Rania Habib, MD (Host): The American Cancer Society estimates that around 10,000 children under the age of 15 are diagnosed with cancer each year. Due to major advancements in both cancer diagnosis and treatment, 85% of these children are expected to survive five years or more.

This is Transformational Pediatrics with Children's Mercy Kansas City. I'm your host, Dr. Rania Habib. To accelerate precision medicine for pediatric oncology, Children's Mercy Kansas City, together with its research institution, CMRI, pioneered a new genetic test for all children diagnosed with cancer. While many pediatric research institutions in the country conduct genetic sequence of tumors, CMRI is one of the few institutions performing both research and clinical sequencing in-house on both tumor and normal DNA samples.

Here to discuss these sequencing techniques is Dr. Lisa Lansdon, the Assistant Clinical Director of the Molecular Genetics Lab at Children's Mercy Kansas City; and Dr. Midhat Farooqi, a molecular pathologist and the Director of Molecular Oncology for the Department of Pathology at Children's Mercy and also for the Genomic Medicine Center at CMRI.

Thank you both so much for joining us today, Dr. Lansdon and Dr. Farooqi. We're very excited to discuss this unique genetic testing.

Lisa Lansdon, PhD: Thank you so much for having us. We're excited to be here.

Midhat Farooqi, MD: Agreed. Very excited. Thank you.

Host: Dr. Lansdon, you and your colleagues at Children's Mercy developed a genetic test for children newly diagnosed with cancer or for cancer patients who experience a relapse. Tell us about this test.

Lisa Lansdon, PhD: Sure, I would love to. So, for this new sequencing test that we established, what we have done is designed it to take DNA that is derived from the tumor or the cancer of the patient, as well as DNA that we can extract from the non-cancer cells or the healthy cells in that individual. So then, what our team does is we use this DNA, we sequence it, and we're able to do a comparative analysis of the sequence variants that are within that cancer as compared to those that are in the germline or those healthy cells.

And, so why this is such a powerful approach is that it really does restrict our analysis to just the cancer cells themselves. And by targeting these sequence level variants within the cancer, we're able to gain information that can be really relevant to the patient's diagnosis or give prognostic information or additional targeted therapeutic information. And then, we're able to create this integrated diagnosis for our patient that really is specific to the tumor. In addition, we're able to offer the germline or again, that healthy cell variant detection and so, there are instances in which these kiddos are predisposed to cancer development. And so, we can offer that testing as well because we have the sequence data available from those healthy cells.

Midhat Farooqi, MD: And what I think I would add is, as you mentioned, children, thankfully, are expected to survive. And given their age, they're expected to survive many more years than an adult with cancer would be. So, having this type of testing allows for more targeted therapy to be given potentially. So, this therapy is specifically attacking genetic variants that are present only in tumor cells. Standard chemotherapy kills both tumor cells and normal cells. You know, it may attack rapidly dividing cells, for example. And so, it has side effects that a child who has survived cancer has to deal with over their lifetime. And it's a much higher burden than say someone who's 85 years old and has gotten cancer. In that setting, you can be more aggressive and maybe less cognizant of what will happen 20 or 30 years down the line. But for children, that scenario is very different.

Host: Absolutely. So by targeting that specific genomic sequence, do you feel that there are less long-term consequences and side effects compared to just the chemotherapy that's attacking the healthy cells and the cancer cells?

Midhat Farooqi, MD: For certain drugs, yes, absolutely. It allows for tumor cells to selectively be killed, leaving the normal cells intact, so there is less of a burden sort of across the body, compared to standardized chemotherapy. That's not to say that precision or targeted therapies don't have side effects, but it's one potential advantage of doing the sequencing upfront.

Host: It's fantastic technology. Dr. Farooqi, could you explain how whole exome sequencing is different from other genetic cancer testing?

Midhat Farooqi, MD: So, whole exome sequencing allows us to look at all parts of the genome that code for protein. So, they're thought to be the important part, or at least those historically in genetics that have been associated with a disease. So, you get a mutation in a gene that then leads to a protein change in function, and that is what causes the tumor to form or another disease to occur, an inherited disease, for example.

So, having it be whole exome-based allows us to look at all genes in the genome that could potentially have a mutation. Not all of them are associated with cancer. But the main advantage for us is rather than having to keep designing a test as new genes got associated with cancer, this has all the genes, at least as far as we know, upfront already being captured and sequenced. So, historically in the past, I guess I'll show my age a little bit, so say, 10 years ago, we were designing very targeted panels, looking at 20 genes. And this would be great until maybe one year later. And now, there were 20 more genes for which there were targeted therapies available. This is more on the adult side. And the pace of this was increasing each year. So, it's a big burden on the laboratory to have to keep designing these tests and clinically validating these tests over and over again. The whole exome-based test allows us a certain nimbleness to we can say, "Okay. Well, this gene was newly discovered as having an impact for pediatric cancer, and we can just take a look at it because it's already in our test and available and analyzable".

Lisa Lansdon, PhD: Agreed. And so, this is a really powerful approach for our patient population, especially as additional findings are coming out every day for our pediatric population. And so, one of the other ways that this whole exome sequencing is different from some of the other cancer testing that's out there is that Children's Mercy already offers a lot of the gold standards in pediatric cancer testing. And so, this is both in terms of pathology testing that's performed as well as cytogenetic analyses. And so, this would be looking at these larger gains and losses or what the actual underlying pathology of a tumor looks like, for example. But then, what this test now offers is even more of a honed-in view into the genetic sequence level variance.

And so now, with this team, we're able to really give our clinical providers a more integrated diagnosis overall, touching on both the pathology, also the cytogenetics, but now these molecular genetics, where we can continue to evolve with any sort of research publications or other clinical publications that are coming out with the testing that we offer.

Host: That is fantastic. So, Dr. Lansdon, how does this whole exome sequencing benefit your patient population?

Lisa Lansdon, PhD: So, what this whole exome sequencing really does, and as we've touched on a little bit previously, is that it allows for this very tailored analysis for each patient. And so, it's tailored in a way that we can take that specific tumor from a specific patIent. And we're able to come back to the providers and say that this patient has exactly this genetic mutation within their tumor. And we think that it means this in terms of prognosis or that in terms of a targeted therapy. This can be hugely informative in terms of clinical trial enrollment or how aggressive those clinicians feel like they should be in trying to treat a particular tumor.

What's also amazing about this particular test is something that I don't think people usually think about, but it's that a positive test isn't always something that is the most important. But what we're finding is that this test can also inform pertinent negatives, where there are different genetic mutations in a tumor that might have a very, very poor prognosis, for example. And if we do not find those in our exome sequencing, we're able to bring that information back to the clinicians and providers as well. And so, that clinical team can say, "Okay. It looks like overall this patient might have a better prognosis than would be expected should one of those underlying genetic mutations be present in that particular tumor type."

Midhat Farooqi, MD: Yeah. Lisa stole my answer. So, historically, that has been something that the field has potentially struggled with, is the initial definition of sequencing its success, was based on whether or not a variant was actionable. So, you would sequence a lung cancer, and if you found an EGFR mutation, then that patient could get a specific drug that targeted it and it was "actionable." But I feel the view that we take of sequencing is that, just like a negative checks x-ray telling you you don't have pneumonia is useful, so it is with sequencing, knowing which variants are there or are not there, at least as far as what we can detect, is equally useful. It can give you a sense of good or bad prognosis, or it can tell you what drugs you cannot use, because that genetic variant was not detected. In addition, we find that it helps find types of cases that are not well captured by the existing tests that we offer. So, for example, children who have variants that are mosaic, so they are present at a lower level, and so standard tests don't necessarily pick them up well. The advantage of a combined approach is that we can look for what variants we expect to be there in the tumor, and then go look at the normal cells to see if they carry this in a mosaic state or not. So, we've had a few patients that would have been shown to maybe not really carry a variant, but in doing this sort of comparative analysis, we were able to find it.

Host: That's fantastic. Dr. Farooqi, how many children do you expect to be positively impacted by this sequencing?

Midhat Farooqi, MD: Well, for us at Children's Mercy, it would be about 200 patients each year. We see around 250 or so kids a year with newly diagnosed disease. About three quarters of them would have the tumor type and the sample that would benefit from the sequencing data. We, again, are trying to do this for every child that has been newly diagnosed or has newly relapsed with a pediatric cancer and have had phenomenal support from the institution to be able to do this. But from a sort of bird's eye view, it would be many, many more children. It's a little bit difficult to estimate the exact number. But for children who are identified to have hereditary predisposition to cancer, that affects their entire family. It affects their other siblings. It even affects their adult relatives. We had one child where this family of multiple generations and tens of individuals spreading back over time had this undefined history of acute leukemia. And we found the variant that sort of explained this phenotype in the family.

And then, stepping back even further, we also do this on a research basis for patients that enroll in our tumor bank study as part of the CMRI. This was started by a pediatric hematologist-oncologist physician, Dr. Erin Guest here at CM. Now, it's been going on six years. We've enrolled almost 600 patients onto this study. We've sequenced so far 200 patients, both their tumor sample and normal sample as part of the study. And we shared this data with researchers across the United States and across the world, through the National Cancer Institute and the Childhood Cancer Data Initiative. So, all of these research data are widely shared and available to benefit children.

Host: That is so impressive.

Lisa Lansdon, PhD: And as Midhat mentioned, we do feel like there are many children within our region, country, and even the world who would benefit from this type of testing. And not to get into too much of the nitty gritty, but just to give some numbers as an example, what we've seen so far since the initial launch of our test is we've managed to sequence and analyze over a hundred patients now. And over 50% of those have had what we would consider a clinically significant finding. And so in kind of the somatic cancer variant interpretation space, and again, not trying to get too technical, but within that space, that would be something that would have been sort of a tier one or tier two. The parallel that people are a little more accustomed to hearing would be something considered to be a pathogenic or a likely pathogenic variant. So, really informative for that patient's cancer. And so far in over half of those tested, we have found that type of finding. And that's not even pointing towards patients where, again, those negative findings are also informative. So, this has already been hugely impactful and we only anticipate that the impact of this testing will grow.

Host: Absolutely. And the impact that you guys are having just based off this test is incredible. I will pose this question to both Dr. Lansdon and Dr. Farooqi. What's next?

Lisa Lansdon, PhD: What's next? Well, that is a really exciting question. and we both feel that the sky is the limit. So, this is sort of building a foundation, if you will, within our molecular genetic testing space for our cancer patients. And so, based off of this paired tumor normal exome-based assay that we have newly established, now what we can do is we can build additional tests from that. And so, some of those that we're planning on launching this year, likely within the next couple of months even, are in collaboration with our clinical pharmacological team here at CM. We are launching pharmacogenomic testing. And so, that's going to help us tailor different drug dosages appropriately according to various genotypes of different genes that are relevant to pediatric cancer therapies.

In addition, we're going to start looking at tumor sequence variants in a more global way. And so with these types of tests, we're looking at things like tumor mutational burden or microsatellite instability or even genomic scar scoring. And so, each one of those will tell us something a little bit more about the tumor and its overall profile or how we expect it to act. But then more importantly, there are targeted therapies that can be utilized should there be high tumor mutational burden or high microsatellite instability, for example. And so, what we're going to be able to do is start to take this existing data from our sequencing tests, our exome sequencing, and then start to build and layer more of these other tests on top that will be informative for our patient population.

Midhat Farooqi, MD: And also excitingly, on the research side, we are applying new techniques of sequencing and genetic analysis to try and get more answers for children with cancer. So, these would be things like long-read sequencing or 5-base sequencing, also chromatin configuration or Hi-C sequencing to pediatric cancer. The reason for doing this is currently, I would say about 10% of our patients go through clinical testing and they don't really have a genetic answer for their cancer. They don't have a genetic driver, if you will. And in kids, we really expect to find a driver. We do for, you know, 90% of children, either through cytogenetic testing or pathology testing or this new sequencing test.

So, why these other 10% of kids develop cancer, but we can't find a driver for them is an outstanding question. You know, we don't have a lot of kids who are heavy smokers or drinkers, but you can't rule out environmental exposure, sure. But we are coming at this from a premise of that there should be a genetic driver there that we should be able to find. So, we are hoping that the application of these more novel sequencing techniques will help us identify a genetic driver for these patients that currently are, at least from a clinical cancer genetic standpoint, uncharacterized.

And for the previous question, I would like to add that the genetic sharing of data was something that was really espoused at a high level by the CMRI. It was a goal to share this data with everyone. And it was very supported by our collaborator and partner in the University of Kansas Cancer Center, for which Children's Mercy is the pediatric arm. So, KUCC was the one that really facilitated us being able to apply for and receive the grant that gave us the resources to share the data with everyone.

Host: It definitely sounds like it's a multidisciplinary team really working for this common goal, and it's really wonderful to hear all the exciting research. As we wrap up, Dr. Lansdon, what is your take-home message for our audience?

Lisa Lansdon, PhD: My take-home message, that's a great question. I would say that that this is a really exciting time in pediatric cancer genomics. As you mentioned, it is a very interdisciplinary field, especially with the teams here at CM. What's been so exciting on our end is to be able to come together with all of these different colleagues and work towards a common goal of helping children with cancer. That's where we are so excited to have launched this clinical test to better benefit these patients and really try to help them to the best of our abilities.

Host: Dr. Farooqi, what would you like to emphasize for our listeners?

Midhat Farooqi, MD: I would like to say to please support sequencing in general, especially for children with rare disease and with cancer. It is extremely vital for patient diagnosis, prognosis and therapy. It gives a lot of useful information, whether or not you find the genetic variant, as far as what the predicted outcome would be for this tumor in a given patient, and also for whether or not targeted therapies would be available.

Host: Dr. Lansdon and Dr. Farooqi, thank you so much for joining us today. It's been such a wonderful amount of information that you've given to our audience.

Lisa Lansdon, PhD: Thank you so much for the opportunity to speak with you. It has been a pleasure.

Midhat Farooqi, MD: Thank you so much for having us.

Host: To refer your patient, or for more information, please visit childrensmercy.org to get connected with one of our providers. To learn more about this exciting research, please visit childrensmercy.org/research. Please remember to subscribe, rate, and review this podcast and all other Children's Mercy podcasts. I'm your host, Dr. Rania Habib, wishing you well. This has been Transformational Pediatrics with Children's Mercy Kansas City.