Liquid Biopsies: Guiding Cancer Treatment & Monitoring Progress

•How does liquid biopsy technology work? Liquid biopsies refer to collection of bodily fluids for analysis, usually blood draws, but can be of any fluid, including bone marrow aspirates. The analysis can look for “circulating tumor cells” (CTCs), which are cancer cells that split away from the primary tumor and enter the circulatory system (metastasis); or “cell-free DNA”, fragments of DNA released into the bloodstream when cells die. The DNA signature of healthy cells is very different from cancer cells, called “circulating tumor DNA” (ctDNA).

•What can patients learn from a liquid biopsy, especially prostate cancer patients who are already getting blood draws to monitor their PSA biomarker? We tend to focus on the tumor cells, but there’s a lot of information in the environment around the tumor cells we can get from liquid biopsies that can help us understand the tumor and its dynamics. For example, a blood test can tell if a patient has an androgen receptor variant (AR-V7), indicating that he will not respond to androgen-targeted therapies (such as abiraterone, enzalutamide, or apalutamide). From UroToday, August 18, 2022, “Integration of Liquid Biopsies in Clinical Management of Metastatic Prostate Cancer - Beyond the Abstract”, Written by: Varsha Tulpule, Gareth J. Morrison, Mary Falcone, David I. Quinn, Amir Goldkorn; Division of Medical Oncology, Department of Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

•How close is the promise of this new technology to widespread access? This technology is in an early research phase that seems like “The Wild West”. We don't have clarity on which types of these l liquid biopsies are relevant for which types of tumors at which stage in their progression. It’s hard to find practitioners who are nimble and are willing to do serial liquid biopsies so we can be addressing genetic changes along the way. It's often hard to get these and other tests done, and they can be expensive.

•What's next? In prostate cancer and other cancers, like breast cancer, patients have lots of treatment choices. We need to maximize the amount of information we can extract from liquid biopsies to make decisions that will yield better patient outcomes. Over the past three years there has been progress in analyzing liquid biopsies, from looking only at circulating tumor cells to understanding other cancer dynamics. There is research in combining multiple tests, e.g., cell-free DNA analysis, circulating tumor cells analysis, and single cell genomics analysis of the circulating tumor cells, enabling better targeting of cancer treatments. And new biomarkers are being researched in liquids which can predict disease progression and target cancer cells, such as a replacement for the PSMA PET test. The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action. You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health. Meeting Notes SUMMARY KEYWORDS liquid biopsy, cancer, cell free dna, patient, cells, ctc, test, disease, super, blood, question, slides, imaging, wild west, androgen, waldo, rick, research, bit SPEAKERS Mike Yancey, Robert Ellis, Saed Sayad, John Laird, Jeff Waldron, Peter Kuhn, Rick Stanton. Robert Ellis 00:04 I'm patient number five in the Prostate Cancer Lab. Our guests are Peter Kuhn and Stephanie Shishido. We're going to be talking about liquid biopsies, which I am very much interested in. Liquid biopsies enable less invasive, more frequent, and lower cost data about disease, which could revolutionize treatment. We're going to be talking about the cutting edge of liquid biopsies in their ability to inform patients about their disease, predict progress and guide treatment decisions. Peter Kuhn, PhD is founder and Chief Scientific Adviser at Epic Sciences, which develops liquid biopsies blood tests to inform cancer patients on their best course of therapy. Dr. Kuhn is the Dean's Professor of Biological Sciences, Professor of Medicine, Aerospace and Mechanical Engineering and Biomedical Engineering at the University of Southern California. He also serves as the Director of the USC Michelson Convergent Science Institute in cancer and the Deputy Director of the Convergent Science Virtual Cancer Center. Dr. Shishido is currently a postdoctoral researcher at the USC Michelson Center for Convergent Bioscience, focusing on the identification and characterization of circulating tumor cells from the liquid biopsy received from clinical trial cancer patients. Her research interests focus on the interactions between the neoplastic cell and the microenvironment Epic's Comprehensive Cancer profiling approach uses multiple technologies to provide up to three types of analyses all based on a single blood draw. Their proven and proprietary circulating tumor cell capabilities along with circulating tumor DNA and immune cell analysis allow for a clearer and more efficient picture for both prostate and breast cancer. Their approach reveals both genotypic and phenotypic data and can offer the most actionable personalized liquid biopsy available, which is specifically of interest to us. The AR-V7 test identifies patients who are likely to be resistant to androgen-directed therapies such as abiraterone, enzalutamide, or apalutamide. The liquid biopsy test for AR-V7 is the first and only Medicare-reimbursed clinically validated predictive CTC liquid biopsy test for metastatic castrate-resistant prostate cancer. Peter Kuhn 03:01 Stephanie has retired from her role as a postdoctoral fellow, and given the success of what she has done during that time is now Director of Clinical Research within CSI (Convergent Science Institute)-Cancer. She is responsible for a substantial portfolio of clinical research applications that range all the way into CAR-T therapies for prostate cancer. We won't talk about this today. That is for a for a future conversation and why it is that we are involved with what we think are the best groups in the world working on this and how we think that we can hopefully help and support them in their mission to enable CAR-T therapy in prostate cancer, which has been one of the challenges up until now. Today is really meant as a discussion and to provide information. I want to be most helpful to you guys. I have slides because that's what an academic does. I have 30 slides that might be useful for this conversation, but I am just as happy, if not even happier, if this is simply a conversation driven by questions that you have when you hear the key words "liquid biopsy." Let me start by asking, "What is it that comes to mind?" Rick Stanton 06:04 It was 2017. I was at Human Longevity. I heard about this company called Grail, and I thought, “This will never work”. It's like finding an attack submarine in deep water in the ocean, which is a job that I did. Then I was just amazed. I've told my wife who's just had breast cancer. She's under care at UCLA. She had a lumpectomy, no genomic sequencing. I have been listening to “The Drive” podcast by Peter Attia, and his interview with Max Diehn from Stanford regarding circulating tumor cells. It came to me that my wife should have her primary tumor sequenced so that someday, circulating tumor cells will be able to identify reoccurrence before imaging. I said, "You need to do this”, but it hasn't happened yet. I just had this conversation with her yesterday. I've been enthralled with Max Diehn's great podcast, and it's helping me understand the power of liquid biopsies. I'm under care at UCLA, and these things aren't even discussed. I'm also under the care of Dr. T at Providence Saint Johns, and I'm hopeful that he will leverage new technologies like liquid biopsies and spatial phenotyping. Jeff Waldron 08:46 I've been working a little bit with a woman in France, Catherine Alix-Panabières. You may know her. One of the many interesting things is the distinction between ctDNA and CTCs, or cell-free DNA and ctRNA. I worked a little bit with Mass General. I'm in the Boston area. We worked a little bit with Torpedo Diagnostics, which had a CTC launch that then got rolled back into Mass General, but not for original detection of cancer, but looking for remission or recurrence of cancer, particularly liver cancer, so they're using CTCs to do that. It's interesting to see the way the applications are rolling out in some of these areas and to try to better understand the distinction between some of them. I'm not sure if that's in your scope for today. John Wadude Laird 10:05 I'm a medical doctor and medical advocate. I'm not a treating physician. My role is really to identify testing and treatment resources. My questions are coming from that perspective. One, it seems like this is the Wild West. I don't have clarity on which types of these liquid biopsies are relevant for which types of tumors at which stage in their progression. The second concern I have is finding practitioners who are nimble and are willing to do serial liquid biopsy so we can be addressing genetic changes along the way. And thirdly, some of these tests are more robust. If you're getting live tumor tissue plus blood liquid biopsies. It's often hard to find a patient who can get all that done at the same time. And fourthly, the cost of these tests is out of bounds for most people, especially if they're done on a serial basis. Peter Kuhn 11:30 This is great because each of you hinted at important aspects. Max Diehn is a super good friend and colleague. We are working together on an early lung cancer detection program. That's another super fun, super important conversation. Jeff, I'm sorry you're stuck in Boston. I eventually escaped from the northeast. I did my tour at MGH with Mehmet Toner and Dan Haber, one of my absolute favorite competitors. Publicly, we chew each other apart, but privately, we are good friends. I have a huge amount of respect for them. Catherine Alix-Panabières is one of our counterparts in Europe. She has done lots of super interesting things, but I'm German and she's French, and those countries have always had a challenging relationship. :) It's a little bit more of the Wild West over there in France. Part of the commentary around Wild West is also important when it comes to the context of what it is that they do at comprehensive cancer centers versus at some of the private clinics. I am a scientist, obviously, and I am all for research, but please be thoughtful around what is evidence-based, and have a true understanding of the risks that we are taking when we are going with early-stage technologies. It's important because that's a big part of this sea change in liquid biopsy that has really changed the face of cancer research. 15 years ago, it was all about model systems and mice and cell lines and all this stuff. With liquid biopsies, we have been able to start using the human as our model system. It doesn't get any better than doing discovery together with the patient with the tumor from the patient. That's exactly what cancer research needs to do. We have seen this huge change of really making real progress by doing basic discovery with the patient, then validating it, and then getting back out into clinical care with a validated product. This is complicated. It's going to feel like, "Oh my god, this is too expensive, or this will never work. Hey, wait a minute, somebody failed so they're pulling it back in.” Or companies say, “What's going on?" Peter Kuhn 15:07 This is a tribute to Rick because there's something important that has happened as we worked our way through the last 20 years of research into liquid biopsy. If you saw a little postage stamp excerpt of this picture, you might think, "What is that, Peter? Is it a broken slide? There is no information there. This is noise. Is that something in the ocean?” Then if you zoom out, you might see a second boat, and that second boat is a little bigger. “Huh?” Then if you zoom out further, you see a bunch of boats. “What is it?” Eventually, you should see there's a chopper overhead. This is a whole fleet. “Wait a minute. If these guys are all here, the actual carrier can't be far away.” Rick Stanton 16:16 I worked on the sonar system that was dropped from that helicopter and would go 40 miles in front of the carrier group looking for deep threats. We used Sikorsky helicopters. I designed all of it, and it was a hard problem. This is hilarious. Peter Kuhn 16:45 This is a really hard problem. We started off by doing nothing else but looking for the carrier only. Because the carrier is the big problem. That's our big hit. That's the one we need to put out of commission. Everybody else is there to protect it and work with it. But at some point, somewhere there is enough signal around to say, “No, the carrier is there. I know it's there. I might not be able to see it right now. But I know it's there. I'm going to come back to this bit over and over.” When I only see this small ship, there's very little certainty on whether the full carrier group is there, or the carrier is there. As I'm adding information, I get to higher and higher and higher certainty. Somewhere in there, I know I need to strike. But it's always this risk balance because typically our information is incomplete. I want to always keep that in mind. I'm a professor at USC. The reason for all the other titles is simply because I was recruited into USC to build something that is really focused on patient benefit. It's super unique. There are not very many places that would support this. (None of the Boston schools. Sorry, Jeff.) None of the Boston schools could ever get there because their ego gets in the way. That's true for Northern California as well because it's too much about empire building. The creativity within Los Angeles is really allowing us to be driven by patient benefit. It's a fantastic place to do it. It's a great way to make progress. I love teasing our colleagues at the outset, but of course, we work very