medicine. On the other hand, we’ve known about this concept and have clearly been working on advancements in this testing technology for decades—it’s about time to come out of the shadow and push into widespread utility, including them in cancer algorithms, and redefining the ways in which cancer work-ups are developed in clinical trials, regulated by safety, and integrated into the toolkit of oncologic diagnostics. In my recent interview with People of Pathology Podcast show-runner, Dennis Strenk, I said we’re not quite ready to replace tissue biopsies yet—but are we close?

When do we go from pushing glass to pushing tubes?

See you next time!

References

Abbasi, J (2020) Blood Test Flags Multiple Cancers in Large Study, JAMA. 2020;323(22):2239. doi:10.1001/jama.2020.9266 → read it here

Alix-Panabieres, C (2020) The future of Liquid Biopsy, Nature 25 Mar 2020 579, S9 doi: 10.1038/d41586-020-00844-5 → read it here

Bai, Y, and Haitao, Z (2018) Liquid biopsy in tumors: opportunities and challenges, Annals of Translational Medicine, 2018 Nov; 6 (Suppl 1): S89, doi: 10.21037/atm.2018.11.31 → read it here

CAP (2020) The ‘Liquid’ Biopsy, College of American Pathologists → read it here

Cohen, J, et al. (2018) Detection and localization of surgically resectable cancers with a multi-analyte blood test, Science 23 Feb 2018; Vol. 359, Issue 6378, pp. 926-930, doi: /science.aar3247 → read it here

Lennon, AM, et al. (2020) Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention, Science doi. 10.1126/science.abb9601 → read it here


-Constantine E. Kanakis MD, MSc, MLS (ASCP)CM is a new first year resident physician in the Pathology and Laboratory Medicine Department at Loyola University Medical Center in Chicago with interests in hematopathology, transfusion medicine, bioethics, public health, and graphic medicine. His posts focus on the broader issues important to the practice of clinical laboratory medicine and their applications to global/public health, outreach/education, and advancing medical science. He is actively involved in public health and education, advocating for visibility and advancement of pathology and lab medicine. Watch his TEDx talk entitled “Unrecognizable Medicine” and follow him on Twitter @CEKanakisMD.

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