Welcome to Yale Cancer Center Answers with doctors Francine Foss and Lynn Wilson.  Dr. Foss is a Professor of Medical Oncology and Dermatology, specializing in the treatment of lymphomas.  Dr. Wilson is a Professor of Therapeutic Radiology and an expert in the use of radiation to treat lung cancers and cutaneous lymphomas.  If you would like to join the conversation, you can contact the doctors directly.  The address is canceranswers@yale.edu and the phone number is 1-888-234-4YCC.  This week Francine and Lynn welcome Drs. Peter Koo and Daniel Morgensztern for a conversation about translational research in lung cancer.  Dr. Koo is Associate Professor of Medical Oncology and Dr. Morgensztern is Assistant Professor of Medical Oncology at Yale Cancer Center.  Here is Francine Foss.
Foss              I’d like to start off by asking both of you, since you’re both relatively new to Yale Cancer Center, where are you from and what brought you here, Peter maybe you can start?
Koo              I was with the MD Anderson Cancer Center before joining Yale Cancer Center. And as a research scientist in cancer biology, working with colleagues that are cutting edge r in the field has always been a kind of dream.  So when Dr. Roy Herbst joined Yale Cancer Center a few months ago and established an office of translational research, I was really fortunate to join this new initiative at Yale Cancer Center and I have great enthusiasm and believe that this office of translational research will make changes to future directions of care for cancer patients.
Foss              And Daniel?
Morgensztern  Yeah, I guess this is my last appearance as a new comer, as I joined the faculty at Yale in January 2011.  I came from St. Louis where I was working at Washington University in the Veteran's Hospital.  I was delighted to come here and work with experts in the field such as Dr. Thomas Lynch and Dr. Roy Herbst and my role here as attending physician is treating patients with lung cancer and cancer of the head and neck, and also I am the Pharm Chief for the inpatient oncology section, which is in Smilow Cancer Hospital, on the 12th floor.
Foss              So both of you here for this translation, or research center, that has been established at Yale in lung cancer.  Can you talk a little bit about that center, what is involved and who else is involved in that with you?
Morgensztern  First we have to talk about what translational research is, which is basically the transformation of scientific discovers into the treatment of patients.  So what we have developed here at Yale is we have a number of basic scientists doing experiments on cell lines and animal models and we try to discover new treatments to apply for patients with lung cancer, and the reason why we are so enthusiastic about this is because we have assembled really a dream team of investigators and we have great expectations for the near future.
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Koo              The office of translational research is basically made up of Dr. Roy Herbst and Dr. Daniel Morgensztern as a physician, and me as a basic scientist, and Julie Boyer as administrative associate director.  At this stage, we are mainly four different members, but the members in other sections and in our section will expand our function in the future.
Wilson          How did this all get started for you guys? Peter, how did you become interested in this field?
Koo              Right after completing my PhD training, I became interested in the development of new therapies for cancer, because it is the most deadly disease and has a high death toll, and even if I am not a physician who is seeing the patient on a daily basis, I put myself in this field in the hopes that our research may help patients with their cancer treatment.
Wilson          And Daniel, how about yourself, how did you become interested in oncology and even more specifically, lung cancer?
Morgensztern  When I was in Brazil during my training, and my training was in hematology, I was always interested in cancer.  So when I came to the United States, my main goal was already set to be a medical oncologist, and at the time when I was finishing my fellowship, we were witnessing some great advances in the treatment of lung cancer, so I had to be a part of it.  This was the beginning of a new era of targeted therapies and we all got very enthusiastic about the promises for the future treatment of this disease.  I just could not escape the excitement about the new treatments from lung cancer.
Wilson          Lung cancer is a really common problem, unfortunately, but how common is it? Who does it affect? Are there differences between men and women in terms of incidence, tells us a little bit about the disease.
Morgensztern  Unfortunately, it is a very common disease.  The American Cancer Society estimates there were approximately 220,000 cases of lung cancer in the United States for the year 2011 with about 115,000 men, and 106,000 women and more of worrisome than that is the number of deaths, 157,000 deaths from lung cancer in the United States.  What we are witnessing is the increase in the rates of both incidence and mortality for lung cancer in women, whereas both the incidence and mortality are decreasing in men, so right now the expectation is that lung cancer in women will be as prevalent or even more prevalent than in men in the next few years.
Foss              Daniel, we hear about lung cancer from passive smoke exposure as well as in people who directly
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smoke, overall is there an increase in the incidence in both of those groups and also are there other risk factors that we should be concerned about?
Morgensztern  There are several risk factors for the development of lung cancer, certainly the most common is smoking, passive smoking is also a risk factor, although it is difficult to quantify.  There was a recent study published in Lancet Oncology showing that passive smoking not only increases the chance of lung cancer, but also heart attacks and other diseases, but typically most are caused by smoking and also some exposures, for example, we were not so sure if a virus can cause it, HPV has been implicated in other tumors of the head and neck and anal.  It could well be one of the causes for lung cancer as well as asbestos leak exposure.  There are several exposures which are just hard to quantify since most of the patients that have those exposures also are smokers, so it probably increases the chance of a smoker to develop lung cancer.
Foss              So smoking is still the number one problem with respect to lung cancer?
Morgensztern  That is correct.
Wilson          Daniel, you mentioned over 200,000 patients a year get lung cancer, but almost 160,000 actually died as well.  It does not sound like the prognosis is so great for a lot of patients.  Can you talk address that issue and talk about some of the standard therapies?
Morgensztern  A lot of questions at once, but again, from the American Cancer Society, the probability of a lung cancer patient being alive at 5 years, is 16%, so out of 100 patients diagnosed with lung cancer, only 16 will be alive at 5 years and that prognosis and treatment basically depend on the stage of diagnosis.  One of the main problems with lung cancer is that unfortunately when patients develop symptoms, the tumor has already advanced.  So more than half of the patients have incurable disease at the time of diagnoses, but the treatment and prognosis depend on the stage, as I said, if the cancer is at an early stage, doesn’t involve lymph nodes and so forth, they can undergo surgery for a chance of cure depending on the size.  If the cancer has involved lymph nodes between the lungs, we call it mediastinal lymph nodes, and there is a small chance of cure with an aggressive treatment consisting mainly of chemotherapy and radiation whereas if the tumor has already spread beyond the chest to other organs such as the brain, bones, liver, adrenal glands, the treatment unfortunately is not curative.  We can improve the quality of life and survival, but unfortunately, we cannot cure those patients.
Foss              We talked a little bit about screening for lung cancer and I know there have been a number of
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 things done like chest x-rays and scans, but do you really feel like we are where we need to be with that and are there any new developments as far as screening, such as blood tests or other things that could be used in people that are smoking to detect these tumors earlier?
Morgensztern  When I was here a few months ago, I mentioned the hope that there might be the development of some sputum or blood test for the screening, but right now what we have since that time is the final publication of the National Cancer Institute Sponsor Screening Trial, which showed that patients having CT scans every year for three years, the chance of detecting early disease is much higher than doing the chest radiograph and that improved survival.  Obviously, this is not applicable for everybody, not all the patients were eligible for this study and this is what we have so far which seems to be a very good idea, but again the hope is that in the future we can do a more affordable and less risky procedure for screening such as a blood test, sputum test or urine test, any type of noninvasive test.
Foss              Peter, is this where you get involved as a translation researcher in terms of thinking about these kinds of issues?
Morgensztern  Yes, and particularly the biomarkers that are present in the serum will be useful for identifying the early lesions of lung cancer or other types of cancers, so we are certainly interested in identifying those biomarkers and currently they are not very good clinically effective biomarkers detecting early cancer.
Wilson          Daniel, you had mentioned some of the standard treatments such as radiation, surgery, and chemotherapy, but there are some new treatments that have been developed and some things that are on the horizon, can you discuss those?
Morgensztern  Besides the surgery, chemotherapy, and radiation, we have improvements on the standard techniques, for example, we have different types of surgery which are less invasive such as (VATS) or video-assisted thoracoscopic surgery, and it is a small incision, almost like laparoscopy of the chest and ideally we have robotic surgery which is a further improvement of this technique.  For radiation, we have stereotactic body radiation, which is focused radiation that has a shorter duration and involves less of the normal cells so it causes less side effects and the results are very promising.  In terms of systemic therapy, which is my specialty, we do have targeted therapies and we have achieved some success in some specific subsets of patients such as those with epidermal growth factor mutations, the EGFR mutation, for which we have a tablet that is quite effective called Tarceva, and also for patients with the EML4-ALK fusion gene for which we have a
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medicine that was recently approved by the FDA called Crizotinib, so besides those two, we are working here at Yale, and actually the whole country, is working on finding new targets or new patient populations that could benefit as much as the ones that are benefitting right now from tablets.
Foss              Daniel, what percentage of lung cancer patients have these mutation that we have targeted drugs for now?
Morgensztern  The percentage of the patients depends on the location where these tests are done.  If we have a lot of referrals, the incidence would be different, but we now believe that approximately 10% will have the EGFR mutation and probably 5% to 6% will have the ALK mutation.  It is not a whole lot, and the FDA approved those medicines only for patients who have stage IV metastatic disease, but that is the start.  Those treatments are very easy to take, one pill a day with minimal side effects, and very good response for it, we just need to expland to other patient populations.
Foss              Can we bounce this back to Peter now? We are talking about these genes, ALK gene and the EGF receptor.  Can you just briefly tell the audience what these are?
Koo              For example, the EGFR is expressed on the surface of the cell and this receptor is responding to epidermal gross factors and EGF and EDFR binding supports growth of the cells and if the cancer cell has a mutation of these, it is highly active.  At same time, it is responsive to the drugs targeting this EGFR and the ALK and EML fusion and these two unique genes are combined together and then become the oncogene which supports, again, the growth of cancer cells.
Foss              We are going to take short break for a medical minute.  Please stay tuned to learn more information about translational research in lung cancer with Drs. Koo and Morgensztern.
Minute          The American Cancer Society estimates that over a thousand patients will be diagnosed with melanoma in Connecticut each year.  While melanoma accounts for only about 4% of skin cancer cases, it causes the most skin cancer deaths.  Early detection is the key.  When detected early, melanoma is easily treated and highly curable and new treatment options and surgical techniques are giving melanoma survivors more help than they have ever had before.  Clinical trials are currently underway at Yale Cancer Center Connecticut and other federally designated comprehensive cancer centers to test innovative new treatments for melanoma.  The specialized programs of research excellence in skin cancer grant at Yale, also known as the SPORE grant, will help establish national guidelines on modifying behavior and on prevention as well as
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 identification of new drug targets.  This has been a medical minute, brought to you as a public service by Yale Cancer Center.  More information is available at yalecancercenter.org. You are listening to the WNPR Health Forum on the Connecticut Public Broadcasting Network.
Wilson          Welcome back to Yale Cancer Center Answers.  This is Dr. Lynn Wilson and I am joined by my co-host Dr. Francine Foss.  Today we are joined by Drs. Peter Koo and Daniel Morgensztern and we were discussing translational research and lung cancer.  Peter, your work, or one of the portions of it, is to investigate and discover therapeutic targets and develop new drugs for lung cancer treatment.  What does this involve and how do you go about doing this?
Koo              First of all, I have to mention that this kind of work can never be done by a single lab, so finding novel therapeutic targets and developing new drugs for lung cancer treatment are not really easy tasks as we’ve already harvested low hanging fruit in this field, we are certainly aiming high to harvest more effective and more clinically useful methods and since we have more information about the human genome and newly developed high-throughput methods to identify abnormalities in human cancer, we will have more and better information about cancer as time goes by. And in collaboration with many centers and labs in nearby cancer centers, including our new Cancer Biology Institute we can certainly achieve this goal in the very near future, but certainly it is not an easy task and support from many other supporting facilities is also critical.  However, support from patients is the single most important element in advancing newer effective cancer treatment.  We are truly grateful for the patients who participate in clinical studies.
Wilson          Are you trying to take active cancer cell lines and identify new targets or understand the mechanisms behind why cancer proliferates? What are some of the key concepts that you are most interested in?
Koo              Both.  We are using numerous different types of resources and cancer cell lines are one of them and certainly it is a starting point, but ultimately the knowledge that we have found through the cancer cell lines will be tested in pre-clinical settings including animal models and ultimately we would like to transport this into the clinic settings.
Foss              Can you talk about the importance of getting fresh patient tissue?  I know Dan, you are in the clinic and you talk to the patients all the time about research and one of the things we ask them is whether we can get a tissue sample and use it for research.  How important is that for you and what you do in translational research?
Koo              It is critical and one of the reasons why I mentioned that we have to appreciate the patient
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volunteers, giving up their tumor specimens, biopsy specimens, and tissue specimens, is that all those are so critically important because the cell lines and animals and all those studies ultimately have to be proven, the targets identified in those early studies has to be proven in the lung cancer patient specimens.  So, the identification and verification in tumor specimens are critically important.  In our research, obtaining those tissue specimens is the most important component.
Morgensztern  I agree with Peter, what we have now is what we call a tissue bank where we try to collect samples from patients with newly diagnosed lung cancer.  There is not extra risk or extra effort during the diagnostic biopsy, just take one or two small extra pieces and we collect them and they will be very helpful for starting new therapies, outcomes, or maybe risk factors for why  patients develop cancer.  We also tried to match that with health, behavioral, and nutrition, all aspects of the patient's life and only through studies like that, I think we can achieve a better understanding of lung cancer. The patients that have been through our clinic since the summer, they have been through this and it is a very thorough exam and interview with them, and I think in a few years we will have a very large collection, database, with samples and blood and clinical history.
Koo              I would like to add that one of the most important examples is the easier finding of mutations in tumor specimens which was led by Thomas Lynch in our institute and because the tumor specimens were available, this study was possible.  And because of this new finding, we open up a whole new avenue of cancer patient treatment, particularly the patient who has easier permutations.
Wilson          Obviously the concept of translational research is very exciting, and over the last five years there has probably been an explosion of this kind of work compared to 10 years ago.  So, obviously there is a lot of activity, a lot of things on the horizon.  Where do you each think we might be five years from know?  Peter, from your standpoint, what do you realistically see might be feasible say in five years?
Koo              We probably will find more mutations in tumors, which will be useful for targeting those mutations for cancer treatment and certainly, new technologies are available for these types of studies.  We will see a burst of information in this field, and also because of that, we will identify new novel biomarkers for therapeutic targets and also the markers to detect the cancers at early stages.  Those areas are really becoming the information area.
Wilson          Daniel, if we make these new discoveries of new targets and come up with new ideas, new drugs, and new targeted therapies, do you have any concerns about some of the lag time that may be
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 involved between making a discovery, developing the drug to attack the target, and the regulatory process?  As you know, this can take years and years sometimes before we can actually get something effectively into standard practice.  What are your thoughts about that?
Morgensztern  In the past, it was very difficult to move such a drug to the regulatory process and the most scientific example is imatinib, Gleevec, which took quite a while after everybody knew it was effective in patients with chronic myeloid leukemia.  On the other hand, the EML4-ALK mutation was discovered in 2007 and by 2009 we had the medicine already.  In 2011, the medicine was approved.  So, the key here is to find medicines that are effective and know which patients will benefit, and if we follow this path, and we know exactly who will benefit, who has a high chance of benefiting, the process will be quicker, and the results will be amazing like we have seen with Crizotinib and Erlotinib, and they cannot deny such major progress.  It is becoming faster and faster, and there was a drug discovered and approved in record time for patients with melanoma and it was shown to be much more effective then starting chemotherapy.
Foss              Daniel, you make a very good point about how these drugs get approved and I think from the point of view of the patient, there may be some reticence about going on an investigational trial with an investigational drug.  Could you just talk to patients a little bit about that, about the importance of taking that step, so that these drugs can move forward quickly?
Morgensztern  That is an important question.  I think that not too long ago, the main premise of the phase 1 studies, or the studies of medicines that were never used before, was just to see the toxicity.  If they are safe enough to be used with very limited expectations about efficacy and the medicines were quite toxic, but this has changed and we have new medicines with limited toxicity and now we are using a better approach, where we are up from trying to find out who are the patients most likely to benefit based on the cancer characteristics we have, we are trying to move beyond the empirical approach where we just give the medicine and see what happens.  Now we have a better idea of the patients that might benefit in participating in such a trial nowadays , and offers a much higher hope for response and benefit than it was in the past.
Foss              In this new model, can you talk a little bit about how you guys actually interact every day, is there a constant dialogue back and forth between you guys and the people in the lab and the people in the clinic about the patients and clinical trials and where we are moving next with the program?
Morgensztern  I talk to Peter almost every day.  When I can’t go and talk to him, I e-mail him, sorry Peter to bother you so much, but I think that this is what we need, a united program where basic researchers and clinicians talk on a daily basis.  We have formal meetings and that is the only way to achieve progress, we have to test our hypothesis using cell lines and animal models before
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we move to the patients, but during this process, we need to have ideas and we need to discuss and we need to plan in advance what kind of experiments we will do, and we also have observations for the patients responding to specific types of treatment and will go back to the laboratory and try to understand how can we predict how other patients will respond as well.
Foss              Peter, how exciting is that for you being in the lab to hear what Dan is telling you about the patients responding?
Koo              That is the most important thing in performing the translational science research, because basically the bench to bedside, bed to bench, concept is really the core of this translational research, and communicating with the clinicians like Dan and Dr. Herbst on a daily basis is really important for the functioning of our basic science research laboratory because many findings cannot be translated into the clinic if we you do not do any extra efforts.  So bringing the clinically important questions and problems into the basic science lab, those questions will be the questions that need to be addressed immediately, so that patients can get benefit from those findings.
Wilson          Daniel, obviously there is a critical mass of lung cancer expertise with yourself, Peter, and the others that you have mentioned here at Yale.  What are some of the clinical trials that you are enthusiastic about offering patients?  Obviously what we have here at Yale and at Smilow Cancer Hospital are a little bit different than one might encounter at any other type of standard community hospital for example?
Koo              That is correct, we have great studies and I am very enthusiastic about a study, or a group of studies, being conducted by one of our partners, Dr. Scott Gettinger, with immunotherapy. We are seeing some early responses and we talk a lot about this.  There is a team of researchers trying to find out which patients are more likely to benefit.  We are also just about to open a study led by our chief oncologist, Dr. Roy Herbst, which is called BATTLE-2 for patient with lung cancer. After the first chemotherapy has failed, you will have another biopsy and try to understand why the cancer is growing and that will guide the second type of treatment.  And this study should be opened very soon; we are very enthusiastic about it.  The first BATTLE study was conducted at MD Anderson and was a great success, and the second study will be available only at MD Anderson and our hospital at Yale Cancer Center.
Wilson          Peter, your thoughts on interesting translational things,  we have talked about targeting new discoveries, and new predictions over the years, but with these kinds of things that Daniel has mentioned, how do you see some of those things really jiving and dovetailing nicely with what you are doing in the lab?
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Koo              Yes, certainty not just my lab, but the top notch and cutting edge labs at Yale University and Yale Hospitals and all the combined efforts are really moving the knowledge about the cancers and aberrant abnormalities of the cancer, all these really guide us in a new direction of cancer research which will occur in my lab and also other labs in collaboration settings, and all this knowledge will guide us through next level of treatment and therapy.  I am really excited and I am so happy to be here.
Dr. Peter Koo is Associate Professor of Medical Oncology and Dr. Daniel Morgensztern is Assistant Professor of Medical Oncology at Yale Cancer Center.  If you have questions or would like add your comments, visit YaleCancerCenter.org, where you can also get the podcast and find written transcripts of past programs. You are listening to the WNPR Health Forum on the Connecticut Public Broadcasting Network.