Cancer Genomic Testing Capabilities

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today I'm happy to be joined again by Dr. Tim Chan, Director of the Center for Immunotherapy and Precision Immuno-oncology at Cleveland Clinic. He was here last year to talk to us about his vision for the Center for Immunotherapy and Precision Immuno-oncology, and that episode is still available. He's here today to talk to us about genomics and the treatment of cancer. So welcome back, Tim.

Timothy Chan, MD: Thanks so much, Dale. It's such a pleasure to be here again with you.

Dale Shepard, MD, PhD: So maybe you can remind us about your role here at Cleveland Clinic.

Timothy Chan, MD: Sure. So I'm a relative recent transplant. I've been here for almost coming on a year and a half, two years now. So I'm the chair of the Center for Immunotherapy and Precision Immuno-oncology, which is the first of these large bridge centers or departments that the Cleveland Clinic has established. And my role here is to build the basic sciences for immuno-oncology, and all also to set up capabilities for cell therapy and onsite cell therapy and CAR T development, as well as shared resources that facilitate early phase trials at the Cleveland Clinic to broaden access to life saving therapies for our patients.

Dale Shepard, MD, PhD: Excellent. Well, today we're going to be talking about genomics specifically, so we've had some recent changes in our ability to get genomic information in our genomic testing. So maybe you could tell us a little bit about where we were and what the new advances have been.

Timothy Chan, MD: Absolutely. And thank you for that question because it is so important. So typically I would say in the last 50 years cancer treatment and diagnosis has been a endeavor that has followed certain workflows. You have chemotherapy, you have radiation, you have surgery. And there were the development of these pathways for treatment of different types of diseases, so that colon cancer may be different than lung cancer, may be different from a brain tumor. So over the last, I would say, 20 years or so, it's become very apparent that there are certain unifying biological alterations that go awry in cancer, and these can be targeted. So you hear about some of the very first targeted agents like imatinib for CML leukemias, or eGFR inhibitors for lung cancers. These have been game changing.

So I think that over the last several years, especially this has heated up. There are now these FDA indications for very broad approvals based on molecular characteristics. And when selecting your patients very carefully, the drugs have the potential to have lifesaving benefit. So this is where the field has been and will continue to go, and you see in the news and in national meetings, ASH, for instance, was just occurring recently, you see the development of these new therapies, both targeted and immunotherapies that are having just amazing life changing consequences for our patients now. And all that is predicated on getting the diagnosis correct. The genetics and also the epigenetics, where the molecular features is an integral part of the diagnosis. It's not just solely from what the tumors look and where they come from, and it's an integral part in folks yourself and myself developing the best treatment plans for our patients.

Dale Shepard, MD, PhD: When we think about testing, we've recently changed how we're doing testing, the data we get from that testing. Tell us a little bit about that.

Timothy Chan, MD: Sure. So I think about 10, 15 years ago, small panels of about 300 to 500 genes have been used, and these cover some known cancer alterations, but they weren't comprehensive. And recently at the Cleveland Clinic, through a collaboration between our center and the Taussig Cancer Institute, as well as pathology with Dr. Rubin, Brian Rubin, the chair of pathology, we've been able to set up a workflow where we sequenced the entire exome, or the whole part of the functional genome, as well as the RNA or what's being used by the genome for all of our patients that need it. And of course the key companion diagnostics, meaning the key markers are still there, but we have the opportunity to to expand the data that we collect now across the entire genome of the tumors of the patients, allowing us to really fine tune which tumors are sensitive to which drugs.

Dale Shepard, MD, PhD: So when we think about the sequencing, and I'm just going to double back, you talked about the epigenetic characteristics. And when we look at genomic things, we typically think about an intrafusion or things like that. Which do you think is going to ultimately be more important or can you put on your prognostic hat and do you think it's going to be more about the genes that are expressed or the epigenetics, or what do you think is going to play a bigger role?

Timothy Chan, MD: Oh, I think that's a great a question, Dale. I think that this is one of the purposes of expanding our genomic testing, because what is important is very broad. So in some cases like lung cancer, you find, of course, translocations are very important, they're life changing, and other types of tumors, for instance for immunotherapy compliant tumors, biomarkers such as mismatched repair or tumor mutation burden have become the first pan-cancer biomarkers that have been approved, meaning that just have that alteration, you can start prescribing that medicine because response rates are higher. So in other words, it's broad based. It involves genes. It involves epigenetics as well, such as with glioma and MGMT. If you have methylation there, you're much more sensitive to chemo and radiation.

So that's a rationale for broadening our testing capability to be able to cover all the bases in as few tests as possible so that we don't leave anything out. So we're very excited to be able to do that. I think in the near future, we're going to continue to gain a lot of information. All the major trials now that are being done with new treatment are all rolling in genomics. And every week, we have a flood of new information on how best to tailor our treatments. So the answer to, I guess, that question is that all of it is important and we're trying to set up the bases here to be able to address all those challenges.

Dale Shepard, MD, PhD: So certainly me from a clinical perspective, as a clinician, not on the research side, but just from a clinical perspective, talking to patients, the two big barriers in the past would be insurance coverage for testing and how often a patient would have something that's actionable. So thinking about the first one, what's changed in the world in terms of our ability to get coverage for patients to get this testing?

Timothy Chan, MD: Well that's another great question, and it's so important because I would say about 10 years ago, the field was not where it was and insurance coverage was not where it was. Actionability was only about 15%. But of all the patients that you sequence, about 15% will have an alteration that will change the way that you practice, what drugs that you're, or what treatments that you're prescribing. Nowadays it continues to go up, and recently there have been the development, as I mentioned before, these pan cancer approvals, meaning these tumor agnostic approvals. If you have, for instance, NTRK fusion, or if you have MSI or high TNB, you're much more likely to respond to certain treatments. For MSI and TNB, it's immunotherapy, and for NTRK, it's basically kinase inhibitors.

Those are life changing, and they span different tumor types. So having these two agnostic approvals really has resulted in much, much broader insurance coverage for patients, and it's a rationale now for approval. These have been approved by CMS and the FDA, and they are parts of standard of care now, level one evidence. So I think that a lot has changed in the last 10 years. No longer are we in a situation where insurances are not covering these, they really should be and are covering these to a greater extent. Now obviously medicine and finances change relatively slowly. We're not at perfect yet. But the rationale is strong there to incorporate this universally in the finances of medicine.

Dale Shepard, MD, PhD: And I guess for those listening in that may not be doing this on a regular basis, tell us a little bit about... Historically we would take tissue and look at genomics. Tell us about liquid biopsies and how that has fit into our ability to get genomic information.

Timothy Chan, MD: Right, so this goes to discuss about how these tests are done. Typically we would have a biopsy or part of a tissue that comes from surgery, a tumor would be removed. It would go to our pathologist and they would send this out where the tumors are then processed and sequenced, and then we would get the data back. So obviously you if you think about this, this is not that easy to do. You can imagine that on treatment things will change and you might not be able to get biopsies all the time when a patient is actively on therapy, so we have a new modality now, or actually it's a family of modalities with a lot of different options to do what's called liquid biopsy. The liquid biopsy basically measures and sequences the amount of tumor DNA that's released into the bloodstream.

So many tumors, because they're tumors, are relatively friable and they can release DNA, these markers, into the bloodstream. And sequencing can actually pick up on those mutations. And it's a bloodless way of doing genomic sequencing. It's making a lot of progress now. It's surely easier on patients, of course, and it is approved in a number of instances, and there's a lot of increased utility of this as well. And it's an ongoing area of a tremendous amount of research now. We're very excited. Actually on a research setting, my department has actually launched liquid biopsy circulating tumor DNA sequencing at the Cleveland Clinic to be available on a research basis here, and we are at actually putting together the clinical side of things as well, so that this is much more available to all of our patients.

Dale Shepard, MD, PhD: And I guess as that becomes more available, I guess a question that frequently comes up is whether the genomic testing should take place with the primary tumor or with the metastatic site. What's your perspective on that?

Timothy Chan, MD: I think that's a really good question. And that goes into the differences between tissue based sequencing and blood. So when you do a tissue based sequencing assay, you're actually looking at only one site. And if you actually look at circulating tumor DNA, it's the amalgamation of the release of DNA from all the different sites. So theoretically, and in many cases, this has borne out to be true by studies, you are integrating the alterations from a variety of different sites. And nothing is perfect. I think that the work continues to go on, but yes, it is very frequent that one lesion may hold a certain alteration that you could prescribe a drug for, but the other lesion may not right. And circulating tumor DNA is theoretically a better way to be able to allow you to tell a difference. This all goes into what we call tumor heterogeneity. When a tumor becomes metastatic, it can become different from each other. One site may become different and circulating tumor DNA is a better way to help us figure that out.

Dale Shepard, MD, PhD: How is your group working with medicinal chemists, the bench side, to work on the fact that we're really, really good at looking at lots and lots of genes now and coming up with lots of alterations, but not necessarily how to target them as for therapies. How are we incorporating that aspect to come up with new agents to target these abnormalities?

Timothy Chan, MD: So classically, for treatment, you can make a chemical, a small drug, or you can make an antibody. And nowadays we have cell therapies where we can reprogram our own T cells or other immune cells to be able to attack cancer cells by recognizing something. So we're doing a little bit of all of the above. Our own shop here, we have an effort now built up at the Cleveland Clinic to identify new targets that are called neo antigens, that are mutated. Some of these can be made into vaccines, and they can be developed into new targets for what's called CAR T cell or engineer T cells that are designed to attack certain targets on tumor cells. So we're doing a little bit of that on each side. We are also developing antibody drug conjugates against mutated proteins on the surface of different cancers.

For instance, we have a very exciting program now in pediatric sarcomas now, Ewing sarcoma that we just started up, where there are these recurrent alterations, very excited about that. But more broadly, besides therapeutics, we're also working on how best to match therapeutics with the best patients, I mentioned before, of which genomic testing is a huge example and we're connecting with course you, Dale, and others, and Nate Pennell and Pauline Funchain and many others in the various services to be able to make the optimal use of C tumor sequencing and to be able to put this data into a new family of trials, basket trials as they're called, based on molecular alterations. There's a lot of drugs on the market. This is basically a effort to match up the best drugs with each individual patient. That requires a lot of data of management that requires broad sequencing, and that requires access to patients. So that's infrastructure that we are deep into the process of building now.

Dale Shepard, MD, PhD: As we develop more knowledge about the abnormalities that might lead to cancers, and we are able to treat them, we've made tremendous progress over the years. Do you think at some point we're going to look back and think it was really naive to treat by geography and to treat lung like lung and breast like breast, instead of just treating the underlying abnormalities. Do you think we'll have a blurring of all of the subgroups of people treating tumors and it entirely be treated by genomic abnormalities or immuno-signatures or something?

Timothy Chan, MD: Well, I think that it's not going to be one or the other, I think it's going to going to be all of the above. Because anatomic location, part of it is that a colon cancer behaves anatomically different than a head and neck cancer, as we both know. So there's things like lymph node drainage, things that dictate where things spread and those are going to be governed by the anatomy in the site. So I think that classic anatomy based treatment and site based treatment is not going away. The last 150 years of medicine for this is going to remain a mainstay of treatment. But I think what genomics allows us to do is really get a peak into the mechanistic alterations that drive those cancers. And they may be the same in many different types of tumors.

However, they are not going to explain away all the differences, that site specific qualities of the tumor are going to require us to be able to adapt for treatment. So again, remember people forget, surgery, it cures many, many patients, early phase patients. That surgery, never going to be the same between a head and neck tumor and a colon tumor. But what comes after surgery to prevent dissemination may be similar, such as PI3 kinase mutations, which happen in both. So I think what we're going to see is an amalgamation and an enrichment of all the knowledge that we all have across multiple fields for improved care, and it's going to be all of the above, Dale.

Dale Shepard, MD, PhD: There have been tremendous advances in the last five years, ten years, as we look forward. What are the biggest gaps? What's keeping us from making those next big moves?

Timothy Chan, MD: Well, I think that target identification and development, there are many tumors that have alterations that we simply do not have a way to hit. Transcription factors, for instance, are one of them, or these proteins that control gene expression. P53, for instance, is the most commonly mutated gene all across all cancers, mutated in over 50% of tumors. If we had a way to hit every P53 mutant tumor, our jobs would be half done. But we don't, because they're very, very difficult to target. The second is acquired resistance. So many of the therapies, especially the kinase inhibitors these days, the erlotinib and so forth for lung cancer, eGFR inhibitors, when you hit one target, they can become resistant because cancer cells, like, bacteria can be very smart, and they can weasel around different drugs, or like antibiotics with bacteria, around how it's something trying to control their growth and trying to kill them.

So acquired resistance is something that we have to deal with in oncology, especially in the phase one program, and as patients become resistant to one alteration or drug, then we have to target other things and figuring out what is the basis of acquired resistance to any given therapy is going to be really critical for us to continue to be able to offer more options for patients. And thirdly, access. Care is so different across different economic strata, different parts of the country. You get an amazing amount of diversity of outcomes just based on where that patient is getting treated. So access and diversity and serving underprivileged areas is really, really a major problem that's increasingly being tackled by the National Cancer Institute and by us here at Cleveland Clinic as well. It's an ongoing battle, but I think it's just as important as the first two science based challenges that I mentioned.

Dale Shepard, MD, PhD: Well, Tim, you're doing incredible work. We appreciate you providing such great insight. I look forward to working with you making more progress.

Timothy Chan, MD: Fantastic. Thank you so much for having me and good luck.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You'll receive confirmation once the appointment is scheduled.

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