Pediatric Cancer Predispositions
Harry (Adrian) Lesmana, MD, pediatric hematologist/oncologist and medical geneticist at Cleveland Clinic Children’s joins the Cancer Advances podcast to talk about pediatric cancer predispositions. Listen as Dr. Lesmana describes gene predispositions for solid tumors vs hematologic cancers as well as the study he is working on to increase the ability to identify these genes through genomic sequencing.
Pediatric Cancer Predispositions
Dale Shepard, MD, PhD: Cancer Advances, a 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 one and sarcoma programs. Today, I'm happy to be joined by Dr. Adrian Lesmana, a pediatric hematologist and medical oncologist, as well as a medical geneticist here at Cleveland Clinic Children's. He's here today to talk to us about pediatric cancer predisposition. So welcome, Adrian.
Harry (Adrian) Lesmana, MD: Thank you so much for the invitation. Glad to be here.
Dale Shepard, MD, PhD: Absolutely. Maybe to start, give us a little bit of an idea, what's your role here at Cleveland Clinic?
Harry (Adrian) Lesmana, MD: Yeah, so I joined Cleveland Clinic in end of 2020, immediately after I finished my fellowship training. So just to give a background, I was trained as clinical geneticist first. So I did my combined pediatrics and genetics training at Cincinnati Children's Hospital, and then I followed that training with three years of fellowship in pediatric hematology oncology at St Jude's Children's Research Hospital. So my role here, I am a medical geneticist and I'm also a pediatric hematologist oncologist. So my appointment are both in pediatric hematology, oncology, and clinical geneticists. So, as clinical geneticists, we see a variety of other genetic conditions, but because of my background and my additional training in Peds HemOnc, I am focusing on pediatric cancer genetics. I also see adult patients with cancer genetics, but my main focus is pediatric patient with cancer genetics.
Dale Shepard, MD, PhD: All right, so let's start from that point. So pediatric cancers, we're going to talk about pediatric cancer and genetic predisposition. So tell us a little bit about what do we know? There's multi-factoral causes of most cancers. Pediatric cancers, are those more or less likely to be genetically driven?
Harry (Adrian) Lesmana, MD: Yeah, so pediatric cancers, as we all know, is definitely different than adults. The spectrum of cancers in pediatrics is different. And then the underlying drivers for carcinogenesis is generally different than adult. Adult-related cancers usually are multifactorial. There are 5 to 10% that are genetics, but majority of them are multifactorial related to environmental exposures and lifestyle changes. And, in adults, as they get older, they continue accumulating more mutations throughout their life through an exposure to environmental agents or toxin or chemicals, but in pediatrics, they don't have that much of time to accumulate. So, obviously, that's always a possibility that there are some carcinogenic agent that were exposed early in life, but some of these patients actually also were born with a genetic mutation that put them at the risk to develop cancers. And multiple studies that has been done in the past one year consistently identified about 10 to 20% of every pediatric cancers. I'm talking about from birth to a young adult, about 18 to 25 years old, they were born with 10 to 20% of a germline alteration, something that they were born with that predisposed them to get cancers.
Dale Shepard, MD, PhD: When we think about these genetically-driven cancers in pediatric patients, are we mostly thinking about solid tumors or hematologic cancers?
Harry (Adrian) Lesmana, MD: That's a great questions. I think multiple studies identified that as cumulative findings, all together, as you mentioned, is 10 to 20%, but each different type of tumors, they have different rate of finding of germline for dispositions. The highest one that we have identified so far is usually in patients with solid tumor. And again, within that solid tumor, there are different sub group of solid tumors where there are more of this germline for disposition syndromes, certain type of sarcomas, for instance, or even brain tumor. So patient with brain tumor, about 20% actually have an underlying germline for disposition, and we can dissect further. Depending on the pathology of the brain tumor, there are certain type of brain tumor that actually predispose someone to have higher chances of having a germline predisposition. Leukemia is about 10 to 15%. So when we talk about pediatric cancers, the two most common one are CNS tumor or brain tumor and then second one is leukemia. So, certainly, you can see germline predisposition both inside tumor and leukemia, but the person age is different.
Dale Shepard, MD, PhD: And again, just to... because we may have a variety of people listening in to just define some terms. How do you define a familial cancer when we think about genetic predisposition?
Harry (Adrian) Lesmana, MD: Familial cancers, obviously, those are clustering of cancers within a family. So then, we need to define how extensive is that familial relationship is. So we typically define familial if there are involvement in first-degree relationship but involve three generations. So that will say the proband, which is the patient's interest, could be a baby of maybe of 15 months old or 2 years old. And this baby might have a parent or which is one generation above who has cancer or an aunt or an uncle who has cancers. And then one step higher than that, which is the third generation, will be the maternal or paternal grandparents. So those are considered as familial if we can see multiple cancers within that three generation from the patient of interest.
Dale Shepard, MD, PhD: Tell us a little bit about some of the research you're doing in terms of determining some of these gene predispositions.
Harry (Adrian) Lesmana, MD: After practicing as clinical geneticists and seeing these familial cancers, despite very extensive medical genetics evaluations, oftentimes... So we still couldn't identify if there is any known genetic predisposition. So what I meant by extensive clinical evaluation is including a genetic testing, so there are variety modality of genetic testing. There are genetic panel. There are whole exome sequencing or more robust genetic sequencing, but there are still patients or families who are clearly having clustering of cancers in their family, but we could not identify all the genes that we could blame it on. So these are my research interests. My focus in research is actually collecting families with clustering of cancers in their family, but we could not identify a faulty genes at this point.
So, at Cleveland Clinic, I was lucky to be sponsored by VeloSano. I received the grant from VeloSano in 2021 to help funding this study. So we are currently recruiting families who are out there that feel like there are so many family members affected with cancers, but we could not yet identify the germline for disposition. They will be eligible to be enrolled in this study. And what we do in this study is actually we are doing a comprehensive genomic sequencing. Most likely, the samples that we are going to use is blood because it's very easy and accessible. And then we will collect the samples, not only from the individuals within the family who have cancers, but we also collect samples from other family members not affected to serve as the control. So, hopefully, we'll be able to increase our ability to identify these faulty genes through extensive genomic sequencing.
Dale Shepard, MD, PhD: And then I guess, for the purpose of this study, are you focusing on a particular type of cancer, or are you looking broadly at a number of different cancers?
Harry (Adrian) Lesmana, MD: Yeah, so just as a background, there are over 100 different type of cancer predisposition syndromes right now recognized. And the number is actually increasing. As we do a lot more genomic sequencing in pediatric cancers, we tend to identify newer and noble genes. And the same thing with my study. We will not limit the type of cancers that the family has. And even if we look at known cancer preposition syndrome, for instance, the one that quite well known is Li-Fraumeni syndrome or LFS. The type of cancers that runs in the family, it's not limited into one certain type of cancer. They can be solid tumor. They can be hematologic malignancy or leukemia, lymphoma. So I think when we just focus on one certain type of cancer, I think we're going to miss this clustering of families with clustering of cancer. So we are going to look at the family as a whole and not looking at individual type of cancers.
Dale Shepard, MD, PhD: Very good. I guess, just to backtrack a little bit, you'd mentioned that oftentimes you would do genetic screens, you would do standard panels, and you'd miss things. I guess I always have these discussions with patients about genetic testing, and I always encourage people if they're interested in genetic testing to actually talk to a genetic counselor or a medical geneticist. Maybe I can get your take, since we have you as an expert here, the dangers of going to the internet and picking up a test kit and sending it off and trying to do your own research.
Harry (Adrian) Lesmana, MD: So yeah, I think direct-to-consumer genetic testing obviously are very accessible these days. Everyone can order it from their fingertips, and all they need to do is just submit their saliva samples or buccal swab, and they get all the information. So I think we will obviously will not control and don't have the ability to control this, but I think there is a need to educate our community that this result of genetic testings are not necessarily screened or evaluated or reviewed by a medical geneticist or a professional genetics provider. So I think we just need to be mindful about getting all of these results. And if you look at the fine print for many of this direct-to-consumer genetic testing, there's clearly a sign that this is not a recommendation for treatment or plan.
And definitely, there's a danger of doing direct-to-consumer genetic testing without providing a solid genetic counseling, because that can be misleading, and that can create a lot of anxiety, not only for the patients but other family members that might think that they also need to be tested as well. So if they think that there is a clustering of cancers running in their family, and if they think that there are something underlying at this predisposition in their family, I really encourage them to see a medical geneticist or a genetic counselors specializing in cancer patients, because the type of testing that we are sending is not the same one that the direct-to-consumer testing will be done.
So there are certain hints from the family history that might give us a clue, like whether this is a concern for a familial cancer or in germline predisposition syndromes. For instance, if there are multiple family members affected with the same type of cancers or different type of cancers or early onset of cancers... So let's say, if someone diagnosed with breast cancer's in their 30s or early 40s, that's definitely concerning. So, in addition to multiple cancers in a family, you also need to look at their age on onset and then also whether this is the correct sex for that type of cancers. For instance, male with breast cancers is very rare. So if you happen to have that type of cancers, then you would need to think closely if there is an underlying cancer predisposition running in this patient or in their family. And the same thing with children. When children develop adult-type of cancers, that is also concerning. So we have patients that develop leukemia or LGA leukemia, which is very rare in the pediatric sites. That's the type of cancers that give you hints there might be something else going on.
Dale Shepard, MD, PhD: And I guess the other thing to clarify... So anytime we think about genetics and testing, and just to clarify, we more and more, at least in solid tumors, for instance, we're looking at genomic markers and next-generation sequencing of the tumor and looking for keys to treatment, for instance. And sometimes you have to have the discussion with patients that there's genetics that involve the tumor, but then there's genetics that involve you. And so what we're talking about today is more the patient's own tissues and DNA.
Harry (Adrian) Lesmana, MD: Right. Yes. And I think with the advancement of next-generation sequencing and how they are very accessible these days, especially in the adult, it seems like everyone's now ordering tumor profiling for every adult patient with cancers. There is definitely an opportunity from this tumor profiling to identify a germline for dispositions. So when we are talking about tumor profiling, the modern type of tumor profiling is not only including the sequencing of the tumor itself, but we also sequence their normal tissues. So, for instance, for someone with solid tumor, we can collect their peripheral blood as the normal control. By sequencing both of the tumor itself and also their normal tissue, which is blood, there is opportunity to identify mutations that is actually present in the blood, which means that not only in the tumor cells. So that's indicating there's a germline mutations, meaning a germline mutation is mutation that present in every single cells in your body.
With the tumor profiling, when we identify mutation, we always think that the mutation is only present in the tumor, but since we now also sequence a normal, there is a chance that we also identify that this mutation is also present in healthy tissues, which means that it's a germline mutation. So, certainly, there is opportunity to identify, and I think more vendors right now are also reporting germline findings, which can be actionable, meaning the presence of that germline mutations might also predict response to certain type of medication. For someone with BRCA2 germline mutations found from tumor profiling, they might be sensitive to PARP inhibitors. So there are certain type of patient that will benefit from a certain medication when they were found to have a germline predisposition. And that's just from therapeutic standpoint from... And obviously there's also counseling implication. When you find one family member to have a general predisposition, you need to share that. You have the responsibility to share that information to your other family member who might be also at risk to have that genetic information, so possibly that you can offer the same testing to other family members. And if they have not had cancers, there are surveillance guideline for this patient who are identified to have germline disposition and at higher risk to develop cancers.
That's from the adult side. When talking about pediatric side, it's the same concept applies, but it's a little bit more complicated because there's a possibility that we are identifying a germline for disposition for an adult onset of cancers. So from this tumor profiling, you might identify your patient actually has a germline BRCA1 or BRCA2 mutation where they're at risk to get breast cancer. So it poses some ethical issues should we offer this for pediatric patients because technically, they're a minor. And for this type of onset disease, we don't typically offer for minor or carrier, unless it does impact their management at that time. So I think the key to that question will be a good genetic counseling. So we always need to counsel our family. Even before sending to more profiling, we need to educate them there's a possibility of finding a germline predisposition, not only for this current cancers but for other cancer in the future.
Dale Shepard, MD, PhD: That's a great overview. And it's a good example of things like BRCA and maybe risk for subsequent cancers. I guess, when we think about the work that's been done previously to identify some of these predisposition genes, has it had the biggest impact on screening, on selection of treatment, early diagnosis? Where do you think this has made the biggest impact so far?
Harry (Adrian) Lesmana, MD: I think, so far, if we talk about adult, I think there are some data out there that the identification of germline predisposition affect treatments, so we certainly started seeing that. We, in the past, always think that identifying germline predisposition are not really affecting their treatment but more of surveillance for future cancers. But there are certainly data out there that the identification of germline predisposition potentially altered their treatment options. I would give you one example, for patients with leukemia, for instance, a patient with leukemia, pediatric leukemia... I'm talking about childhood leukemia... some of this leukemia can develop because the child has a germline disposition to develop that leukemia. One instances of genetic condition where they are predisposed to get leukemia is Fanconi anemia. So a patient with Fanconi anemia, they are at risk to get AML and a solid tumor when they grow older.
So by finding this germline for disposition of their condition, meaning that we find that the patient actually has Fanconi anemia, we will modify that treatment option when they are undergoing treatment for their leukemia. And if the patient happens to be needing bone marrow transplantation, we need to modify their conditioning regimen because they will fall apart if you use the same conditioning regimen as if this patient doesn't have a germline predisposition, because their cells will be very sensitive to certain chemotherapeutic agent, and they will sustain too much of toxicity from the chemotherapy. So their germline findings might inform the best potential conditioning treatment for transplantation. That's just one example.
And obviously, that's from therapeutic standpoint and, as I mentioned earlier, there's also benefit from counseling other family members and informing future cancers. And as far as surveillance goes, unfortunately, not every cancer predisposition has a clear cancer surveillance guideline or a well known or well-defined cancer predisposition syndrome, such as Li-Fraumeni syndrome. Clearly, we have a well-defined surveillance guideline, but these are not always available. And this is the role of how medical geneticists or cancer geneticist, who meet with the family, inform the result and discuss their risks for cancers and come up with a surveillance guideline that is reasonable to be followed by the family.
Dale Shepard, MD, PhD: What do you think are the biggest gaps that remain in terms of making forward progress? Is it coverage for testing? Is it access to medical geneticists? What do you think are the biggest gaps that remain?
Harry (Adrian) Lesmana, MD: Yeah, great question. I think the answer is, all of the above. So I think access to genetic testing is certainly still a problem. We might not see that as much here, if we are talking about Cleveland Clinic because everyone has pretty good access to genetic testing, but some other states, outside of Ohio, they might not even have a genetic counselor, especially those specializing in cancer genetics. So, obviously, access to genetic testing and genetic counselors or any genetic providers are still limited in certain part of the world as well, not only talking about United States.
Coverage, talking about coverage, I think, in the adult world, there are clear guidelines, especially from the NCCN, as far as who can get genetic testing, but there are limitation on who can get this testing covered because most payers will only cover testing if it's mandated by the NCCN guideline. And clearly, NCCN guideline is not the most comprehensive guideline out there. And I'm glad to hear that I think with the Cancer Moonshot 2.0 that was recently launched again by President Biden, there is more money delivered to do more studies and investigation. And I think the goal is to have a more open guideline to make genetic testing more accessible, not only for those who have cancers but also other family members who might be also at risk, because current NCCN guideline only mandates those affected but will not cover the relatives who has cancer. So I think expanding that coverage will also help us making sure that the delivery of care is reaching more patient populations as well.
Dale Shepard, MD, PhD: So, as you've noted, there's a need for more research, and I'm happy to hear that VeloSano is supporting your current work. I'm going to shamelessly promote VeloSano as the medical director. So if people want to find out more about what we're doing in terms of getting money for cancer research, then go to https://www.velosano.org/ and learn more.
Harry (Adrian) Lesmana, MD: Yep. And I think we have upcoming events in the next few months.
Dale Shepard, MD, PhD: Well, thank you for being with us today. You've provided some great insight.
Harry (Adrian) Lesmana, MD: Thank you for inviting me.
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