 Our last speaker is Dr. Jonathan Maren. Dr. Maren is an instructor in pediatrics at Harvard Medical School, a clinical ethicist at Boston Children's Hospital, and an attending physician in pediatric hematology oncology at the Dana-Farber Cancer Institute in Boston Children's Hospital. Dr. Maren's research focuses on clinical genomics, ethics, medical uncertainty, and informed consent. He's been the recipient of various awards, including the American Society of Clinical Oncology Educational Scholar Award and a Harvard Medical School Certificate of Excellence in Teaching. His recent work focuses on patient, parent, and physician decision-making and pediatric precision cancer medicine. Before going to Boston, Dr. Maren was a both the McLean fellow, but he also spent a year working with Mark as one of his research assistants. And today, he's going to give a talk titled Ethics and Communication in the Precision Medicine Irrepediatric Oncology. Please join me in welcoming back Dr. Maren. Thank you so much, Laney. Yeah, so in many ways, this is a little bit of a homecoming for me because straight out of undergrad as somebody with no marketable skills, because I was pre-med, I didn't know what I want to do with a year off before going to medical school, so I came in, worked for Mark as his research assistant. Mark worked me into the ground as he is wanted to do. But it made it very clear for me even more than it had been before how exciting the world of clinical ethics is. I went on to medical school and did my residency in pediatrics before coming back, as Laney said, to be a fellow here. And then I've gone off to Boston, where I now get to be faculty at another ethics center, someplace on the East Coast. So it's wonderful to be back with all of the colleagues and mentors and professors that I've had in the past. So today I'll be talking about something that I've been working on over the past handful of years, ethics and communication in the precision medicine era in pediatric oncology. So because this is a clinical ethics conference, let's start with a case. Let's consider for a moment Billy, who's a six-year-old boy who's just been diagnosed with his third relapse of rhabdomyosarcoma, which is a very aggressive soft tissue cancer. At this point, with this being his third relapse, there are no curative treatment options. Billy has widely metastatic disease, but presently he has actually a very good quality of life. When he'd relapsed the last time, he'd had tumor genomic sequencing, and as a result, his clinical team now has in hand the sequencing that Laney spoke about a little bit earlier, but looking specifically at his tumor rather than his germline sequencing. Billy's medical team tells him and his parents that the sequencing found an actionable target. There aren't any human studies, but there's a study agent that shows promise with this target in animal studies. Billy's mother responds to this, that drug sounds like Billy's best chance of cure. Let's do it. This is something that happens nearly every day in the pediatric oncology clinic. So a few questions that I hope to address over the course of the next couple of minutes. So one, what is this admittedly abbreviated conversation tells us about Billy's mother's understanding of everything that's going on? What does it tell us about her informed consent or the possibility thereof? How does precision cancer medicine impact communication and informed consent in the world of pediatric oncology, which in some ways we think of as the ideal circumstance in which to use genomics and precision medicine because if we could find a drug, not just our standard cytotoxic chemotherapy, but a drug that worked on the Billy mutation in his rhabdomyosarcoma, that would not only presumably be much more effective, but with our fewer side effects. How do we talk about that based on these expectations, these hopes, but also the reality of where the science actually is today? And finally, what can and perhaps even more so, what should pediatric oncologists do about all of this? So a quick aside, because we're talking about ethics, this is a pediatric session. Informed consent doesn't really exist in pediatrics. When we talk about informed consent, we're usually talking about something that the parent is doing for the child or on behalf of the child. Sometimes this is referred to instead as parental permission. We'll have hours and hours of long discussions about is parental permission. The same thing is informed consent, is it a completely different entity? Notwithstanding, ascent is incredibly important and actually quite unique in the world of pediatrics. But for the sake of discussion for these next 15 minutes or so, I'll be using the term informed consent to refer to sort of an agreed upon decision between the child and the parents, though as the pediatricians of the room know, unfortunately that is not always the case and that's when things really get sticky. So Beecham and Childers put forth the idea that there's seven individual pieces of informed consent. These can be broken down to three larger elements. The threshold elements or preconditions, the information elements, and finally the consent elements. The era of precision medicine and the complexities therein really hit on each of these different pieces. So speaking to capacity and voluntariness, the patients who are considering precision medicine in the pediatric oncology setting are extremely vulnerable. These are ones who haven't responded to standard treatments. I hear often in the clinic, parents saying, what else can I do? Though it's not coercive per se, it certainly is a situation in which there are large questions about vulnerability and that's perhaps acting upon that vulnerability and perhaps not being able to make fully informed decisions by the parents. In the second area, in the informed information elements, disclosure, recommendation and understanding, hugely often, we will see massive amounts of miscommunication, of misunderstanding, of blurred lines between what is research, what is clinical care, what is a little bit of both of those and I'll get into each of those things in just a couple of moments. And finally, when we think about the actual consent elements, decision and authorization, far too often in this hurried situation of a patient's cancer having come back, we wanna do something now, we wanna do something right this instant, or else we can't do anything. We'll hear things like just sign here please, which for everybody in this room knows that is not informed consent by any stretch of the imagination. An oncologist that I work with in Boston, who will remain nameless, has told me time and time again when I talk about the work that I do, patients and parents just don't get it. Informed consent in oncology is unattainable. While there probably are nuggets of truth in this and I'll get to some of the data in a moment that's at least in part support this, I hope that this is at least a little bit of a cynical and exaggerated look at the actual reality of things. Former clan fellow Rick Kodish 15 years or so ago did demonstrate some of the data that informs this statement in oncology clinical trials. Rick and his team demonstrated that exactly half of patients, excuse me, of parents of children with leukemia don't understand randomization at the time they're considering enrolling their child onto an actual randomized controlled trial. So really understanding the fundamental piece of what they're about to be engaged in was lacking. Furthermore, in phase one trials, so the earliest of early phase clinical trials, only 32% under a third of parents demonstrated what was defined as substantial understanding of the trial's scientific purpose. And 35%, actually greater percent, demonstrated little or no understanding of that concept. So clearly there is some lack of understanding, some misinformation about these very important and fundamental concepts in the world of clinical oncology research. Now in the era of precision medicine, perhaps not surprisingly, we're seeing similar data emerge. In a study that we did a couple of years ago, we found that over half 59% of parents and young adult patients who underwent tumor sequencing as part of a clinical trial, hoped that doing so would increase their child's chance of cure. This in the setting of the fact that they were told very explicitly, the goal of this as research is to learn information that we can use going forward, not to help your child or to help you. Nearly three quarters hoped that it would provide a greater number of treatment options, though when this was all done, the likelihood of that was actually quite slim. Furthermore, 32% nearly a third stated that the main purpose of the tumor sequencing study, again, a research study that was intended to find data going forward, not to help the people enrolled in it, was to improve treatment of themselves or their child, and nearly one in five stated that the most likely result of their participation was an increased chance of cure, nearly one in five. We still don't know exactly what the true answer to that question would have been, but probably less than one-tenth of that one in five. So why might this be? Why might there be this huge discrepancy between what we can provide, what is thought that we can provide, and the communication between those two? So let's come back to our case with Billy. Billy's team told him and his parents that sequencing found an actionable target. In response to this, mom says this sounds like Billy's best chance of cure. Well, this speaks a little bit to some of the outcomes that we use in general medicine, but particularly in the world of oncology. What are the outcomes of the ones that we look for and what are the outcomes that matter? When we do sequencing studies that are happening all day, every day these days, we're looking oftentimes these report rates of actionable results, but actionable can be one of a variety of things. It certainly can mean we find a mutation that we have a drug for, that drug can hit that mutation and cure that cancer, but that's incredibly infrequent. Much more commonly, it's something about a nuance of the diagnosis, something about a cancer predisposition syndrome, something about a purely, a completely unrelated finding alluding to some of the ACMG pieces that Lainey talked about a little bit earlier. Perhaps not surprisingly, then we see these relatively often. So actionable or potentially actionable results, depending on which study you look at, are found between 39 and 78% of cases. That sounds awesome. And that's why these papers end up in places like JAMA, JAMA oncology, New England Journal, things like that. These are really exciting numbers. However, the likelihood of direct clinical benefit via receipt of a targeted therapy appears to be far, far less often. As best as we can tell right now, this is actually only in three to 19%. So this is the situation in which we find a mutation in the cancer, that there's a drug that acts on that mutation and we may see some effect on the child's cancer. The rate of cure, so survival, do explicitly to the genomically targeted therapy. We have no idea how often that takes place, but it's certainly even less than this three to 19% number. Without a doubt, each of these different types of outcomes are incredibly important. But even more important is being clear. When we as the physicians talk about the outcome that we're looking for, is that the outcome that's being desired by the parents that is at the outcome that's expected when we talk about doing sequencing. At the risk of coming off as a complete skeptic about this, we are seeing really exciting steps moving forward. Immatnem, DLIVAC, a decade or so ago, was one of the first drugs that was really showing that genomics and the application of genomics into cancer medicine was really exciting and really a great possibility for benefit. In the past couple of years, we've seen even additional drugs that have come to market that are showing great promise. Lerotractinib, that you see up here on the left, was published in the New England Journal, is a really promising drug that we're seeing benefits in children. And on the right, you see one of these really impressive changes in an MRI for a new drug in a pontine glioma that previously, prior to this experimental therapy, had really no treatments available. So we're seeing these new exciting steps forward. However, these still are exceptions rather than the rule and we have to be very careful when we're talking to patients, when we're talking to families, that we don't leave them expecting that this is what's going to happen in the majority of cases because these still are unfortunately few and far between. So let's come back to Billy one more time. Billy's medical team tells him about the agent and says that there is promise with this target in animal studies. So clearly the animal is not the patient of the situation but we often have these preclinical data and the question remains, what do we do with this? Be remiss in 2019 to talk about communication and not to mention something about social media. About six months ago on Twitter, there's an account that started called just says and mice. And what this account does in a kind of fun and funny sort of way, it talks about some of the really exciting press releases and papers that come out. This one reads, avocados may help manage obesity, prevent diabetes. Your guacamole may hold the key to managing obesity and helping delay or prevent diabetes according to a new study by a university researcher in mice. That's not a mice how holding that avocado and presumably that press release that says your guacamole is not referring to mice's guacamole but this is what happens in the public press all the time. My own institution puts out these press releases all the time for the Harvard researcher who has now figured out that this new situateness, new thing in cardiac medicine or in cancer medicine is going to cure X, Y, or Z. But what is true in mice unfortunately is very infrequently actually true in humans. That seems quite obvious but the hope of the clinicians can sometimes take over. At the annual meeting for the American side of clinical oncology just this past June, one of the sessions was talking about genomic treatments in pediatric cancer and there was an interactive session where the question was asked, how likely are you to recommend therapy based on promising preclinical animal models when no clinical data is available? Nearly 50% of the pediatric oncologists in the room said either they were likely or fairly likely to do this in the absence of any clinical data. I won't speak to whether this is right or wrong but it certainly raises some questions. And I think some of this speaks to a concept that Chris Feutner and Wyn Morrison wrote about a couple of years ago, this darkening veil of do everything. When I was a research assistant with Mark 15 years ago, if Billy had come into clinic at that point, he would have had absolutely zero therapeutic options available at that time with the goal of curing his cancer and it would be symptom paliation alone. Today because we have so many of these options, these genomic technologies are opening up new doors, we have new standards of care, we have new experimental therapies, this is really exciting for pediatric oncologists and even more so for pediatric oncology patients and families. But it's unfortunately not infrequent that these opportunities can then be seen as obligations which then lead to less consideration of our standard good old fashioned chemotherapy which actually in pediatric oncology usually is quite good. And perhaps even more importantly in a setting like Billy's to discussions about palliative care because we can do something, the implication is that we should do something, can therefore ought. But I think sometimes we need to be a little bit more thoughtful about whether indeed we do want to be doing everything. But lest I could be called a cynic by all of my oncologist friends, I do think that the glass probably is still half full. So some of the research that my team has done over the past handful of years demonstrated that over two thirds of participants in clinical genomic sequencing studies in oncology demonstrated at least a basic understanding of the primary purpose of genomic sequencing trials. So this referencing back to some of Rick's data from a decade ago. And interestingly among those who state that the primary purpose was to improve their or their child's care. So those who at least have some degree of misunderstanding nearly all also identify that it's aim was to benefit future patients. And 93% also correctly recognize that their or their child might not have directly benefited from participating. So there's this balancing act, this duality that patients and families are able to have that perhaps we as the clinicians aren't quite capturing or not quite understanding or at least giving them credit for. In an ongoing study that we're doing at 18 institutions across the United States, we reported some of the interim results just a few months ago, trying to understand do patients and parents distinct have identified difference between what they hope for and what they expect to happen when they undergo tumor genomic sequencing. What we learned is it appears that they do because though 58% when asked what they most hope for as a result of sequencing, 58% said they hope for an increased chance of cure for themselves to their child. Only 21% said that that's what they actually most expected to have happen. Similarly, though only a quarter said they most hoped that doctors will be better able to find cures for future patients, nearly half 45% said that that's what they most expected to have happen. So it appears that a large number of patients and families really have high hopes for these types of technologies but recognize that those hopes might not actually come to pass and their expectations perhaps are more guarded. So ultimately we must make sure that we are working with patients and families to navigate this challenging balancing act when we're communicating goals and everything else in the era of precision cancer medicine. We want to support hope while providing realistic expectations and encourage participation in research studies while ensuring understanding of research and clinical care and the differences therein. And finally we must inform patients and parents what we do and even more importantly what we don't know but provide this information using easily accessible terms in language. Since I know that I'm the last thing between us and lunch I'm gonna script through that summary make mention of my acknowledgements because I do not do this work on my own and say thank you to all of you, thank you. I guess they're hungry. Thank you very much. Just a reminder as we finish this session lunch is in the south green and just because it is a school day and so the law students will be there. We're expected to come back at two o'clock so a little bit over an hour and thank you all very much.