dr mary jane lymphat is a neuro oncologist at the odette cancer center at sunnybrook health sciences and a clinical clinician sorry investigator at the faculty of medicine university of toronto she has a clinical interest in treating patients with cns tumors and neurological complications of cancer including nervous system metastases she also has a clinic clinical interest in young adult patients with gliomas she's a recent graduate of the joint neuro-oncology fellowship program at massachusetts general hospital dana farber cancer institute brigham and women's hospital and harvard medical school her research interest is in using large patient cohort data sets to study the relationship between imaging genetic biomarkers and clinical outcomes in patients with gliomas this presentation will review the current use of molecular and genomic markers in glioma and clinical care and some of the potential benefits and current limitations we will also discuss how these markers are impacting management decisions for specific groups patients with gliomas in particular young adult patients and this topic is the topic that you had submitted for the research grant so uh dr limfat is one of our research grant recipients from 2021 so congratulations to that and the floor is yours to take it over thanks for joining us today thank you thank you so much janik and thank you to btfc first off for the opportunity to speak today and also for this wonderful grant um you know if any donors are on the line this is where your money goes to try to improve outcomes to uh you know all sorts of populations of brain tumors i'm very thankful for that opportunity and for that grant and we'll switch gears a little bit and i also want to thank kylie for sharing her very moving story with us today i think this is the patient perspective that we all need when we talk about what we're doing for research and in the clinics because at the end of the day this is what we're trying to do we're trying to help people like kylie and others on the line to just have you know a better life and and you know much more longer and and better quality time with their families as well so today like i mentioned i wanted to talk about molecular markers in glioma in particular and i just wanted to say that my presentation will talk about some molecular testing that are not necessarily what we call standard of care across all institutions so you may or may not have access to these tests or these tests may or may not have been offered to you and every patient situation is a bit different so speak with your primary team to discuss you know what may or may not be an option available to you so briefly what i was hoping to cover today are these following questions as these are questions that come up a lot in our clinic so you know people hear a lot about molecular testing and gliomas but we don't know you know often which ones are the most relevant ones for each patient so that's an important thing to go over and the next question we often get is how does the testing change the treatment plan or approach to each person's tumor so does it impact your diagnosis the prognosis or treatment considerations and the last thing is does everyone need molecular testing uh understanding that you know within the single peer system in canada some testing may be available uh you know and is covered by ohip but some may not be and does everyone need to undergo the same type of testing or do we have to consider special populations and special needs within different groups so i'll cover all of that today uh but first let's take a step back and talk about brain tumors in general i think this group is uh well versed in this but just to review we talk about primary brain tumors when brain tumors arise from cells in the brain and these are different than secondary brain tumors or brain metastases which are cancers in the body for example breast cancer lung cancer that eventually go to the brain so today we'll be talking about primary brain tumors in particular gliomas and glioblastoma is the most common malignant primary brain tumor it is still quite rare so its incidence is about 4.1 per 100 000 cases per year and unfortunately the overall survival as uh we know for gbm remains quite poor so gbm is the most aggressive one but for sure there are other types of lower grade tumors that have a much better prognosis so we've come to an understanding of these tumors by looking at biomarkers and in particular some molecular biomarkers so taking a step back again to understand how molecular biomarkers have become part of a clinical practice in gliomas i think kylie's stories uh you know story uh did talk about this a little bit in the fact that you know we often require biopsy we we need a biopsy essentially to be a hundred percent certain as to what a type of tumor is we can look at the mri and say this looks like a low-grade glioma as was in her case um but you know to know at a hundred percent we need to have tissue and this can be quite challenging especially in cases like hers where the tumor was in an eloquent area of the brain or in a part of the brain that houses vital function so things like language movement surgeons don't necessarily want to go in there unless they have to because surgery comes with specific risks so we are limited by what we can do and before 2016 how we used to diagnose these brain tumors is that you know after surgery when we have a sample of this tissue pathologists would look under the microscope and see what the cells look like do they look like they're aggressive cells or do they look like they're more benign cells and then grade the tumor based on that from a grade one to a grade four and this is how we get our diagnosis of glioblastoma versus the low grade tumor for example but as you can imagine there was a lot of difficulties with that so first if you're you have a very small amount of tissue and you're not looking in the right place you may under call or overcall well mostly undercall a tumor and you know there can be some variability from and pathologists when they're also reviewing the tissue so it was not a perfect system so in 2016 there was a revision to the classification of brain tumors and that's because we are now using more and more molecular or genetic markers so these are different from looking at the tissue under the microscope we send the tissue for specific mutations and we know that certain mutations are you know associated with more aggressive behavior because tumors acquire these mutations as they become more aggressive so looking at these molecular markers we can now confirm the diagnosis so knowing exactly what type of tumor it is is it a glioma is it another type of tumor convey prognosis meaning do we think that this is a more aggressive tumor because of the genetic changes that it has undergone and we can also now in some cases match patients with specific therapy so there is a mutation for which there is a targeted drug and we think that mechanistically it can help reduce the tumor growth down the line so because this is a little bit uh you know confusing in terms of what we mean by molecular markers and genetic markers i just wanted to sort of go back and explain a few things as well so when we deal with the cancer it is usually because something happens in the normal uh process of cell division the cells acquire a mutation and start undergoing division that is not control and there's a number of mutations that can happen uh from the start of a cell that will lead it to become more aggressive and in some cases uh you know there are multiple mutations that need to happen for it to become more and more aggressive so um certain genes like i mentioned are mutated in cancer cells that are not mutated in normal cells and when we mean when we talk about genetic mutations this is exactly what we mean mean that these specific cells in someone's brain somehow started undergoing these mutations and then became malignant there's often a little bit of confusion when we use the term genetic a lot of people think we mean that it is inheritable or familial meaning that it gets passed down to our kids but that is not the case so it's a mutation that happens within someone's tumor and this is not something that is passed down genetically unless there's a very strong family history of brain cancer for example but that's usually due to another uh sort of inheritable condition and when we talk about someone being a mutant in a gene that means that that particular gene carries a mutation and the opposite of that you know i'm just highlighting these terms as i'll be using a few of them in the next few slides the opposite of being mutant is being wild type so you carry the normal variant of the gene and how do you assess these alterations in gliomas so there are several techniques and many of these will continue to evolve over time we can stain slides to look under the microscope as to whether or not a mutation is present we can do what we call chromosomal analysis we can do also next generation sequencing which is looking at dna and rna and i think some of you may have heard about foundation one medicine and the molecular testing that they do so theirs is a type of next generation sequencing and now uh we are also uh starting to use methylation profiling more so in the research environment but that's another way of detecting molecular changes and again currently not all of these techniques are part of standard of care and some like methylation profiling for example is only available at certain centers for research and the tests can be quite costly so you know if people are paying for example out of pocket for foundation one testing some of their panels typically run uh to the order of a thousand to two thousand dollars um depending on the panel that people pick um so how has the grading and the classification of gliomas evolve in the context of these new biomarkers so first off um we know that we still need to look under the microscope at the type of glioma that we have at the type of cell that's present but the second big branch point and i'm sure some of you have already heard about this is whether or not an idh mutation is present and this is because we know that idh between tumors so the ones over here uh in pink uh tend to behave in a more indolent way and those that do not carry the mutation so the idh welted tumors tend to be the ones that are more aggressive like the glioblastoma that is right here the next sort of big branch point is whether or not someone has a one p19q code deletion this is another biomarker and what this tells us if someone has this co-deletion is that we are dealing with a type of glioma called an oligodendroglioma and this distinction is also important because we know that patients with oligodendroglioma in general tend to do better than patients that have astrocytomas and the way that we treat them is quite different as well lastly another biomarker that you may have heard being used in the care of glioma patient is this mgmt promoter methylation and that one is more relevant for patients who have a diagnosis of glioblastoma and it can help us make treatment decisions as i'll go over in a little bit because having an mgmt promoter methylation will help tell us whether or not we think people will respond to particular types of treatment like temozolomide and radiation so let's now focus on how molecular advances have impacted the cured idh mutant tumor so again we're dealing with this side of the flow chart here which tends to be tumors that behave a bit more indulingly so i'm sure some of you have seen uh mris in the past this area of white here represents this idh mutant tumor and as you can see um it can it is visible but it can look a lot less aggressive or indolent than the glioblastomas that i will show you in a little bit so we this slide looks very busy but all to say that when we look at idh mutant gliomas um after we have confirmed the diagnosis so with a biopsy or resection is when we are able to further stratify them within these groups so to someone's point earlier about whether or not temozolomide was used in kylie's case you know we're not able to make that distinction or that recommendation yet because again we don't know where she would fall within these without a tissue diagnosis and then based on that and based on understanding what type of tumor someone has and based on other uh what we call prognostic factors so things that we think will determine how they do uh with their tumor looking at their age their neurological deficits how big the tumor is and what type of resection they had were able to make recommendations so sometimes that is watching and waiting after surgery and sometimes that is radiation followed by chemotherapy and the type of chemotherapy can depend on the type of tumor that you have so if you have an oligodendrogliomas some centers will recommend getting pcv chemotherapy and some centers also used hemozolomy so that can be a bit of a practitioner-based preference as well so all to say that we are stratifying those molecular biomarkers in conjunction with the other prognostic factors to then make a treatment recommendation but it's not as easy as that so as we've talked about there are a lot of questions and you know again this ties in very nicely with kylie's story because you know we don't know when necessarily the right time to intervene is in these tumors especially in young patients where we have to worry about the side effects of the treatments that we are proposing so idh and tumors are predominantly a tumor of young adults and like i said they can behave indolently and appear radiologically benign so it's perfectly okay to observe them for some time before uh treating them especially if the tumor itself is in a difficult location so ideally you know in a perfect world we would be able to take out the entire tumor and treat it and a lot of the times that treatment can entail radiation therapy and chemotherapy but we know that these treatments also over time can come with side effects so we have to weigh all of this in making that decision one thing i have to mention is that uh there is a lot of uh research and a lot of progress that has been made and not only understanding these tumors but maybe in thinking about other ways to treat them that will maybe circumvent the need for radiation and chemotherapy so we know that idh meeting tumors arise because of a mutation in the idh enzyme so this is where that genetic mutation takes place and then leads to the formation of a low-grade or high-grade idh mutant tumor and if we can just target that mutation or target that mutant enzyme technically we will down the line reduce the formation of the tumor so this busy slide is all to say that you know there are inhibitors that we're looking at on the research front that will be able to specifically inhibit these mutant enzymes and hopefully you know prevent this down downstream activation of the pathway that leads to the formation of these tumors so one particular idh inhibited trial that is worth mentioning as it is now open in many centers in canada including in ontario and vc is this indigo trial that uses an oral idh inhibitor in patients who have low-grade gliomas that have been resected so we're very excited that our patients have been able to go on this study because you know down the line hopefully this is the way of the future that we'll be able to give an oral medication to patients following surgery and then prevent the need for other interventions like radiation or more toxic chemotherapy so as i mentioned the benefits of targeted therapy and idh and tumors uh in theory is that you know we are blocking the pathway specifically at the site that is needed so that you know you would reduce side effects on the whole body or you know from a systemic standpoint from other types of therapy and early phase studies also suggest that these drugs are very well tolerated without frequent significant side effects and they may also prevent therapy induced resistance and transformation of the tumor down the line which we know can happen even when we treat with uh medicate with chemotherapy and with radiation we know that tumors can somehow figure out a way to develop resistance and become more malignant so as i said you know we focused on the left side of the chart earlier we'll look into how molecular markers are now affecting care and idh well type tumors which includes glioblastoma so if you remember the mris i showed earlier where there were small areas of brightness in the mri this is what in comparison at gbm looks like so it can be larger you know more aggressive looking and can actually cross over in the brain um so essentially there are many ways in which molecular markers have helped change management in glioblastoma the very first important way is that it has actually changed the way we define glioblastoma so if you remember earlier i was talking about how we used to grade these tumors by looking at them under the microscope so we would look at the the tissue under the slide to see for example if they look like they were rapidly multiplying if there was signs of what we call necrosis or changes in the blood vessels and that would give you a grading for a grade four which we would then call glioblastoma but we now understand that the grading doesn't equate to the idh status so first off we know that to have a glioblastoma now we need a tumor that it is idh well type so say you have these features that i described and you were graded as a grade four but you had an idh mutation we have to now call these tumors grade four idh mutant astrocytomas we're not calling them idh mutant glioblastoma anymore because we know that what drives the formation of these tumors is quite different in that these patients do much better than the patients that have an idhwa type tumor a true glioblastoma so that's one distinction and then the other on the other hand what we are also now doing again you know going back to the fact that grading is not that accurate is that if you have a grade two or three astrocytoma but you don't have an idh mutation so your idh well type if you have in addition some molecular some mutations so the egf or amplification the terp promoter mutation you can be quote unquote upgraded to a molecular glioblastoma and that's very important because we know that how we would counsel patients on treatment therapies prognosis and clinical trial relies on this accurate diagnosis so all to say that grading has become less less accurate and molecular classification and glioblastoma has become more important so you know just as a refresher or as a primer for patients who are for people who are not you know already aware of the treatment for glioblastoma we typically treat patients with gbm following surgery with a course of radiation and chemotherapy together followed by what we call adjuvant chemotherapy so a period where we give chemotherapy alone without radiation and this is what we've been doing basically since 2005 since this large study came out that showed that the addition of temozolomide with radiation really help prolong survival in patients with glioblastoma compared to radiation alone and the the mgmt comes in here as i mentioned before because we know that this mgmt status can predict even further whether or not we think patients will respond to this strew protocol or to our standard of care so what mgmt is is it's a dna repair enzyme that rescues tumor cells from temozolomide induced damage so the chemotherapy works on the the cancer cells by breaking up their dna and if your dna repair enzyme is working basically what that will do is that it will just undo what the chemotherapy has done but if you have a methylated or defective mgmt you will have a better response to this treatment because essentially that enzyme isn't able to work anymore so we can see here in this survival curve which is basically showing uh that the percentage of patients that are alive at x number of months that the patients that are methylated actually do much better than the patients who are unmethylated so we can see that there is a difference there in the percentage that have survived for example at 36 months and that's important to us because we're dealing unfortunately with the disease still and you're still in need of a cure and where quality of life is extremely important as our patients can have a limited amount of time so putting patients through chemotherapy when you do not think that there's a high chance of success really needs to be weighed against the side effects and patients need to be counseled about this in clinic so as you see the recommendations for management relies now heavily on this mgmt promoter methylation so sometimes if someone is non-methylated for example we'll choose to actually just do radiation alone or we'll choose not to follow up with more chemotherapy after the initial course of radiation i think more importantly you know this is a group where we have now identified a bigger need for clinical trials because we know that the standard of care isn't as effective so a lot of uptrend clinical trials in glioblastoma actually are occurring patients who are mgmt and methylated so knowing that status ahead of time is very helpful and that's one test that i think is now quite routine across all centers in in north america or at least it should be and so the last application of molecular sequencing and glioblastoma that i want to talk about i don't want anyone to get scared by this slide that looks very busy is just again to show that when we talk about these pathways that get disrupted that cause the formation of of tumors we can see here in the white boxes that there are a lot of investigational agents that are being looked at that can target these particular mutations uh within the aberrant pathway so identifying these mutations in each patient's tumor would in theory allow us to know which pathways to target and maybe which clinical trial which drug to try in patients down the line so so that's sort of where we are aiming to be hopeful in the next five to ten years where we can identify a specific you know area of dysfunction and treat it right at that area so to show you what an exceptional responder to targeted therapy looks like uh this is a patient of mine that i saw dana farber uh that had this mutation in this b-rock v600e gene and she had an adult type glioblastoma and as you can see here this was her tumor which is bright on her mri and she was started on a targeted treatment because this mutation actually is is quite common in other cancers like melanoma and and we do have agents that they use in melanoma to target this this mutation we were able to study it in a clinical trial in patients with glioblastoma and we can see here that her tumor actually responded quite well to this treatment and she actually maintained that response for close to a couple of years so she eventually recurred but you know that provided her with a long time of what we call progression free survival and it's it's a much uh much better of a track record that some of our other treatments have had and she tolerated this beautifully as well it's an oral agent that she was taking uh every day but no significant side effect and as you can see here objectively the tumor actually almost completely went away so then i think that the next logical question is should we be looking for targetable mutations in all glioma patients so this is a question that i've been personally very interested in because you know the system here in canada is very different than uh the one that i trained in in the states where basically you know most patients could have access to this at a center with specialized cns oncology but it's much more difficult here in our single peer system because these are not necessarily covered by ohip as they are not yet changing the standard of care so you know are the the nccn guidelines which are the guidelines in the us that provide uh guidance on how to deal with uh brain tumors in general they do recommend that we complement the standard analysis by with a molecular information however i think here in canada we're still behind a little bit in that not all of these tests are available for all of our patients we know that these panels like in like i mentioned can cost up to several thousands of dollars depending on the mutations that are offered on each panel and the challenge is really that while some actionable mutations can be found like the case that i showed you uh these are quite rare still in brain tumor patients so that b rav v600e mutation for example is only present in less than five percent of glioma so not a lot of patients will have that there are certain groups of patients that are more likely to have it such as young adult patients so i think the important thing to remember when we look at the cost and the value is that you know it may not benefit all patients alike but if we do find a target and there is a drug but it can really change the management in some of our patients so one patient population that i mentioned that benefits the most from molecular testing are young adult patients because we know that their tumors are biologically very different from the ones in older adults so the typical glioblastoma for example may not benefit as much as pediatric type tumors that are found in young adults so this these are just some examples of some tumors that i think you know have a potential where molecular stratification or molecular profiling can actually help change management therefore i think it becomes much more relevant to try to find these uh markers and mutations and young adult patients so anyone who has a diagnosis i would say under 40 should you know ideally in a perfect world have access to more molecular testing so outside of their biological differences a reason why i want to highlight young adult patients today is that we know that the mortality rates across adolescent and young adult cancers and and by that i mean anyone who's aged from 12 to 40 has declined overall but increase in cns tumors and cns tumors are unfortunately a main cause of cancer-related morbidity in these patients we know that these are patients that often transition from a pediatric to adult center and they can be lost to follow up if they are just sent back to the community so they really need to be seen at specialized centers so we need uh to have a multi-disciplinary care uh for these patients so i think you know we alluded to social work support earlier a psychosocial support neurocognitive assessments uncle fertility discussions these are all needed in patients who are younger and are diagnosed with a brain tumor and and the these patients are still quite underrepresented in clinical trials and that's something that uh you know our our brain tumor group as a community needs to really change in the future and i think that's why um i think uh btfc's uh community uh can really help in in highlighting these issues in young adult patients with brain tumors as well so in an effort to address the gaps that i just mentioned we started an initiative in toronto which i'm really happy to share with you guys today which is our adolescent and young adult cns oncology consortium so these are rounds that we are now holding that are basically across canada uh where we um a group of practitioners come together to discuss challenging cases of young adult patients with brain tumors so for example if we were to take kylie's case you know we would show her images and there would be a panel made up of neurosurgeons and neuron oncologists and radiation oncologists that would discuss for example the benefits and the risk of going for surgery in her case and then usually you know the the presenting physician is the one who sees the patient in clinic and brings forward her case and then um provides a recommendation to the patient after we found this extremely beneficial because as you can imagine getting multiple opinions on cases like that is extremely helpful but also for patients on which we have tissue and we can identify specific mutations we are then able to brainstorm and talk about clinical trials that are available at the different sites about treatment strategies et cetera et cetera now i mentioned that sometimes it can be very difficult to obtain molecular testing and the way that our group has been able to overcome that is that we actually applied for a grant to get money to pay for the molecular testing for the pieces that are presented at rounds so it's really become an evolving project that is really translating into the clinic and impacting clinical care and something that i think would be really interesting to push forward in terms of advocacy down the line to further illustrate this growing movement to study and improve outcomes in young adult patients i want to highlight a few projects that are happening in the adolescent and young adult glioma space so there's a project right now looking at low-grade glioma over time from julie bennett at sickkids there's also a big funded project looking at young adults with brain tumor over time and seeing how they progress across their cancer journey and lastly again to put my little plug-in and thank the brain tumor foundation of canada this grant that i receive will look at assessing molecular clinical and imaging predictors of response including neurocognitive outcomes and young adults with low grade glioma so this is something that i look forward to sharing with all of you again hopefully in a few years when we have collected more data so in the last few minutes let's summarize where we are in terms of molecular markers and what we should be looking forward to so here's what it where i think we are in 2021 so we've identified that molecular markers can help us with refining diagnosis we know that targeted therapies are sort of the next big hurdle to overcome if we can find better therapies that can be effective then we'll really be making our way here where we can use this uh these molecular markers to be able to help every single patient with a brain tumor find the right therapy for them at the right times but this this should really be the goal here the challenge though is manifold and especially around this little mountain here because uh even if we find some agents that do well in the lab so on animal models etc it's quite challenging to actually deliver everything to the brain because of the blood-brain barrier and clinical trials can take time especially in a relatively rare disease like glioma so we need to turn a lot of patients and observe them over a long period of time and potentially test out many different agents to really find a good one that works so so this is actually uh you know quite uh significant when we talk about the barriers to finding effective therapies in glioma so how are we making strides in all of these areas so there are now new methods of drug delivery to the central nervous system and one of them is this technique called the focus ultrasound which was actually spearheaded on the world stage at sunnybrook and we now have a number of different trials that are open looking at opening up the blood-brain barrier and administrating treatments for patients with either newly diagnosed recurrent or recurrent glublastoma or cns metastasis so this is something that hopefully you'll hear more about down the line and we can start testing out other drugs in combination with focus ultrasound to ensure that there is a high concentration of the drug that reaches the brain and the tumor so another way that we're improving uh our trying to get to finding more effective therapy i should say is that we're refining clinical trials to improve efficiency so one big trial that is now open at sunnybrook and princess margaret and that the m i is called this uh it's called the gbm ad agile trial where we are using a rapidly adaptive trial with multiple arms at a time and a lot of interim analysis so we look at the data before we reach that end point to try to optimize the amount of time that someone has to be on these trials in order to make a meaningful conclusion so using this uh you know schema and improved platform for trials we should be able to reduce the time to get to meaningful conclusions but also reduce the amount of patients that we need for clinical trials and lastly there's a need to improve and encourage research outside of clinical trials and this is an important point to stress because it's not mutually exclusive patients can be a part of a clinical trial and also be part of a non-clinical trial research study and i think collection of patient data over time and databases for example can provide helpful information in rare diseases such as glioma and this is why at sunnybrook we have launched an initiative where all gliomas will be sequenced and patient outcomes and imaging variables will be captured to better help us understand how these molecular predictors affect things like survival but also quality of life neurocognitive function etc also hopefully down the line we'll be able to incorporate what we call non-invasive biomarkers so looking at biomarkers in blood and cerebrospinal fluid to give us more information lastly i would just like to drive home that every patient can make a difference as collection of this data over time uh like i mentioned will really help us come to better conclusions uh when it comes to the evolution of gliomas in general so in summary testing for molecular biomarkers is important for an accurate diagnosis in brain tumors and in the future it will help match patients to the right therapies or clinical trials again we're not there yet but i think this is where we should be heading and patients can contribute to research and biomarkers which can improve our understanding of the evolution of brain tumors and um again this may in particular benefit young adult patients a group of researchers currently lacking and last but not least i think advocacy groups such as btfc can really help improve access to biomarker testing in canada and especially to ensure that as we implement this we are not causing more disparity in access as we move towards making this testing available for everyone in canada and lastly precision and collaborative care in cns oncology is here patients have a major role to play specifically in research and advocacy and the time is now so um this uh is all for my presentation today really just wanted to thank first and foremost all of our patients and their caregivers you are the reason for which we are uh involved in research and we are in clinic um so thank you for your support and for being strong advocates for yourselves and for your loved ones i would also like to thank the cns oncology group at the odette cancer center and at sunnybrook and also to my colleagues across u of t and my partners across ontario and canada and last and not least to the btfc again for your support and for the opportunity to present today thank you so much dr lymphat that was a great presentation and you really explain things in a way that um let me show my video here that helped us understand so thank you for that that consortium that you guys have put together for the adolescent and young adult groups that's that's such an amazing collaboration excuse me at brain tumor foundation of canada we do offer programming for those two populations so if there's any if there's ever any opportunity for us to come and speak to the to the consortium i'm sure our support team would be uh would be open to that to sharing the different resources and and programs that we do do for adolescents and young adults now uh the last few years so we do have quite a few questions that have come through so i'll just read them to you if um you're good for for staying on for a few more minutes absolutely yeah so the first question was why the difference between practitioners using temazolamide and those using pcb yeah that's a great question you know the the data this uh sort of variability really has to do with the fact that we have not done a clinical trial that compares these two head to head meaning you know radiation plus temozolomide versus radiation plus tcv in patients with either astrocytomas or oligodendroblima there is a trial that's underway but as you know because our patients survive for a very long time you know we won't have results from this trial for another decade maybe um i would have to say that it's not a canada thing you know when i was in the u.s at dana farber they would prefer one regiment and that mghd would prefer another regimen and that also has to do with the fact that we know that temezolomide is better tolerated but that pcv has in theory better data in terms of the survival so we always i personally always discuss both with patients i know sometimes you know there's a bit of a balance touching upon the point of you know the provider has to make the decision for the patient but i think sometimes it's a two-week conversation and we come to that decision together so i always explain that you know we have better data for pcv temozolomide is much better tolerated we haven't done a head-to-head comparison but my recommendation would be to go with x or y thank you another question was could a chemotherapy that has been clinically proven as to not have any effect on a wild type non-idh mutant gbm tumor negatively impact the quality of life if taken by a patient who has already gone through standard of care treatments as well as surgeries so i don't know if you're referring to taking the temozolomide in an mgmt unmethylated tumor in which case you know we always discuss um again the data with patients oftentimes in the absence of a clinical trial i will still try temezolomide in an unmethylated tumor because again we don't have any better treatments or trials to offer and there's not much to lose if they are otherwise tolerating it okay so we monitor their blood counts we monitor their symptoms and if they're they're doing okay we would try at least for a couple of cycles to see how they do that's been my approach anyway again because there hasn't been anything better and we know that the data we have again you know it's based on a number of population a sample but at the end of the day you know i you cannot guarantee a hundred percent if this patient that you have in front of you just by these markers is going to behave like the rest of the curve so i think to give patients the benefit of the doubt we often would then try it anyway okay thank you um do you know when the data from the indigo trial might be published yeah so they have some interim data that is being you know discussed at conferences in which there seems to be a pretty good response rate of these idh inhibitors i suspect that the actual trial will wrap up sometime around summer of next year and again we'll have sort of small updates but the actual sort of wrap up will probably not be for another year or so i suspect at least or even longer perhaps thank you says university of sherbrooke is developing gliotraff for diffuse gliomas if you have any um any thoughts around this potential treatment yes i'm not sure exactly what that trial or study is i would have to look that up because again you know we have different trials named different things but you know for sure i think everyone right now is very interested at looking at molecular markers and precision medicine and targeted therapies a good thing would be to always and that's what i encourage all of my patients to do is to just bring the information to your next appointment and if like me your physician isn't aware of this particular study we tend to look them up and discuss them with you thank you do we use mgmt mechanism for treatment by affecting temozolomide sensitivity can it be used for early stage detection as well um so we're using it more again now to sort of help us predict whether or not we think patients will respond to the standard of care treatment so it's not helping in the diagnosis per se it helps more you know once you have a diagnosis to understand whether or not your tumor is going to respond to treatment down the line we hope to explore ways to actually change the mgmt methylation or affect that pathway so that we can make tumors that are currently resistant to treatment may be more resist more susceptible to treatment i think that would be sort of another nice bullet to have in our treatment of arsenal for sure thank you um following surgery why not administer agents directly into the tumor so so people are looking at that you know intra-tomorrow tumor injections and tritamoral virus injections a lot of clinical trials have looked at that too so putting chemotherapy directly in the brain um there isn't one that i would see has a very good track record uh because again there's no way to continuously do that so you'll have to sort of eventually close up you know the patient and then there's no way to routinely continue administering that um the trials have so far not been too successful uh but i'm sure people are looking at developing other and newer ways of doing this in a safe way yeah okay thank you um there's a couple of comments there okay i think just this last question um focused ultrasound therapy i don't know if you can comment on that it's kind of a tool to deliver drugs to cns or is it a treatment itself yes so it is both i would say in the treatment of gliomas uh right now it's being investigated as a way to open up the blood-brain barrier and let in the chemos they would be used in conjunction uh they've looked at actually using the focus ultrasound the actual ultrasound to break up the tumor or to affect the tumor like almost in a surgical way or in the same way that radiotherapy radiation therapy would and it hasn't been as effective in that sense so we're using it as a as an adjunct or as a mechanism to break up the blood-brain barrier and then add on a drug at the moment it is being used in other types of diseases so things like parkinson's disease depression to actually directly like i said localize uh provide localized treatment to areas of the brain to then stimulate uh production of dopamine or you know neurotransmitters to help in things like depression alzheimer's and parkinson's so it's a really interesting area and one that you know we've had a lot of experience with at sunnybrook awesome thank you so much um uh yeah somebody was asking about the presentation we are recording it so it will be uploaded to um our website and um there was another question is gamma knife surgery still used and how much success i don't know that's kind of a different topic but um i can send you information about that uh to the person who has asked so i can follow up via email regarding gamma knife so thank you so much uh dr lymphat i really really appreciate you taking the time out of your busy schedule to be with us and uh to share your knowledge and your expertise and if any other questions come through via email i'll touch base with you directly and for everybody who's online thank you so much for joining us today um and uh yeah keep an eye out for the recorded version up on our website we will send an email out to everybody who registered to let you know when that is up in the next week or so and um that's it that's our last webinar of the year so please make sure to complete the survey when you close out of here and uh we'll see you all in 2022 thanks everybody thank you janik thank you everyone take care