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MedConference 2012


What has the heart to do with clinical trials?

Medical and ethical considerations

Dr. Canetta:

I have chosen this title for my talk because I believe that ethics is one of the most misused and abused words in the medical literature and otherwise. There is hardly any difference between sound medical and sound ethical judgment. Conflicts of Interest and disclaimer declaration: a pseudo disclaimer says that I have already solved the problem of cancer, thus I am personally unaffected by it: It’s evident that this is not the truth, but this is a way to exemplify how ideology can manipulate a self-evident truth. The truth is that, irrespective of who pays our salaries, we are part of society, we are part of the system, we are part of life, and everybody contributes to the process of healthcare according to their specific knowledge and capabilities.

These are basic considerations. The important thing is that, clearly, what we do know is much less than what we should know. And that we are daily humbled by the fact that there is a reality that it is much bigger than what we think. Of note, this applies to research as it does to many other situations in life.  Knowledge starts with amazement and with hope. I was trying to find the most appropriate English language term to describe this, and that term is ‘fascination.’  I can assure you that in my job I am really fascinated by the things we discover, we uncover, we learn. Even if we are not speaking as scientists, we need to approach reality with this type of awareness. And true awareness poses even further questions. When you realize that what you know is less than what you should know, you cannot stop there. You are prompted to ask more and more questions by looking at the reality you are faced with. This is the case whether it is a problem of a single cell, of a tumor, or of the whole patient. In our field, asking questions of these realities is what we call clinical research. Let me clarify that I believe that this is the job of anybody who is involved in patient care. Not only of the physician, not only of the principal investigator, not only of the academic institution, not only of the industry’s department of clinical research. Everybody who practices healthcare and medicine needs to ask questions about the reality of the disease, the reality of the patients, the reality of the questions that suffering is posing to our society.

Last but not least, in this business competence is not optional. We always say, and this was evident from the movie “Red Beard” by Kurosawa we all watched yesterday evening, that there is no passion (for the science, for the medicine, for research) without compassion (for the patient). This is absolutely true. But it is equally true that there is no real compassion without passion. In other words, to be good  people, good natured people, is not enough. What our patients need is much more. And if we are serious about that compassion we need to nurture a passion for research, for discovery, and for improving the experience of the patients we want to take care of. Now, what we are doing in clinical research is that we develop standards of treatment. And, in this country, standards of treatment, whether it comes to drugs or devices, involves a Government agency, the Food and Drug Administration. In other countries it involves ministries of health and other health authorities. Basically, any treatment that can be sold is a treatment that has to be approved by a monitoring health authority.  In order to prove that a treatment is safe and effective, normally it involves the demonstration of an effect on certain end points. You heard, yesterday Dr. Costa speak of a number of potential endpoints in neurology. In oncology, there are several accepted endpoints: prolongation of overall survival is one.


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Delay of disease progression is another one. Durable tumor burden reduction is yet another important end point, as well as improvement of the patient’s quality of life.  Now, what the drug is approved for is listed on the label. The label constitutes the contract between the government and the sponsor—the manufacturer— for it to be able to sell the drug. Why do I say that? Well, because the authorities regulate the commercialization of drugs but they do not regulate or mandate the practice of medicine. Sometimes we use drugs whose indication is not on the label although, by law, this use cannot be the subject of advertisement. Often off-label use of drugs is not reimbursed by health insurance companies or organizations. However In the U.S., there is a mechanism whereby if there is sufficient scientific evidence to support it, the use of off-label drugs is both legal and reimbursed. But, it has to be listed by a specific small group of highly selective compendia documents.  Now, when we conduct an experiment as a sponsor of a new drug, this is possibly the most intensively regulated segment of industry. I can only think of the FAA (the Federal Aviation Agency) as being as strict and as regulatory as our health-related regulatory agencies. And, we are constantly under regulatory scrutiny as a sponsor or as people that use experimental drugs. The authorities need to approve the experimental drugs that we administer and often also the laboratories we use to assess their effect. Institutional Review Boards [IRBs] must review on a regular basis and authorize what we do. In addition, we ourselves, as sponsors, need to review what our investigators and their research nurses are doing. And then there are even independent data monitoring committees. Clearly, there is an incredible scrutiny of everything that is to be done with patients that involves experimental treatments. And, of course, nothing is being done without the consent of the patient or, in the case of minors or incapacitated patients, of the appropriate legal representative.  Despite all of these structures of oversight, at the end of the day the patient is still the weakest, the most fragile subject in clinical research. Why is that? Well, because the patient depends upon a number of factors, pathological, physiological and psychological factors. The patient also depends upon us—the healthcare providers. The patient demands effective and safe therapy, and, increasingly, the patient demands appropriate information. Today’s patients are much more informed and much more eager to seek information out as compared to what was the case many years ago.  So, with this introduction, I will talk about a personal experience in clinical development that involves three of the drugs I have worked on. This is not a commercial. This is not an advertisement. I am not using brand names. It is about my personal experience. And, I have been told and taught to speak about personal experience.  I will start with dasatinib. It is a small molecule tyrosine kinase inhibitor. And it is approved for the treatment of chronic myeloid leukemia, including its accelerated and blastic lymphoid and myeloid phases, and for the treatment of acute lymphoblastic leukemia—Philadelphia positive. Just for you to know, chronic myeloid leukemia is a neoplasm of the myeloid line. Until 15-20 years ago it was a disease that brought to death the majority of the patients. Only a minority of patients with the then existing treatments was able to reach remission. And this remission often was short lived. This was happening until imatinib, a predecessor of dasatinib, became available. The development of imatinib was the work of Brian Druker, as the main investigator, and of Novartis, as the sponsor. What imatinib did was to increase the percentage of responses from 20% to 80%, and their duration was also sustained for many years. We had not seen these kinds of responses for years and years before. We know today that selected patients who had been in complete molecular response with imatinib after several years can stop any treatment without recurrence. However, 60% of them relapse very rapidly, indicating that viable leukemic cells are still there. So, imatinib is a great drug. Despite it is a drug manufactured by a competitor, I always remind my colleagues to never say anything bad about this drug. It is a fantastic drug, however it has some weaknesses.


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What happens when chronic myeloid leukemia develops, two chromosomes fuse themselves— chromosomes 9 and 22. And they give birth to an abnormal chromosome that produces a protein, which is called BCR-ABL kinase. Imatinib is a compound that reaches a part of the BCR-ABL molecule, binds to the protein and inhibits the abnormal protein production. As the abnormal protein is what makes leukemia cells grow, its effect stops and therefore the leukemia cells die. However, there is a problem. And the problem is in a particular segment (loop) of the BCR-ABL protein.  In this segment, which is difficult to access by imatinib, mutations can occur that enable continued production of leukemia cell growth stimulation Thus, these mutations are often responsible for the relapses of the disease.  Our dasatinib was able to reach that loop, and basically provided a way to treat the patients who have already developed resistance or would develop resistance in that segment. It has been now proven by comparative clinical trials that dasatinib is more effective than imatinib.  Now, the reason I am showing you this is because it is a beautiful piece of science that came from Charles Sawyer from the University of California in Los Angeles. But there is more beautiful science: when we went to test dasatinib in human beings we could actually measure whether our drug was doing its job, through the measurement of the phosphorylation of another protein (CRKL) downstream of BCR-ABL. When you give the drug twice a day you maintain a complete inhibition of the target. If you give it once a day, you see a reactivation of the production of the downstream protein. So, we decided to select for further development a twice a day treatment schedule. And the drug got actually approved, initially, with this twice-a-day regimen. But, the reason why I show this is because, as I said at the beginning, you should always challenge reality, and let reality challenge you. So what we did was a very, very, very simple thing: we looked at our patients and at their data. These were patients who entered in the phase I experiment. Twenty-one patients were given a once-a-day and 19 a twice-a-day regimen. What we realized was that those patients who were getting the drug once a day were not doing any worse than the other patients. And, actually, we saw that they had a better tolerance to treatment.  So looking at the patients and taking the patient as the heart of the issue told us that we could challenge even a beautiful piece of science, which we did. And the way we did it was by designing a larger clinical trial. We invested in more than 600 patients with chronic myeloid leukemia, and they were randomized to receive dasatinib either once-a-day (with a lower dosage as well) or twice-a-day regimen. And, guess what? The lower dosage, once-a-day, won and that’s what is today included in the label of dasatinib. Each of the treatment arms produced a similar efficacy effects. And in the safety, the profile was much better for patients who received the drug once-a-day. What is the teaching of this story? It is that you can challenge the science, if you start from the patient and with the awareness that you know less than you think you do.  P.S.: just for the record: when was last time you heard about a pharmaceutical company investing a large amount of money in a research study after the drug had already been approved for decreasing the recommended dosage? Hmm…think about it! Cetuximab is another type of drug. It is a monoclonal antibody that targets the epidermal growth factor. It is currently approved for the treatment of locally advanced and metastatic head and neck cancer and for the treatment of metastatic colorectal cancer without K-ras mutations. Basically all of the carcinomas of epithelial origin are fed by the epidermal growth factor. So a drug like cetuximab that blocks the receptors is fantastic, because then you take away the nourishment from these carcinomas. However, the response rate (i.e. the tumor size shrinkage) of these tumors to cetuximab was not 100%, not every patient benefitted from the treatment. So, what was going on? Well, we were treating these patients, we were looking at these data and we started asking questions. And, in fact our research group is one of those which led this research activity. We found out that there is in colorectal cancers a


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mutation of the gene K-ras, which is a way by which the tumor escapes the blocking of the epidermal growth factor receptor. And what a mutated K-ras gene does is basically the activation of a different pathway that keeps the tumor growing even when the receptor is blocked. It is a sort of by-pass mechanism. Mutations of the K-ras gene affect about one-half of the patients with metastatic colorectal cancer. So we looked once again at our patients, we looked at our data in patients with far advanced colorectal cancer. Only in the group with wild-type (i.e. non-mutated) K-ras gene did the patients benefit and experience prolonged survival when they received treatment containing cetuximab. Patients with mutated K-Ras gene did not live any longer than those not treated with cetuximab, and, moreover, were exposed to the cetuximab side-effects. Thus we applied for a restriction of the cetuximab label to focus on patients with non-mutated K-ras. P.S.: think about when was last time you heard of a drug company doing a study to give less of its drug (meaning to 50% of the patients) when the drug had already been approved before for 100% of them…. . The third drug Ipilimumab is a completely different beast. It is a monoclonal antibody, but it is not directed against cancer. It is directed against our T-lymphocytes. And our T-lymphocytes are the custodians of the immunological memory and they can activate themselves against tumors. Tumors are very smart though, and hide themselves by telling the T-lymphocytes, “I am a friend and not an enemy.” And, some of the T-lymphocytes believe that; and they believe that because they are induced to express receptors such as the CTLA4 receptor that prevent them from recognizing the tumor as a foreign aggressor. Ipilimumab has been approved for the treatment of metastatic melanoma. Now, there are several ways to aggress a tumor. You can attack a tumor by damaging it directly (radiation or chemotherapy), by denying the tumor nutrients (hormonal or targeted therapy) or you can attack the tumor by waking up the immune system to activate itself against the tumor. When we started treatment with ipilimumab of patients with melanoma, many of them had an increase of their tumor lesion. Normally the dogma in cancer treatment is that if the tumor grows, you need to stop treatment. It is useless to continue. But with these patients what we noticed was that without changing the treatment, without introducing different therapies, we saw at times remissions that followed tumor growth. It happened once, then it happened twice, then it happened with many more patients. The only reason I am saying this is that by looking at the patient and by keeping the patient at the center we were able to uncover something that is now changing the practice by which we administer certain treatments. Because now we have ways by which we can ask the question, “How can you tell that it is ok to continue treating my patient if the lesions are increasing?” Well, what we did was that we reviewed our entire database–of hundreds and hundreds of patients. We were able to codify some of the patterns of immunological response. It might actually take months to reach that level of response. One would think that our bodies need the time to “wake up” the T-lymphocytes and initiate an immunological response. So we published these results and made them available to the scientific community. And today these criteria are being used by many investigators.  Before the advent of this type of novel therapies, the median survival for patients with metastatic melanoma was about 6-8 months, with only episodic occurrences of long-term survival. What we see today with this type of treatment is a good proportion of about 20-30% of the patients who are still alive after several (4-7) years of follow up. Did we find immortality? No, these patients, sooner or later (hopefully later) will die like we all will die (also hopefully as late as possible…). Are these patients cured? We don’t know–probably not, because some of them have tumor nodules that reappear from time to time. We biopsy these nodules and often they contain tumor cells, but their host, the patient, keeps on living for years with the tumor without seeing symptoms increase. This is not an episode because we have thousands of patients who had a diagnosis of metastatic melanoma who are now alive


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for more than two years. This is unbelievable. When I was much younger we had treatments for melanoma that were really despicable, and palliation was the only therapeutic goal achievable. Now, there are 2 ways to look at this: 1) you could say: this is a triumph for science and medicine. It is indeed a great promise, or 2) you can look at the survival graphs and say that there is a great mercy in this curve because no one has ever seen anything like that. But then you start looking at the left part of the survival curve, where you have the patients who do not benefit from treatment. And my question is: what can be done for the patients that don’t do well? These are the patients who die within two years: why are they dying? Don’t they have enough time to mount an immunological response? Are there factors inhibiting the activation of their T-lymphocytes? This is what we do for a living—we keep asking questions because reality is posing questions continuously. And we must take these questions seriously.  Ipilimumab induces toxicities because when you wake up lymphocytes (you dress them up, they are ready to go) and if they don’t find the tumor or if the tumor is not where they are looking for it, they go crazy in the organs they would normally live—the gut, the skin, the endocrine glands….and they can make damages there. So, treatment with this new type of drugs needs a particular type of monitoring for side effects. And also a particular type of treatment for these side effects, which is often very different from the treatment that a normal oncologist would give to address the same side effects but with other types of drugs. So the education of the oncologist and of the nurse as well as of the patient is part of our job. It might be less visible, but this is also part of clinical research. You need to take into consideration all of the factors.  I could go on forever today, but I will only mention a couple of aspects of clinical research that are frequently reported in these days in the press, lay or scientific: 1) Use of placebo therapies: administering a placebo when there is no existing effective treatment is justified. We prefer to use a placebo by adding it to a treatment that is the standard of care. So that in any case the patient will still receive an active form of treatment, even when assigned by randomization to the placebo arm. In any case, best supportive care is always the standard even when patients are assigned to the placebo-containing arm of a study. 2) Access to promising experimental therapies: If a patient doesn’t qualify for a research protocol, you have often patients or their families who demand unrestricted access to experimental drugs. On the legal side, the U.S. Courts have ruled that this is not a Constitutional right. The patient does not have right to demand, buy, or obtain an experimental drug as he or she wishes. There are strict rules that apply to the use of experimental treatments. I can tell you that I have personally denied access to experimental drugs to certain types of patients that in my judgment as a physician, as a professional, were not suited for receiving them. As hard as it can be, we still need to keep the patient at center of our judgment and to apply what we have learned because that is our responsibility.  Our responsibility (and here I want to go back to something that was said yesterday and also in prior medical conferences) is to test and generate options of care. Whenever we come up with new treatments we generate options. But, the worst possible scenario I can think of is when physicians tell the patient, “Ok this is your vending machine, you have five options and there are five buttons to push. I will leave and you can choose on your own the treatment you want.” This type of approach takes the very relationship with the healthcare provider away from the patient, leaves the patient more alone and even more at the mercy of bogus information, and it avoids our responsibility. Our parents have paid for our education. We spend year after year studying medicine, nursing, surgery, doesn’t matter. We are professional and our responsibility is to utilize this knowledge so that we can propose to the patient what we as professionals believe is the best for the patient. The patient can always say yes or no. Offering a proposal is part of the human relationship we have with our patients. This is a medical, not an ethical issue.


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Now keep in mind what I said at the beginning. It is clear that what we know is less than what we should know. And therefore there are many medical needs that are still not met. You can make an idol of the science or you can look at it with the proper, adequate point of view of fascination. Look at reality and ask questions.  The patients are the essential source of our knowledge: we cannot rely only upon beautiful molecules, cells in a flask or mice in a lab. We do all of this because of the patients. And then the medical needs of our patients, met or unmet, are only part of a much broader human need we all share. Thank you for your attention.

I am just going to go quickly through my own personal experience in clinical research to which I was introduced to a large extent by that trial that Renzo talked about when he asked me if I could be its Canadian investigator. And that was my introduction to clinical research. I am a surgeon—a breast surgeon. I have a laboratory in which we focus our studies on how cancer forms but slowly and surely through the pressure, so to speak, based on experience with patients, but not only patients, with friends and family, I became more and more interested in translating the findings we find in the lab to the bedside. And I thank Renzo for giving me that opportunity ten years ago.  This is why I do clinical research. This is a patient, not one of my patients, but a patient from one of the clinical trials. And that arrow points to the little holes where we did biopsies on the tumors. We did the biopsies for research. We weren’t giving the patient new treatment at all. We wanted to find out what happens to the tumor when it becomes resistant to the treatment. This next picture is what happened in time to this patient, a really sweet lady: the tumor grew. And we took more biopsies at that time to study what had happened to the tumor. So that constitutes a good part of my research. Now there are three faces here of people very dear to me: the one on the left is my cousin whose anniversary of death is today: she died two years ago today, of metastatic breast cancer. She lived for 9 years with metastatic breast cancer. It was pretty bad in the beginning. It came back quickly. She was 35 if I’m not mistaken, maybe 36. Then it was gone, responding to treatment but it came back a year later. Treated again and then came back a year later. It came back a year later, and was treated again. And every time I was there, I wanted to do something but I couldn’t. I wanted to take a biopsy and see what molecular changes were in the tumor. But, the technology was not there. Even if I took a biopsy and were able to sequence it, I could not do anything about it. You know the kind of information Renzo was showing about the mutations K-ras, it really wasn’t all that available or only available for a few drugs. The middle person in the picture, some of you know her, died 11 months ago today and she also had metastatic breast cancer. She was a great fundraiser for our hospital and we became friends. And she had the same story: for 16 years her metastatic breast cancer kept on coming and going. I opened a clinical trial at a certain moment and she became really excited about that, but then I realized she wasn’t eligible for that trial because it was for a different type of breast cancer. She was very disappointed because she really wanted to help. And, I will come back to that. And the third one at the age of 32 died about 4 months ago and we attended a memorial service two weeks ago. She also had metastatic breast cancer for about 5 years or so. So this contact with these patients, these friends, really led to this question of what can I do in the face of this recurring, relentless disease? Why does it become resistant to therapy? That is the case with most of these cancers—they become resistant. Why? This is why people die of cancer because the tumor becomes resistant to all of the therapies thrown at it.


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St. Bernard gave reasons for why one would do research: curiosity, vanity, profit, charity, and wisdom. So with time, one hopes that charity and wisdom will dominate our motivation and in fact inform how you are with the patient. So clinical research is neat because you have the interplay between biology and medical care. It is really fascinating. It’s an experiment in which the clinical reality of the biological alteration is tested in humans. Bedside to benchside and back bedside and then back to bench, to understand why the observations in the clinic make sense. And the reason ultimately we do this is thinking of the patients, the love of the patients, since charity is the gift of self moved by the other.  We have to think of patients while doing research. When you’re doing research the question always comes up, why are we doing this? What is the point? What is happening in clinical practice? Let’s not do something crazy by asking questions that have no relationship at all to what is happening in the real world. So much science is being done in that way. Clinical contact really focuses your attention to what is real and allows you to learn from it. I want to go back to Jerome Lejeune. We heard Clara, his daughter, so eloquently, so beautifully talk about this yesterday, quoting her father about people with Down Syndrome: “They want to kill us and we are unable to defend ourselves. You must defend us.” As abortion became legal in France, he wrote in his diary, I am paraphrasing, “Now that abortion has become legal, the only way left is to cure them and quickly. So, I will devote all of my energy, both day and night, using physiology, molecular modeling, biochemistry to find a way.” It is incredible that he would do research in the context in which most people would have abandoned it a long time ago. Because how can you cure Downs syndrome? Downs syndrome is an extra chromosome in every single cell in your body. How can you change every cell in your body? And if you go the other way—it happens at the very first cell of the body, you can’t see the very first cell in the body. You can’t do anything. Yet he was so convinced. As he said, a Christian knows that the universe is made in the image of God as we are. And that is why we can relate to it. He had this incredible indestructible hope, because of this Christian conviction that God made both us and the universe. And as you heard yesterday from Alberto Costa, people are working on finding a cure for Down syndrome today and with today’s technology we have a better chance.  I work on biomarker research. What are biomarkers? They are these molecules, factors inside the tumor and inside the blood that allow us to predict whether the treatment will work or not work, or whether the patient will live longer or shorter. Take a look at the drug taxol in breast cancer studies: you see that you actually have an advantage in giving this drug to women with breast cancer as there is actually a small increase in survival, which is about 5% at 5 years in this study population. It is significant. You want to give this drug if there is a possibility of 5% increase in chance of survival. The problem is that 95% of those women do not potentially benefit from that. A lot of women are resistant to that drug. Those are the ones that will die despite giving the drug. And then also a lot of them don’t need the drug. They will survive without the drug, without all of its toxicity, but we don’t know who these women are. And it goes back to what Renzo said about looking at the left curve and saying, “why do they not respond?” The same with other drugs; it is the same with all of oncology basically. There is always a survival advantage or gap where things work and above this gap on survival curves are the tumors that become resistant quickly. And below are the patients with tumors that don’t seem to need therapy, and they do well regardless. So we need to better select patients for therapy. A lot of times a patient is treated and the only effect is the side effect. And this actually has ramifications socially and economically because precisely the example that Renzo gave with cetuximab in K-ras shows that we are saving approximately $6 million per year by identifying the patients who won’t benefit from this drug.  Then we have to link research in the lab with the patient. That is what we do, called translational research. We try to bring these lab findings to the patient. And then what we learn from the patient is then studied back in the lab. But there are many pitfalls: the complexity of human beings, not just of the tumor. Obviously there are many factors that affect tumor biology and response to therapy. Also,


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for a research finding to be true it has to be reproducible and reproducing these kinds of clinical studies that Renzo has talked about to see if it remains true in different populations is expensive, time consuming, and, of course, in this case, it has a human cost. Here is an example. A few years ago a biomarker for this drug tamoxifen was found. Basically what it showed was that women that metabolize that drug faster do better. These are the results from the Mayo Clinic. So it is wonderful if we have a way to select which women with breast cancer will get the drug: we will give it to those women who metabolize the drug really well and not give it to the women who don’t. So, my patients would come to see me and I would spend a half-an-hour discussing these things with them because of stories like this in the media where the Mayo Clinic is recommending this gene testing for women with breast cancer who are about to be given tamoxifen therapy. Yet, this was not yet validated. This was just one study. When further studies were done we found that it this is not a very good marker for tamoxifen. It was not validated! So often for reasons that are strange to me but it seems to happen again and again, the findings in science, especially in clinical research, but not only, seem to be always more true the first time than the 2nd or 3rd or 4th time the study is repeated. Sometimes it remains true and we use those drugs, of course. But often that is not the case. So a lot of the science doesn’t make it and this involves a lot of patience, a lot of money, a lot of suffering on the part of the patients participating in clinical trials.  To help avoid such mistakes, the Institute of Medicine has come up with these very strict criteria about how to bring biomarkers into the clinic. You can see that this is a very complex thing—you have to keep on repeating things, making sure the test is working, and then repeat again, and so on and so forth. And to make all of this work, most of the time you need a tissue sample—you need to take a piece of the tumor.  Tumors grow, tumors evolve. They are never the same a year later, especially because there has been some drug that has changed them. Or just the mere growth of these tumors will result in their evolution. So you need tissue samples to check your molecules. And they need to be of good quality. In my laboratory, we have spent a lot of time looking at that and trying to figure out how to do that properly. What we are doing in one of my bigger studies right now is actually taking 4 biopsies from a tumor. And also regular blood samples. We have had to figure out when to take those biopsies, how to take those biopsies, what to do when those biopsies are out (i.e., how to process them, how to use them, and how to store them). Each one of these is a different step, and it has taken quite a bit of work to figure out. And it is not very scientifically exciting at all, but it is necessary. All of the work that follows will build on this quality control process. Here is one of the studies we are working on. It involves asking women with metastatic breast cancer for biopsies of their tumor at time 0 prior to treatment. The patient is then treated. And then, as is usually the case, the tumor will, at first, shrink or respond to therapy, and then it will no longer respond and begin to progress. At this point we do another biopsy, the same as at the beginning. Breast cancer can spread to the liver, lungs, and the skin. So, it is not always easy to get to these tumors and it’s going to be a painful procedure. And don’t forget that we are doing this just for research, not to treat the patient. There is no benefit to the patient at all.  Another study that we are doing that is a bit easier. This involves patients that still have the tumor in the breast, before it has spread, and who are waiting for surgery. We do a biopsy of the tumor, we give a treatment (chemotherapy), and then do another biopsy of whatever tumor is left after the chemotherapy. Because we do the biopsies of the breast, it is much easier and much more accessible. But on the other hand we are asking these patients to be treated before surgery. That is psychologically a bit scary because you have this tumor sitting there and you are getting treated. What if over time the treatment doesn’t work. You still have the tumor there, which may be growing. So that is scary. On the


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other hand, what we have noticed is that, most of the time, the tumor shrinks before our eyes. So it is really a positive experience for the patient as well. So these are the kinds of issues we have to deal with. Coming to the patient: there is a lot of pressure to help support research. And there are a lot of walks and other activities to raise money for research. Here is an example, “The Weekend to End Women’s Cancers!” Well, the truth is that women’s cancers will not end. Cancer will not disappear. But as Renzo showed, perhaps we can live with cancer and control it, such as what is being done with AIDS right now. However, thanks to these events in the media, the patients are very much open to research and they want to contribute. In fact, this has been called the “perfect marketing success story.” We actually had a sociologist look at some of our patients and questioned them and asked them how and what it was like for them to participate in this type of research. They asked why seriously ill patients would want to participate in research that might be burdensome and with no direct benefit, as with my research biopsies. So, we found that patients are very willing to volunteer for this research fundamentally because of altruism. They recognize the benefits of today come from sacrifices that research volunteers made in the past. This is true. Reciprocity, was another answer. “After all of the doctor did for me, when he asked me I just couldn’t say no.” And, convenience—there are no new treatments, no new side effects, it’s a relatively fast procedure. Trust, trust is so important. A patient responding to the doctor on the first time meeting, the patient asked the doctor, “Do you believe in God?” The doctor responded, “yes.” The patient said, “Yes, me too. Let’s work at this together.” I put the faces now of the women who are asking patients to participate. This person, Carole, spoke at this conference a few years ago. She is such a human person and she and the others are able to talk to these women and tell them about the research biopsies that will be added to her regular diagnostic biopsy. And the people at the top are people from my lab.  On the other hand, this happiness to help in research is not always the case. This is an email that one of my patients sent to me and to my colleagues about 6 weeks ago. Saying “You are a great doctor” etc…, “But I think I would have been better off without the treatment. Why did you treat me? I am going to die in any case [which is not true]. As a layman I was naïve. You are more interested in the research than the consequences for the patient.” We have to ask ourselves, is this true? I want to end with a quick case: a 55 year-old woman with a 2 cm breast cancer, spread to the lymph nodes. She needed chemotherapy. And so, I very much like the idea of doing preoperative chemotherapy both to understand the biology of the tumor and to see how she would be in the future.  If the tumor disappears completely with the chemotherapy, her prognosis is excellent. So that is naturally what I would like to propose. At that time, there was also a study testing a new way of examining the lymph nodes at the time of the surgery. This is a new diagnostic test that we could use on this patient and so I usually propose it to these women to see if they could participate in this. It’s an extra little injection on the skin and a little bit more work for me but not much.  And it would help to tell us whether this test would work or not. As I was going with the plan and I heard that the patient had been sent to an oncologist. The oncologist said, “I don’t want to treat this patient preoperatively, I want to treat her after. Why? Because there is another study here that is going to test if adding a new drug to her chemotherapy when it is given after surgery can improve her survival. So then here I was, clearly my lymph node study just doesn’t have the value of this other study because her survival is at stake.


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So, these are the kind of ethical situations we are in where what is tested is: what is important, what is of most value to you, who do you love more, what do you love more? Is it indeed the patient or not? Why do you do what you do? This is in a sense what propelled me to talk to you this morning–these kinds of issues were coming up about “What really urges you to do clinical research? Why do you do this?” The future is looking very complex. As tumors are being sequenced now, we are learning that each and every tumor is quite different from the next. So different, that ultimately every tumor may require its own treatment and it’s going to drive Renzo crazy. In fact, a patient was being treated at my hospital with a drug developed by Renzo’s group. The drug failed in clinical testing, except for that one patient. And so, the company decided to continue to produce that drug just for that one patient. The patient survived years because of that drug. And we are going to be seeing that more and more. How we are going to be able to adapt business models for drug companies to these kind of situations, which will be more and more frequent, I don’t know.  In conclusion, love for the patient is what urges us to do clinical research. Keeping the patient’s well being above any other goal, within a relationship of trust between you, the physician, you the healthcare provider and the patient. And most patients are willing to undergo research just for altruistic reasons, and mostly because of this trust.