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Episode 6  |  54:00 min

S1E6 | Precision medicine: The gene’s role in cancer treatment - Part II

Episode 6  |  54:00 min  |  09.21.2020

S1E6 | Precision medicine: The gene’s role in cancer treatment - Part II

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This is a podcast episode titled, S1E6 | Precision medicine: The gene’s role in cancer treatment - Part II. The summary for this episode is: From the color of our hair to the way our bodies tolerate medicine, our genes play a critical role in our health, and our ability to fight off or develop illness and disease, including cancer. But the genes in our DNA profile are not the only ones dictating our health. The genetic profile of a tumor is also critically important in determining how the cancer behaves and grows, and oncologists are now using that information to personalize treatments in very targeted ways. In this episode of Focus on Cancer, the second in a two-part series on how genes are used in cancer treatment, Pat Basu, MD, MBA, President & CEO of Cancer Treatment Centers of America® (CTCA), and his guest, Maurie Markman, MD, President of Medicine & Science at CTCA®, discuss how precision medicine has revolutionized cancer care over the past decade or two.
From the color of our hair to the way our bodies tolerate medicine, our genes play a critical role in our health, and our ability to fight off or develop illness and disease, including cancer. But the genes in our DNA profile are not the only ones dictating our health. The genetic profile of a tumor is also critically important in determining how the cancer behaves and grows, and oncologists are now using that information to personalize treatments in very targeted ways. In this episode of Focus on Cancer, the second in a two-part series on how genes are used in cancer treatment, Pat Basu, MD, MBA, President & CEO of Cancer Treatment Centers of America® (CTCA), and his guest, Maurie Markman, MD, President of Medicine & Science at CTCA®, discuss how precision medicine has revolutionized cancer care over the past decade or two.
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Maurie Markman, MD
President of Medicine & Science, Cancer Treatment Centers of America®
Early in his career, a mentor reminded Dr. Maurie Markman to approach the practice of medicine as a “people’s doctor.” This advice resonated with Dr. Markman, and he continues to carry it with him as he treats patients today. A nationally renowned oncologist, Dr. Markman is President of Medicine & Science at Cancer Treatment Centers of America® (CTCA). Previously, he was Senior Vice President of Clinical Affairs and National Director of Medical Oncology. “From the beginning of my career, I recognized the importance of practicing medicine as a ‘people’s’ doctor,’” says Dr. Markman. “All of my research and work has been motivated by the thought of giving patients every option to beat their disease.” Dr. Markman has decades of experience in cancer treatment and gynecologic research at some of the country’s most recognized facilities. In June 2011, he received the esteemed American Society of Clinical Oncology (ASCO) Statesman Award. Presented annually, the Statesman Award recognizes individual ASCO members who have shown extraordinary volunteer service, dedication and commitment to ASCO, their hospital community and the patients they serve for at least 20 years. Most recently, Dr. Markman served as the Vice President for Clinical Research and Chairman of the Department of Gynecologic Medical Oncology at M.D. Anderson Cancer Center in Houston, Texas, where he also served as a Professor of Medicine. Prior to that, Dr. Markman spent 11 years as Chairman of the Department of Hematology/Oncology and Director of the Taussig Cancer Center at the Cleveland Clinic Foundation. He also spent five years as Vice Chairman of the Department of Medicine at Memorial Sloan-Kettering Cancer Center in New York. A Diplomate of the American Board of Internal Medicine, Dr. Markman is board certified in internal medicine, medical oncology and hematology. He also holds a Graduate Certificate of Advanced Study in Bioethics from the Department of Philosophy at Cleveland State University. Dr. Markman began his undergraduate education at the University of Southern California, where he earned a bachelor’s degree in Biology and graduated summa cum laude. He went on to earn a medical degree from New York University School of Medicine. Following medical school, Dr. Markman completed an internship and residency in internal medicine at Bellevue Hospital-New York University Medical Center, where he was named Chief Resident in his final year. He then completed fellowship training in hematology and oncology at both the National Cancer Institute and Johns Hopkins University (Sidney Kimmel Comprehensive Cancer Center) in Maryland. Dr. Markman also holds a master’s degree in health policy and management from New York University Graduate School of Public Administration. Dedicated to finding new and innovative ways to treat cancer, Dr. Markman has published more than 1400 articles, editorials, peer-reviewed manuscripts, book chapters, reviews, letters and abstracts. Dr. Markman has written or co-edited 10 books and served as an editorial board member on over 40 journals. He is currently Editor-in-Chief of numerous oncology journals, including Oncology Digest and Current Oncology Reports. He is also a Fellow of the American College of Physicians and the American Society of Clinical Oncology. Dr. Markman is regularly listed as one of the “Best Doctors in America” by Best Doctors, Inc., one of “America’s Top Doctors” by Castle Connelly Medical Ltd., and one of “America’s Top Oncologists” by Consumer’s Research Council of America. In 1999 he was recognized as the Lee and Jerome Burkons Research Chair in Oncology by the Cleveland Clinic. He is widely regarded for his knowledge and expertise as a practicing clinical oncologist and is frequently asked to be a visiting professor and guest lecturer at universities and medical schools across the country. He has served as a member of hundreds of national and regional oncology committees. Dr. Markman joined CTCA® in September 2010. He currently serves as the National Director of Medical Oncology and Senior Vice President for Clinical Affairs at our hospital in Philadelphia. He says he was drawn to CTCA by the hospital’s patient-centered approach to cancer care and philosophy of treating the whole person, not just the disease. Dr. Markman is a member of numerous professional organizations, including, but not limited to: the American College of Physicians, the American Society of Clinical Oncology, the American Association for Cancer Research, the American Society of Hematology and the Society of Gynecologic Oncology.
Learn more about Dr. Markman

Dr. Pat Basu: Hi, I'm Dr. Pat Basu, the President and CEO of Cancer Treatment Centers of America and the host of Focus On Cancer. The show where we explore the issues that patients deal with in their battle against cancer, with answers from experts in cancer care. Today, I am pleased to welcome one of the world's experts in cancer care, Dr. Maurie Markman. Dr. Markman is the President of Medicine and Science at Cancer Treatment Centers of America and a remarkably renowned oncologist in the field of medicine. We are very excited to welcome you back to the show, Dr. Markman.

Dr. Maurie Markman: Thank you, Pat. I'm delighted to be here.

Dr. Pat Basu: Well, last time really enjoyed our discussion. We covered an important topic in pharmacogenomics, we covered a range of things from just breaking down that word. What is the pharmacology side in terms of how drugs interact with our body as well as the genetic side, in terms of the role of genes and what they play in our lives and our health and the role they may play in cancer. Just to ground us again, Dr. Markman, can you just give our audience a reminder, an overview of what is a gene and what is the role of genes in our health?

Dr. Maurie Markman: Well very important, very critical question. A gene is, I guess, most easiest to describe is that functional unit within the DNA of the germline... We're talking here now about, of course, the genes in all of us that they're there from the time of conception when the egg and the sperm come together and a half of the DNA come from the male and half from the female. And that double helix reforms the unit that determines individual proteins, individual regulatory components of how proteins work. That is defined as a gene. And it's estimated that each of us have somewhere between 20 and 25, 000 genes that again, they're these units that determine all of our biology, all our physiology.

Dr. Pat Basu: Absolutely. It's a remarkable world to think that we are so similar, but also unique in these various blueprints that we have. And the various combinations that result in our differences in eye color, and hair color, and in some cases even personality differences. So it ties us together, but also makes us so unique. Let's talk about it specifically in the cancer arena, what are the roles that the genes play in cancer?

Dr. Maurie Markman: Well, in cancer they play a critical role. Let me distinguish first what we were just talking about, and to some extent what we were talking about our last time we spoke, and that is the germline. Again, emphasizing the germline here because we're going to contrast that in a moment to the cancer. So the germline is what's in all our cells, all normal cells, every cell from, as I said, the moment of conception till the moment of death. And that's the fundamental aspect of again, not who we are, but in terms of that foundation, that infrastructure, you could say, that's our genes. And those genes play a critical role in related to cancer. They determine a potential risk in certain abnormalities, we call them mutations, major abnormalities may increase that risk of certain cancers. The very well known is the gene BRACA and abnormalities in BRACA can increase the lifetime risk for a woman for breast cancer, ovarian cancer, and in males prostate cancer, and in both males and females pancreas cancer. So these are in again, from the time of conception and they become very important. Then these abnormalities can relate to a variety of things we can do, including screening strategies because of increased risk. And again, potentially strategies to at high risk, even do a prophylactic procedures that might have a very positive impact and the potential for developing that cancer. But again, I'm emphasizing here that genes in the germline. And then we turn to the cancer itself. And of course, one of the things that characterizes a malignancy, a cancer is a dysregulation, a dysfunction of the genes in these cells that become a ligament. So here, we're talking about genes that are abnormal and these abnormal genes can result in the production of proteins that accelerate growth, cause invasion of a cancer through the normal tissue throughout the body that can lead to the resistance to chemotherapy. So these are genes, but these are abnormal genes and they are related to the cancer itself. And so those genetic abnormalities that actually just for those who are interested in some of the technical language, they are called somatic. They're not germline, meaning they relate to the cancer, not to all of the genes that we have in our body. So you have these two very critical components of the cancer gene story, that's abnormalities that are potentially present within the germline and then major differences abnormalities within the cancer itself.

Dr. Pat Basu: That's right. And I often tell patients it's an important distinction. So just to recap that the genetics that we're really describing are exactly what you described, the blueprint, that might relate to a risk factor to go back to analogy I've used, might be the blueprint for your house. And if there's something that's not up to code, a stove that's located too close to an electrical line or something like that is something intrinsic and that term line that can lead to a greater risk. So that's the genetic side of the house. Separate but a related concept is this idea of genomics where we are understanding the mutations within the cancer, within the tumor. And that is a very important aspect of something I want to double click into today. So let's talk in that second category, Dr. Markman, about the role for advanced genomic testing. Can you just share an introduction of what is genomic testing, and then we've got to get into a little bit more of the details around that?

Dr. Maurie Markman: Yes. Pat, this is as you highlighted a very important discussion. But before I answer your question, I just want to emphasize to those listening that I empathize with some of the complexities of understanding this, because we often use the same language, same terms to talk about the same thing. So when we talk about genetics or genes, as we just discussed, we could be talking about germline, we could be talking about the tumor, we could be talking about both. So it's really important as we have this discussion and other discussions and patients and families potentially have this discussion with their oncologist. That is very clear what you're talking about germline genes, genetics, cancer, genes, genetics or both. So when you asked the critical question about what we call advance genomic testing is critical to emphasize. There's also an element of gene testing that is critical, that relates to the germline. Again, we're not going to focus on that, I don't want for anyone to believe that all that's important is looking at the cancer itself. But we look for potential abnormalities in the germline. This is a genetic testing to look for family risk, increased risk of potential cancers. But we also then look, the term we use is advanced genomic testing specifically at the cancer. And here we can potentially see major differences, variations, complexities of abnormalities because quite frankly, that's what makes the cancer a cancer. It's this dysregulation. And sometimes you see abnormalities that are quite frankly and critically targetable. I know we'll come back to that in a moment, meaning these are abnormalities that characterize the cancer, and there are potential abnormalities that we can actually target to treat. On the other hand, as I emphasize, since cancers are so dysregulated, we often can see many abnormalities, sometimes dozens of abnormalities that in fact are, you might say, just there. They're part of the dysregulation of the cancer, but in fact, they don't actually drive the cancer forward. They're there, you can measure them, you can monitor them, but doing something about them, trying to target them is not going to affect the cancer. And one of the major complexities of this whole world is for the scientists. And then ultimately the companies and academics developing drugs is to determine which of these are which. And it's a very exciting area. It's a very complex area. But again, this advanced genomic testing is going to identify many abnormalities. Some of which are critically important, and we learn all the time about new ones that are critically important. And there are also abnormalities that are bystanders. They're the result of this dysregulation. But as far as we know, they are not relevant in terms of our being able to target them and have an impact on the outcome of cancer in an individual patient.

Dr. Pat Basu: So, Dr. Markman, again, this is really fascinating, and I agree with you that this can be a very confusing topic. So, essentially we're going down this pathway of really understanding let's call it the cancer or the tumor itself. And maybe to bring this to life for patients. And in addition to evaluating the various blueprints or components within our bodies, now, let's say there's a tumor, and now we're studying essentially getting deep diagnostics of the tumor itself. And as Dr. Markman mentioned, in some of these cases, we might find something about that tumor that allows us to treat that underlying abnormality. In some cases, we might get the information, but we don't yet have a treatment for that. Those treatments for those underlying abnormalities are often referred to as targeted therapies. So Dr. Markman, let's do a deeper dive into this notion. So we've studied the tumor, we've done advanced genomic testing. Can you share some examples with us of some target therapies?

Dr. Maurie Markman: Yes. This is actually, in my opinion, one of the most exciting areas of all of medicine. And just to highlight both the relevance and what we're learning is really to go back and say this is not a new concept. It's a very old one. In fact, the initial therapy of all of cancer, well over 50 years ago was targeted. We just didn't know that that's what we were doing and what I'm referring to is if you look back historically women with breast cancer would have their ovaries removed, and there will be a temporary reduction in the local mass, in the breast, if it is extensive or in the metasteses. Men with prostate cancer would have orchiectomy to get out of their testicles removed. And it was recognized that there would be aggression of prostate cancer. Now, again, no one knew why this work, we know it today. In the case of breast cancer, this was a removal of estrogen that had been causing some of these cancers to progress. And in the case of prostate cancer, it would have been the antigen that the male sex hormone. And what the hormone was doing was by this surgical procedures actually targeting indirectly the source of the growth against the receptors in the cancer. We then learned 50 plus years ago about receptors for estrogen of breast cancer, and antigens for prostate cancer, and then developed medications to treat these conditions based on these receptors. The reason I'm saying all this, these were targets, the targets were receptors that were now growing because of the growth factors that went to the cells. And we try to lock the ability of those receptors respond just like we're doing now with more advanced testing. So this is a very old concept, but now we understand what's happening at the molecular level. We can actually measure the abnormalities, the presence of these mutations or excessive numbers of receptors on cells when they're present and then develop very specific drugs, which target those abnormalities. So the first step is to molecularly diagnose or measure the presence or lack of presence of a particular abnormality. And then if it's discovered to use a drug, which we know targets or inhibits the effect of some growth factor, and that's the concept. So again, directly answering your question use of Tamoxifen to treat breast cancer, which has been done for 40 plus years, is to block the estrogen receptor on breast cancers. And the way you knew this made sense is at that point, or even today, to look for the presence of estrogen or progesterone receptors of breast cancer. Next major advance in that area actually was also in breast cancer is drug known as Trastuzumab. The Herceptin was the brand name. And again, the way one knew that this made sense was to look at the tumor to see if in fact there was excessive number of the receptor. Actually, the receptor is known as HER2. And if the tumor expressed more of receptors than normal that's when you'd use the drug Trastuzumab. And if you didn't see this excessive number of receptors, overexpression, the term is much more of it as you can measure, the drug wouldn't work. So again, this is the idea of targeting. And of course, more recently we've seen incredible advances in lung cancer. For example, we can identify about a quarter of patients with lung cancer, so called non small cell lung cancer about a quarter of cases that have a particular mutation in a very important receptor known as EGFR, epidermal growth factor receptor. So in the quarter of patients who have this mutation, particular therapies, which are now widely used, are highly effective. In the absence of this mutation, these drugs don't have an effect. How do you determine this? You check the tumor, you test the tumor for these abnormalities in this area that we call advanced genomic testing.

Dr. Pat Basu: Okay. That's right, Dr. Markman. And for our audience again, to really set this in context, we're zooming inside the body, we're zooming specifically to the tumor, and we are exploring, other attributes about this tumor that allow us to specifically attack that tumor preferentially with something known as targeted therapies to make an analogy that only goes so far. But I think can be helpful as many of our audience might be familiar with the idea of a bacterial infection and an antibiotic. There are antibiotics that work more generally. In other words, they might disrupt the cell wall of a bacteria and thus it stops the bacteria. It might stop the bacteria from replicating in a certain way, and thus it affects most bacterias. But there are other types of antibiotics that might be much more specific. They might take advantage of something that works for one bacteria, but not another. As we move into the world of cancer therapy, we might have systemic chemotherapy. Things that can cause damage to a wide variety of cells. But as Dr. Markman and I talked about in a previous episode, there is something called a therapeutic window. The idea that not enough of a dose doesn't give the effect, but too much of a dose can cause more side effects, rather. So if we think about that in the context of a targeted therapy, in contrast to systemic chemotherapy, systemic chemotherapy will have more likely collateral damage side effects, if you will, than a targeted therapy. Because the targeted therapy is looking for something very specific on this tumor cell. So one time with the patient in the Navy, I use the analogy that imagine that there's wooden ships and metallic ships, an example of a type of targeted therapy, not very specific would be weapons system that has a magnet to it. So the enemy ship with the metal is going to be affected, but the one made of wood will not be. So this is a complicated subject. And really, we want to try and bring it to light for you, what these targeted therapies do. So along the lines of targeted therapies, and frankly in the realm of precision medicine, Dr. Markman, no discussion will be complete without a touching on the topic of immunotherapy. This is an area where you are a world expert, you've done a tremendous amount to advance our knowledge and care and immunotherapy. Can we touch on that topic? First of all, what do we mean by immunotherapy, Dr. Markman?

Dr. Maurie Markman: I go back to my comment that I made about the first therapies for cancer were targeted therapies, even though we didn't know it at the time. And then you make the same statement about immunotherapy. 100 plus years ago, there was evidence that some cancers would regress for uncertain reasons. And there was actually hypotheses much information to suggest in obviously a medical literature that was very different to the day that actually in the presence of infection that a cancer could regress. The idea is well, that somehow this infection would stimulate the innate immune system that would then also attack the cancer. In fact there was a very famous physician who was actually, I should say, run out of town, ridiculed by the name of Coley. And his idea, the things he uses, Coley's toxins. He tried to stimulate by these various toxic strategies that the immune system and they all, of course, had terrible side effects. But in fact, now we realized he was really onto something, of course, at point not understanding what we understand today. But the idea is that somehow, the inherent immune system of the individual, or all of us in general is able to deal with foreign invaders. You mentioned about infections. Well, we are all infected constantly from the outside. Again, you think about the fact that we are exposed to carcinogens. Those are agents that can cause cancer; the sun, things that we eat, we inhale. And then when you think about the fact that people live 70, 80, 90 years, and the fact is that they're exposed to these potential toxins their entire life. Why don't we all develop cancer early? Well, the general answer is because we have mechanisms within all of us, each of us to identify these abnormalities and to remove them, having nothing to do with therapy. inaudible this is what happens naturally. So the idea of the immunotherapy would be, has been, continues to be, that we could somehow enhance the activity of the immune system and that individual with cancer, we step back a moment. Clearly when a patient develops cancer, something has failed within that individual's, I mentioned the protective part of their whole life doesn't develop cancer or something went wrong because the immune system wasn't able in this particular patient at this particular time to control that cancer. So is there some way we can stimulate the immune system of that individual to enhance that individual's immune system to now eliminate, or at least control the cancer. And that's the concept of the immune therapy. And there are lots of approaches that have been tried over the years. There are lots of approaches being tried. Now, there's the two basic concepts are number one, to try to give something thing to a patient to stimulate their immune system, or almost the exact opposite is to give something to a patient that will eliminate the blockade that currently exists in their immune system. So it's not to directly stimulate, is to eliminate some kind of a blockage that the tumor has been able to induce, and then allow the immune system to be functional. And this latter strategy, this somehow eliminate the blockade is what is quite frankly over the last half dozen or dozen years, that's truly revolutionized the care of cancer. A group of drugs known as checkpoint inhibitors. They inhibit this blockade and in many tumor types, this is now become a standard of care. It's an immune therapy's approach.

Dr. Pat Basu: So Dr. Markman, I love your explanation there. And I agree that immunotherapy is such an exciting area where we've already made such tremendous progress in. And frankly, I know you and I agree that there's much more to be excited about down the road. One of the analogies that I like to use with the immune system it's Homeland Security and its primary function is to keep out let's say infection, which in this case might be foreign invaders invading our bodies. And although that's not an easy exercise, they're at least easier to identify. One of the difficulties with cancer and the tumor cells is really this idea that they are born from within, it's like Homeland terrorism. And so they're not wearing foreign military uniforms, maybe they have American passports or American citizens. And so immunotherapy is really trying to give the body an edge. And let me just take a step back, you made a good point earlier, which is that, that Homeland Security function is constantly doing its job. You mentioned sun exposure, you mentioned carcinogen exposure. It is picking up those domestic terrorist threats, if you will, on a regular basis. And that's why we don't constantly develop cancer because those crimes, if you will, are being stopped. But when a certain tumor type is able to evade those responses, immunotherapy, to continue this metaphor works in a certain way to make it easier to identify and stop that target. So maybe as an example, there's a domestic terrorist gang and they all are wearing, I don't know, I'm making this up, red hats or green hats or something. And now we're able to say, " Okay, we've identified, look for everybody in a green hat, and that might be able to help us identify them." And so really I like this analogy for the patients I speak to because it puts it in that context that, " Yes, the body is constantly doing its job, but in some of these cases, the tumors escape detection and immunotherapy can be a way to really bring our bodies, Homeland defenses, much more to bear on the tumor by giving it some advantage." Anything you'd like to add to that?

Dr. Maurie Markman: Many, many years ago I was one of these bright- eyed bushy- tailed, the young individuals who thought we were going to cure cancer with immunotherapy. I spent a couple of years at the laboratory of Immunology International Cancers to try to see how we could help really stimulate the immune system. And we did some pretty aggressive things to try to treat the patients, stimulate the immune system. One of the things we learned, however, and quite frankly it took the brain observation that Dr. Jim Allison, who recently was awarded the Nobel Prize for his, in retrospect, very simple observation just like you were trying to point out, is it but the immune system is working and yet there's these invaders that are successful, what Dr. Allison said. But if you actually look at the tumors, you see lots of lymphocytes, where they're making these immune systems work for these cells they're present within the cancer, and yet they're not working. And the idea that it was the cancer that was producing substances, that suppressed an immune system that was actually working in overtime. It wasn't that the immune system was failing, it was that it was being blocked. And the observation by Dr. Allison and others said, " Well, let's see if we can remove the blockade so that these invaders that you're mentioned cannot be nice. Again, that immune system isn't revved up, it's being blocked. And that was an incredible observation. And that's led to where we are today.

Dr. Pat Basu: So, yeah. Terrific. Now I think Dr. Allison's work there is a great example of... It's almost like they're using fake passports or something to do it. And we're giving the immune system back a chance to better recognize these terrorists. And for the record, Dr. Markman, I still consider you a with your excitement and your passion, despite your experience, bright- eyed and bushy- tailed, and all the things that you're that you're helping advance for the field of medicine and oncology. So maybe actually along those lines. And I mean, this sincerely. I mean, your personal contribution to the field has been tremendous. So many of us as colleagues are so grateful for all that you've done in advancing the knowledge and caring for patients. But I know that our work is far from over. So paint for me a picture, in addition to being a phenomenal physician, I consider you to be a visionary, as exciting as precision medicine is exciting as the advancements are that we've talked about frankly, on these episodes from pharmaco genetics to immunotherapy, but this broad topic of precision medicine, what does the next decade look like? What can we all expect to see or hope to see on the horizon?

Dr. Maurie Markman: Well, Pat, this a critically important question. I am incredibly optimistic for the future. I would predict the next five years we'll see more advances than we have seen last 25, 30 years. And the reason is because of precision medicine in general and precision cancer medicine specifically, let me emphasize what I mean by that and you alluded to this earlier. It's the idea of being more precise. It is not that standard chemotherapy, it didn't hit a target. It did, it just hit lots of targets. And hit lots and lots specific targets causing a lot of toxicities. So the goal with all concept of precision medicine is to be more precise in the targets that are relevant to eliminate side effects. And very importantly, if a drug is not going to work or not going to have a positive effect at a particular point in time in the natural history of that individual cancer not to use it. So my prediction is we are going to see far more specific precision medicine approaches, where we will not only start our therapies based upon the abnormalities present within a cancer but on a regular basis. And I mean, perhaps monthly monitor the course of the illness through the blood. I note that the FDA has very recently approved two different companies platforms to evaluate these molecular abnormalities, not in the solid tumor itself, but in the blood. Meaning that there are characteristic molecular abnormalities that can be detected in incredibly small numbers of cells that might be circulating in cancer patients to use this information to more precisely divine therapies that will work to stop therapies that are not working or not to start them. So the future will be much more precision medicine- based, including in the immunotherapeutic approach where we can anticipate what will work. We can anticipate the development of resistance. We can alter the therapies quickly. We will develop new strategies that are focused on very specific targets. I think the next five years we'll see a increasingly rapid revolution in our care. Let me emphasize this will also fairly impact, as you mentioned, the therapeutic window to you can justify some of the side effects. If you can have a major therapeutic positive effect. And you can't justify the side effects if the drugs are not going to work. We're going to see much more focused on that relative side effects versus benefits. And of course, it's critical to mention that the cost of these therapies. So that if you're going to give a therapy that has a very high probability of course having clinical benefit improving quality of life substantially improving survival. One can say, you can justify certain costs. Whereas if these therapies are not going to have an effect on be toxic, why should they be given? Why should the individual patient employer? I'm sure, society pay those costs. So again, I think all of these developments will be very positive as we move forward.

Dr. Pat Basu: Absolutely. Dr. Markman, I share your enthusiasm and your optimism, I think the next five years definitely will bring a greater acceleration and greater rate of advancement than we've even seen in the last 25. And so I think that's tremendous. I agree with some of the things that you said, and I just want to reiterate them this notion that we have traversed in all of medicine, but particularly in cancer from what used to be long time ago, much more of a shotgun approach, or sort of a general dropping a bomb on the enemy sort of approach. We've gotten much more smart and targeted and sophisticated. And what that allows us to do is to widen that therapeutic window to cause damage to the cancer cells while causing a limited and hopefully no damage to our own cells which does eliminates the cancer while reducing side effects. And I think the widening of this therapeutic window, the narrowing of that scalpel- like, laser- like precision is going to be phenomenal to watch. And your comments on the cost, I think is spot on as well because you're right. Something that is just a general bomb approach should not be as rewarded, or reimbursed, remunerated as something that is much more targeted. I would be remiss in saying if I didn't mention this, and I know you agree that given the prevalence of cancer in the world, given aging population, and the increase in cancer diagnoses, the cost of cancer that we need to continue to not just make advancements in the science of oncology, which we are. But also the accessibility and the affordability of cancer care therapy in this country and around the world because it's sad. I know you and I work very directly with organizations and certainly with CTC and patients to make sure that patients can get the care that they need, but all around the United States there are examples of patients who sadly defer their cancer care or can't afford their cancer care. And collectively we need to work together to make sure that that oncology care is accessible and affordable in addition to the advances that we're making. So speaking of making sure that our patients are well cared for and have access to all the wonderful things that we're talking about, let's move to that same portion when I had you on the show last time, where we go directly to some patient questions. And this is from a patient who asks, can you have immunotherapy to slow down CLL? Dr. Markman, what would you say to that patient?

Dr. Maurie Markman: First of all is a wonderful question. And it really does emphasize what we alluded to that earlier about what we're learning. CLL is a complex disease. It's actually a common hematologic malignancies where the lymphocytes are accessive number in the bone marrow and in the blood, the early stages of the illness. It could literally be known solely because of the presence of an increased number of blood cells that are detected in a routine blood test. No symptoms at all. Later, this can result in growth of lymph nodes, a dysfunction of the immune system in general, organ dysfunction, and really a transformation into a very serious ultimately fatal condition not the benign process that I started with. So CLL is a very complex disease and early data suggesting that immunotherapy does have a role. And the role may very well be in the really yet today on the more advanced stages where there's this transformation into a much more aggressive malignancy. And there's some data there that that drug can be quite effective in some of these patients and perhaps less so in the early stages. But the key to point is that much more research needs to be done. We need as a society and oncologists to support these research efforts to truly define where these therapies work. And again, this emphasize, again, the importance of we talked about advanced genomic testing, use of even a more general term biomarkers determining at the molecular level what are the markers that will determine if therapy will work or not. They may be genetic information, but there may be other markers that are relevant that we need to determine. But CLL is an area of very active development immunotherapy today.

Dr. Pat Basu: Terrific, terrific. Here's a question from a patient that I've heard before and related to today's topic. The patient wants to know, are personalized medicine and precision medicine the same thing? I feel like I've heard those terms used interchangeably. What would you say, Dr. Markman?

Dr. Maurie Markman: I'm sort of a day attack that one when I was saying we don't have very good nomenclature here because we use genetic testing, which in germline and genetic testing, which is a tumor. We use the same terminologies and patients may scratch their head and say, " Well, what are they talking about?" Here's a wonderful example. Different people have different definitions. I personally because of the issue of to have to make up your own definitions, I would use the term precision medicine to focus on that part that relates to the biology of the cancer: the molecular abnormalities, the biomarkers I referred to as my personal definition. I would use the term personalized medicine to be much broader than that. Clearly personalized medicine includes precision medicine because it's the focus on the cancer itself. But it's much broader than that. And obviously includes all of the issues that relate to that individual patient that includes their comorbidities other diseases they might have. It includes their associate's economic status, their behavioral medicine needs being personalized. So it's a broader definition. Now I'm fully aware that some would use personalized medicine the same way they use precision medicine. But I think personally that it's important that we do distinguish these two because they're both are critically important. Precision medicine is absolutely not all that's important. Biology is critical, but the large aspect of that individual patient goes beyond the biology of the cancer. So I would see personalized medicine is a much, much broader and critically important definition.

Dr. Pat Basu: Well, Dr. Markman, I would personally agree with your precise definition there, and maybe I just to add to that patient's terrific question. Agree with Dr. Markman, I think of personalized medicine as a broader category, which basically says instead of treating a one size cookie cutter approach, one size fits all approach. Every patient is the same. Let's look at the patient individually as Dr. Markman mentioned. Do they have diabetes or do they have obesity? What are aspects of their care that might change the diagnosis and therapy? Behavioral medicine, some of the access to medications, all of those being incorporated and treating an individual patient as an individual. As Dr. Markman mentioned precision medicine, we would agree is really the much more biological scientific nature of really exploring at the molecular level, what is happening inside of the cell or inside of the tumor in order to deliver a much more targeted therapy. So a good question. And we hope that that's helpful. So just a couple more here that I think are important and germane. This patient said, " Do targeted therapies and immunotherapies have more side effects than say chemo or radiation, or are they easier to tolerate?"

Dr. Maurie Markman: Again, a very important question. And this always is difficult when you are talking about a high level answer, which is all I can give versus that individual patient who might've said, " But I had X, or I had Y, or a family member at X and Y." I cannot talk about that individual patient because what they experienced is what they experienced. But in general both targeted therapies and immunotherapies are less toxic, have less side effects than what we traditionally call chemotherapy or cytotoxic chemotherapy. And the reason for that is we followed, alluded to Pat, we talked about the nonspecific nature of chemotherapy. The drugs Cisplatinum, which I've been involved with now for over 40 years it's an incredibly important drug. But if quite frankly, is the drug that gave medical oncologists their bad name, where people said things like, " Well, life is not worth living because of this drug, Cisplatinum." Why don't we give it because it was so effective? But it had tremendously nonspecific toxic effects in addition to its specific effects on the tumor. And in general, again, I may emphasize in general, these targeted therapies, including the immunotherapeutic approaches are less toxic. And that's a very good thing.

Dr. Pat Basu: Couldn't agree with you more, we in this battle against cancer or the war on cancer I sometimes do find that metaphor of that war to be germane here. And I agree with Dr. Markman that generally speaking these immunotherapies or these targeted therapies are designed to spare more innocent or civilian lives while damaging the foreign enemy. And so generally speaking, these targeted therapies are designed to do exactly that is to affect specifically the enemy in this case, the cancer cell with less effect, or hopefully no effect on the surrounding tissues or those innocent lives. So maybe there's time for one more question. This is from a patient. Is advanced genomic testing available for stage four cancer patients?

Dr. Maurie Markman: Yes. I want to emphasize is not just stage four cancer patients, but it's certainly available for stage four. And for those in the audience, stage four it's a classic definition, which means metastatic disease means the cancer has spread to organs outside of the area of the site of origin of the cancer. And yes, the answer is this is where this advanced genomic testing quite frankly, can be most helpful in a setting where, for example, the primary known effective therapies for a particular condition identified in large space through randomized trials, either no longer working, or they never worked to try to find that unique abnormality in that individual patient's tumor that can be targeted to favorably impact outcome. This is a very much in my opinion, absolutely standard of care today.

Dr. Pat Basu: Absolutely, Dr. Markman. And along those lines, maybe we'll close with something that's kind of the corollary to that patient's question. Are there patients who should not, or are not candidates for genomic testing, or is this something that if somebody has an existing diagnosis of cancer they should get a genomic testing? Can you help just discuss for patients who is a candidate and who should be considering genomic testing versus who should not be?

Dr. Maurie Markman: Yeah, Pat, a very good and important question. Unfortunately, it's a complex answer, so I'll try to simplify it. Clearly, we have been focused in this conversation on the patient, the population of patients, where we are looking for treatments that might improve outcome better than superior to existing therapies. That being said a very large proportion of cancer patients today are managed extremely well, extremely effectively with highly favorable outcomes set and an absolute acceptable quality of life with standard of care treatments. And I certainly would not want to suggest in any way that we need to throw away our effective treatments. So many of which exists today and substitute it with this, let's get genomic testing and throw that out. This is, we are learning more about the advanced approaches, we are incorporating more of these into standard of care, but in many clinic settings. The standard of care is highly effective and that what should be considered first. It doesn't mean that one does not want to get additional information that might use later if necessary. It's perfectly reasonable to have the tumor tested to look for abnormalities, but that might be employed later. But in fact, they may never be employed because the standard treatments today that have existed for five years, 10 years, 20 years are highly effective. And the patients standard treatments, surgery, radiation, standard chemotherapy work, the disease goes away, never comes back. Can't argue with that. So I think it's very important to point out that standard of care therapies today they remain very effective, not suggesting in any way that one should take these new strategies and replace them. That of course, is the purview of clinical trials. If someone wants to sort of say, " Well, let's try something new as a standard approach that out of the examined in a properly designed trials."

Dr. Pat Basu: Well, Dr. Markman as always you've done a remarkable job taking a complex set of topics, and terms, and really putting them into understandable and digestible pieces that can benefit a patient education and patient care. So we thank you greatly for that. Thank you again for coming back on the show. Very enlightening conversation around the world of precision medicine and advanced genomic testing as well as a variety of other topics that we hit on during the show here. So I know you're a busy man and I really just wanted to thank you again for taking the time away from patient care, and research, and continuing the battle against cancer. So thank you, Dr. Markman.

Dr. Maurie Markman: Thank you, Pat. I'm delighted to have been able to participate and look forward to doing in the future.

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