S04 EP04: Glimpses of Hope for Leptomeningeal Metastases 

(Ft. Dr. Priya Kumthekar) 

[00:00:00] Lisa Laudico: Welcome to season four of the Our MBC life podcast from share cancer support, dedicated to exploring life with metastatic breast cancer from the perspective of us, the people living with this disease and the experts who partner with us to help make our lives better. I’m Lisa Laudico and I’m really glad you’re here. Here is the second installment of season four’s road to a cure series with producer and host Dr. Paula Jane. 

[00:00:29] Paula Jane: Thank you for being a part of our road to a cure series. We’ve been focused on exciting innovations and research that are helping some of us with MBC live a little longer and moving the field closer to the goal, which is all of us living a full lifetime with a good quality of life.

As we were conceptualizing the series, it was important to the team that we not sugarcoat the very hard realities that many of us are living with. And that we at least touched on some of the clear areas in MBC that need major innovations and treatment. One of these is leptomenigeal metastases also called lepto or LMD, a relatively rare type of metastasis for which very few treatment options have existed.

And because of that, it usually means that once diagnosed with lepto the average person with MBC has only months left to live. There’s a terrifying diagnosis in an already difficult disease. It’s also an area where research is desperately needed. On this episode of road to a cure we’d like to share with you some hopeful work happening within the lepto research.

Before we talk to the medical experts, however, we wanna highlight our own voices. What is it like for someone living with MBC to hear the words you have leptomenigeal metastases with her family’s permission, we share a blog post by the wonderful Emily Garnet, as she recounts the symptoms that led to her lepto diagnosis, her clear explanation of what that means.

Most importantly, how it all felt. Emily’s words are read by her dear friend, Abigail Johnston. 

[00:02:07] Abigail johnston: I had started experiencing flashes of left side facial numbness. It felt similar to what I’m told Bell’s palsy feels like, but the numbness only lasted for a few moments and then was gone. It was very strange and very unpleasant, but I didn’t think much of it knowing that I had a brain MRI already scheduled.

And of course those symptoms were something. My brain MRI came back showing a new, very small three millimeter lesion, but also some shadowing that coupled with my facial numbness was a strong indicator of leptomenigeal metastasis. What that means essentially is that cancer cells had grown on my meninges, that thick membrane that protects the brain and on my spinal cord and had crossed into my cerebral spinal fluid and were circulating within that fluid.

In other words, it’s similar to meningitis infection. But instead of the infection being bacterial or viral it’s cancer, this is considered in many ways, one of the worst types of disease progression to have, because it’s notoriously difficult to treat. Cerebral spinal fluid is designed to act as a protective barrier for the brain and central nervous system.

So it’s very hard to find drugs that will cross that barrier further. It’s a very nutrient rich environment that allows cells to proliferate without much risk of interruption. Lastly, the current treatment options, generally radiation are not able to fully access all of the fluid as it circulates, making it nearly impossible to fully eradicate the disease from the spinal fluid.

So this was pretty terrible news. Actually it was the absolute worst news. Left untreated lepto Mets can spread very rapidly, often causing someone to die in a matter of weeks, maybe months, even with conventional treatment options, life expectancy is considered in the span of months. I felt and continued to feel the narrowing of the lens through which I view my life.

Making plans for weeks, even months ahead of the now is a trigger for me. More often than not when a well meaning acquaintance makes an offhanded remark about an indeterminate time in the future. I’m reduced to tears. I know the likelihood that I will see that time is very small. 

[00:04:15] Paula Jane: Even given her grief and fear, emily continued to be her badass self in the months between her lepto diagnosis and her eventual death from liver mets several months later. I remember seeing the being with babish episode that she did for her husband, Christian. The host, Andrew Ray, offered her a glass of wine. And he very thoughtfully checked in with her about whether she felt comfortable drinking it.

And I remember Emily laughed and said “whatever my liver is already effed” and immediately, but unrepentantly apologized to the camera even while still laughing. I remember being so drawn in by both her frank acknowledgement of what was happening to her and her simultaneous achievement of living fully in that moment that she had.

And even though we never met, Emily modeled for me, how we can hold these awful contradictions and do it well, a follow up blog post by Emily’s husband, Christian captures the fear, anger and frustration that so many of us feel living with a disease that can mutate and he discusses how essential it is that research in MBC continues.

[00:05:31] Christian Garnet: The last two and a half years have often felt like a chess game. One played against an opponent who was smarter and faster than you and could change the rules at will. But didn’t have to tell you of the rule changes until they had already taken several moves. Cancer cheats and it isn’t fair. Someday justice will come as it does to all cheaters and we will get the upper hand.

We had thought we had hoped that Emily would live to see that day that science would come through that the breakthrough would come in time to save her. It did not. Science failed her, but it doesn’t have to fail the next person. We are on the cusp of so many great things. And if Emily has taught us anything, it is to push, to reach, to strive for more, for better, but it will take commitment, dedication, and resources.

Emily spent the last two and a half years of her life fighting not only for herself and her family, but for the thousands of others, like her. 

[00:06:32] Paula Jane: Emily Garnet was an amazing advocate for herself and others. Thankfully, she was not alone in this fight and the work to understand MBC and specifically lepto is continuing.

We’d like to introduce you today to a researcher and clinician, Dr. Priya Kumthekar who is working to help people like Emily get more time. But first we ask Dr. Nancy Lynn to share a little bit of an overview about why leptomenigeal metastases are so difficult to treat. So here’s Dr. Lynn. 

[00:07:02] Nancy Lynn: So disease is breast cancer or can come from other kinds of cancer, but cancer that goes into the spinal fluid.

And one of the reasons it’s so hard to treat is the fluid travels. So the fluid constantly travels from your brain around your brain, down the spinal cord and all the way back up. And so when cancer cells land in that fluid, it means that if you radiate, for example, one the cells will just travel to another area and it becomes very hard to treat.

It’s also an area where it’s hard to get chemotherapy in our current treatments involve radiation treatment, sometimes we give chemotherapy directly into the spinal fluid, but because of the fact that chemotherapy is toxic, there’s very few chemotherapies we can safely give in the spinal fluid. And then sometimes we give systemic either intravenous or oral chemotherapy or target therapies, and sometimes they work, but often they don’t work for very long.

[00:07:58] Paula Jane: It’s clear that we need more research on so we asked Dr. Lynn why that research was so hard to do.

[00:08:04] Nancy Lynn: One of the things that is very challenging about leptomeningeal diseases it’s quite rare. So even among people with metastatic breast cancer, it’s not that common brain metastases, meaning actual tumors in the brain are relatively more common, but, even the highest risk groups like lobular breast cancers, the risk is not very high.

And that makes doing clinical trials for these patients really hard. So if you try to do a clinical trial for estrogen receptor positive metastatic breast cancer in general, there are many patients who can participate in such a trial. If you try to do a study just in leptomeningeal disease, which is already rare, And then only about 6% of U.S. Cancer patients go on a clinical trial ever.

So if you take 6% of a rare disease, it’s very difficult to run any kind of clinical trial. And certainly not one that’s gonna lead to FDA approval. So I think that’s been a real barrier as far as progress. It is hard to find patients for clinical trials and patients are all over the United States and around the world.

And if you have one or two study centers, it it’s very hard for people to get to these places. So I think that’s part of the limitation. 

[00:09:15] Paula Jane: We then ask Dr. Lynn about any promising research and what subtypes are benefiting from it.

[00:09:21] Nancy Lynn: There are some hopeful studies and they are in the, her two space. So there have been now several phase two studies looking at actually giving Herceptin directly into the spinal fluid and it turns out it’s safe to do it.

And in some patients, it, it really does work and we are seeing longer survival than we did before we started using this treatment. 

So I think there is some progress and for other subtypes where it can feel like what about us? There is little bits here and there for estrogen receptor positive breast cancer.

My colleague, Dr. Sarah Tulaney published a study with Ave Cyclin which is CTK four, six inhibitor in patients with leptomeningeal disease. And Dr. Parsons actually has a, a patient that she cared for, who actually has a BRCA two mutation and responded very well with leptomeningeal disease who elaborate PARP inhibitor. So there are these sort of glimmers that if we work at it, we can make progress.

There are more people working on leptomeningeal disease than ever before. , there’s definitely a lot more going on, even if it’s not quite enough. 

[00:10:29] Paula Jane: We agree with Dr. Lynn that more research on leptomeningeal metastases is needed. We wanna introduce you today to Dr. Priya, Kumthekar a researcher and clinician who is helping people diagnose with lepto to get more time.

Senior producer, Victoria Goldberg. And I sat down with Dr. Kumthekar to talk more about current treatments and the upcoming research, including an exciting phase three clinical trial for MBC patients, newly diagnosed with lepto so here’s Victoria, 

[00:10:59] Victoria Goldberg: tell us a little bit about your research area and most importantly, how you decided to become a neuro oncologist.

What brought you into that field?

[00:11:10] Dr. Priya Kumthekar: Victoria thank you for asking, because I do actually enjoy also discussing the impact. The science is obviously the heartbeat of my career, but I also enjoy the other questions. So I guess when I was a medical student, I didn’t actually even know the field truly existed.

Neurooncology specifically, I came to, um, Northwestern to do my neurology residency because I was interested in the brain and fascinated by it. And so within that, I started to see a lot of patients here at Northwestern that were brain tumor patients. And I found myself just gravitating towards them, both in the inpatient and outpatient setting.

And it’s interesting cuz as a medical student, I never had that epiphany moment that a lot of my colleagues had where they were opening up a heart and surgery and were like, I have to do this. I never really had that sort of. Magnetism until I met my neuro on patients. And then it felt really like gravity to me.

And I found myself exactly that just being pulled towards, wanting to take care of these patients, developing those relationships. And to me just became a point that I, I felt like if I didn’t do it, I would regret it that this was a field that was made for me in a few different ways. So over a decade later from that decision, I’m so glad that I made it and I truly, truly love my job and feel really lucky to be in it.

[00:12:37] Victoria Goldberg: Do you know, what drew you to those patients? What was it that was so compelling? 

[00:12:42] Dr. Priya Kumthekar: You know, for me, it’s the relationships in my real world or in my life. I think all of it’s in my real world, but in my life, outside the clinic, I’m a relationship person. And to me, it’s the reason we live. And so to be able to interweave that into my day to day work life as well, and to develop bonds and use whatever brains I have to be able to help patients.

But then at the same time, be able to develop these really important and, and sort of intimate relationships with patients and their families being allowed the privilege to see them through these high stake moments is a gift. And so I think that’s probably why I was pulled to it is just kind of feeling the ability to have that with patients on a daily and weekly basis.

[00:13:36] Victoria Goldberg: It’s interesting that you say that, because that seems to be a theme through every single interview I’ve done and Dr. Sarah Herwitz Dr. Ho ProGo, all of them said exactly the same thing you did that this is what attracted them to do oncology. They wanted to maintain longstanding relationships with people, not just to see them for a minute.

So that takes a special person, I think. 

[00:14:04] Dr. Priya Kumthekar: Yeah. And I also view it as a gift to me. Right. I’m so lucky that these patients and these families let me into the corners increases of their lives. It’s not something I take for granted. Thank you. 

[00:14:18] Victoria Goldberg: That means a lot to us. 

[00:14:20] Paula Jane: Thank you so much for being with us. I know it’s an odd combination of a series on cure, and we’re asking you specifically about lepto on brain Mets, but we became very aware as we were thinking about this series, what are the major barriers to a potential cure in MBC?

And one of the biggest ones is what happens when we live long enough that we outlive the current treatments and the cancer escapes to other parts of our body where we don’t have efficient treatments. And so we think lepto is an incredibly important topic to be included in this series because it’s one of the biggest barriers and kind of frontiers.

And so for our listeners who may not be familiar, would you mind doing an introduction? Are there subtypes that are more prone? 

[00:15:09] Dr. Priya Kumthekar: Sure. So not to bore you with a three hour long lecture, but I think some really key bullet points. So we talk about brain Mets a lot, and sometimes lepto gets grouped into that, but it’s really a different anatomy just as you’ve so eloquently pointed out in your question.

So we have the brain, which is of course then connected down to the spinal cord and around that, the fluid that the brain and the spinal cord live in. Called cerebral spinal fluid or CSF. And basically when there are cancer cells that live in that fluid, it is then called leptomeningeal disease. But there are some subtypes, of course, that lend its way to lepto one is her two positivity in terms of her two positive and CNS or central nervous system disease as a whole.

So that means brain spinal cord and fluid. It’s about 30 to 50% of that population. And I would say about 15%, so far, fewer, but still enough to be highlighted, do, go on to get leptomeningeal disease. And another frequent subtype that has that affinity towards the CNS is triple negative disease. So those are the two most common settings that we see it in.

[00:16:28] Paula Jane: Yeah, because we are here to talk both about the science and the lived experience of it. So I’ll start with the science treatment side of it. What treatments are currently available for MBC patients who develop lepto

[00:16:43] Dr. Priya Kumthekar: I’ll tease your question into two, right? So there are please therapies that are available that we utilize, but in terms of therapies that are specifically FDA approved for the setting, or specifically shown in a large randomized study, that latter part is lacking.

We utilize therapies that are given systemically. So through either your bloodstream, IV or oral medication, that’s what we mean when we say systemically. And then there are also medications that we can give intrathecally. And that means directly into that sack of fluid basically. A third, which is a non-medication pathway is radiation.

It’s another therapy that we utilize a lot in the leptomeningeal setting. I’ll give a few highlights of the systemic therapies that we sometimes use as a whole cancer care is evolving towards not only the drugs of past, which is traditional cytotoxic chemotherapies. And we’re moving of course, towards a world, hopefully fingers cross of more targeted therapeutic agents.

That being said, we still lean on a lot of those agents. So systemically, we might use therapies such as IV methotrexate. We found in certain doses that it gets to the brain and it gets to the CSF. There are newer drugs. Like Tucatinib that has shown penetration into the CNS as a whole. And right now there is an ongoing study.

That’s looking at it specifically in leptomeningeal disease. And it’s certainly a drug that we utilize for her two positive patients in leptomeningeal disease. And then when we’re talking about delivering to the intrathecal space, some of the drugs that we use are, again, methotrexate, except intrathecally this time we might use a drug called topotecan.

So both of those are a little bit of the. Past generation of traditional cytotoxic chemotherapies. And then we also use intrathecal trastuzumab or intrathecal Herceptin, as you might know it, we have had an oral abstract presentation at a couple different meetings where we’ve presented our phase two data on intrathecal Herceptin for leptomeningeal disease.

And it really is showing some early promise in terms of being able to potentially increase the overall survival from the historic normals that we’ve seen. So there are a couple different directions there. And then of course there are the merging therapies that we all are hopeful about and that we’re towards

[00:19:30] Victoria Goldberg: in our next segment, we will ask Dr. Kumthekar about emerging therapies. But before we do that, I would like to spend a few minutes on intrathecal trastuzumab, which is more commonly known as. both Dr. Kumthekar and Dr. Lean refer to it. When talking about treatments for patients with her two positive disease, the word intrathecal does not roll off your tongue easily, but it’s an important and effective mechanism of drug delivery to the brain.

Our brain and spinal cord are protected by three layers of tissue. called meninges between two of the layers is cerebral spinal fluid or CSF in a place called the intrathecal space. That’s why cancer fighting drugs placed into that space are called intrathecal chemo drugs. There is plenty of evidence that trastuzumab does not reach an adequate concentration on CSF after intravenous application. For patients with her two overexpress in metastatic breast cancer with leptomeningeal disease in application of trastuzumab is an alternative therapeutic approach. One way to get this treatment is with lumbar puncture, also known as spinal tap.

Herseptin of course, is given over a long period and many doses lamb puncture just does not cut it. So different delivery mechanism is generally used. This is a small dome shaped device called an OMY reservoir. It’s placed on the patient’s scalp during a short surgery. It has a catheter that connects to intrathecal space getting treatment this way is like getting it through an IV port.

Now let’s get back to our interview. 

[00:21:29] Paula Jane: We are also very interested in the emerging therapies. I know that Victoria will be sitting down with Dr. Lynn to discuss the Gib trial later this season, and we’d love to hear a little bit about your own upcoming phase three trial. Would you be willing to tell our listeners a little bit about it?

[00:21:45] Dr. Priya Kumthekar: Sure.

So the upcoming phase three study, we’re calling the angled study and that a and g part comes from the therapeutic a and g 1005, which is the name of the drug. It has not been FDA approved in any setting. So basically it’s a newer version of a drug that we all know paclitaxel, which is a drug that’s been used for many years and has shown to have a lot of efficacy in breast cancer, but it just doesn’t get to the brain or the C CSF properly that Cerebra spinal.

This compound has been engineered in such a way where it can, it’s basically three molecules of paclitaxel. That’s been glued onto something called an L R P one receptor antibody. So I know it’s a lot of deep science there, but basically that protein is called angio pep one mm-hmm that allows that compound a and g 1 0 0 5 to basically stick on to the endothelial cells.

So the cells on the blood vessels, and then be basically welcomed into the cell where those paclitaxel molecules can then be cleaved or cut off. and then they can get to work. Think of it as almost like a chaperone that allows it into the brain. 

[00:23:04] Paula Jane: am I getting this correct? So it’s like the smart bomb approach for the brain where it allows it in, it has the past to let it in and then releases.

Would that be a way to look at it? 

[00:23:16] Dr. Priya Kumthekar: Yeah, absolutely. Exactly. It’s exactly doing that. It’s allowing it in cuz otherwise it’s locked out. Mm-hmm 

[00:23:26] Paula Jane: so with the study, that’s coming up, where is it? Where will we be recruiting? Who would be eligible? I’m sure people would be very interested in 

[00:23:35] Dr. Priya Kumthekar: this is a great question.

And, and maybe before I talk about the phase three study, I’ll give just a one liner on the phase two that we published last year. Cuz I think your listeners might wanna hear that the phase two study was. Published last year in a journal called clinical cancer research or CCR. And in that journal, we went over all the phase two data where we looked at both parenchymal or the actual brain tissue Mets, as well as leptomeningeal Mets.

And, and really what we saw with all comers of the leptomeningeal disease is that these patients lived longer than what we expected from lepto. To sometimes threefold higher. And also they were entering the study. Many of them having had on average of about three prior treatments. So they’re heavily pretreated patients.

They had gone through radiation and interestingly, pretty much all of them had had prior taxing. So they’d had this drug, but they didn’t have that chaperone to take it to the brain. Right. And so this allows that to happen. So really motivated by those phase two results. That’s what then inspired the angled study.

And that was the scientific decision to then move forward with the phase three study. So the phase three study will hopefully open early 2022. And basically there are about 30 sites across the country, cooperating together to hopefully get this done. It’ll enroll about 150 patients and patients are gonna be randomized to either a and g 1 0 0 5, or they’re gonna get the physician’s best choice, which will be determined in advance.

So some of those therapies that we talked about before, um, methotrexate, capecitabine, And basically the primary outcome is survival. And patients who have leptomeningeal disease will be included. We wanna make sure that we’re comparing apples to apples. So we want the patients enrolled on this study to be on their first line of lepto therapy, so that we’re comparing equally amongst groups.

So patients may have had prior radiation from let’s say a Parum moment. So a patient who would qualify would be, let’s say somebody who had a few brain meds who had gamma knife or stereotactic radiosurgery of some sort. and then went on months or years later to develop lepto. That would be a prime candidate.

Somebody who had had, you know, whole brain radiation from prior brain paral, brain tissue Mets, and then later go on to develop lepto. Those are kind of the prime candidates. We often see that brain Mets is a preceding event of lepto it’s not true in all cases at all, but it’s just a general trend. And so try to design our city to reflect that of the real world population.

So that’ll be the phase three coming up, the angled study. 

[00:26:41] Paula Jane: Oh, that’s fabulous. I think it’s important then that we get the word out to the community. 30 sites is amazing. Mm-hmm , that’s amazing. and it makes sense that you would need to right. To get the numbers that you need to for the study. I have a number of different thoughts.

I think one is it’s wonderful. And just to put it in perspective, when you’re talking about the phase two trial, having an impact on survival, that’s two to three times what the normal survival is. I think for people who are new to NBC research, hearing that somebody gets to live two months longer.

Doesn’t seem always like the big deal that it really can be. And so let’s just lay it out. What is that median lifespan for somebody with MBC who’s newly diagnosed with lepto? 

[00:27:27] Dr. Priya Kumthekar: So I’ll tell you what I tell my patients, which is I’m gonna give you the fact, because I’m a fact girl, mm-hmm, , I’m be straightforward and realistic, and then I want you to take them and flush ’em down the toilet.

That’s take on it. I’m so happy to share that and, and give you that information. But then for your listeners, I, I would say, you know, we are truly each our own statistic. And I think that, because we say that not to, I’m sorry for the long caveat here. 

[00:27:58] Victoria Goldberg: No, but we totally understand the caveat 

[00:28:03] Dr. Priya Kumthekar: . Absolutely. And I say that not to sugarcoat things about it. It’s more just that I see those exceptions on a weekly basis. And so for me it hope, hope is very important. But to answer your question more directly, probably, um, the, the two largest consecutive studies, uh, show that for all comers of breast cancer, who go on to develop lepto from the time of diagnosis, survival is approximately three months with treatment.

Mm-hmm without treatment, it can be less. So, yeah, numbers that I hope that. When we do this next time that we’ll have orders of magnitude different to tell you, right. That’s what the statistics show us. 

[00:28:52] Paula Jane: But I think that’s an important point for people to have in their minds because when you see a phase two trial, which I’m assuming, then you might have seen survival of six to nine months, 

is that yeah.

[00:29:04] Dr. Priya Kumthekar: So basically for all comers for lepto is roughly eight months mm-hmm and then the, her two actually wears tiny bit longer in that. So about nine ish. And just keep in mind that it’s not apples to apples because these folks were not newly diagnosed lepto for the most part, but yes, you are absolutely.


[00:29:25] Victoria Goldberg: And we’re getting a little bit off base, but I think it takes a certain amount of scientific appreciation and emotional maturity to understand how meaningful and extra three months could be. Once you’ve been. There’s nothing else we can do for you. And having an extra three months to our normal person who has a lifetime is nothing.

But to do that end of life work. It can make all the difference in the world. It really gives a person a time to, as much as you can process, process and be with the people you love and have meaningful moments. It’s almost impossible to put in the words what the worth of doubling or tripling a short time could be.

And so I, I think that’s why I’m pushing on it a little bit, because it sounds small if you’re just looking it on paper, but it can mean the world. I don’t need to tell you you’re with these patients every day, you, you get it, but 

[00:30:27] Dr. Priya Kumthekar: I just, but I appreciate you calling it out because it’s such an important thing.

We can all hope for more and work hard for more, but we should appreciate the fact that it is something. And it’s meaningful. It’s meaningful 

[00:30:40] Paula Jane: Yeah. And so along those lines of talking about the small steps that we’re taking, like saw some research that you’ve done lately on CTC or liquid biopsy and how that can help us to monitor and follow either diagnosis or progression of left and how that compares to how we do it now.

[00:31:00] Dr. Priya Kumthekar: Yeah. So I’ll start backwards. I wanna tell you guys how we do it now first, because that’s really important to the CTC conversation. So how we do it now, lepto is basically di the diagnosis of it falls in sort of three buckets, the first and probably most definitive and classically diagnostic is CSF cytology.

So that means that just like a blood draw, you would draw CSF and then it’s spun down and looked at under a microscope to look for cancer cells. So it’s CSF cytology. The second is neuro imaging. So MRI, classically MRI with contrast brain and spinal cord. Really? And then the third bucket is clinical symptoms.

Now there is a. Reason why each of those are flawed in its own way. Cytology has very poor sensitivity. Sometimes the specimen isn’t appropriate, the cells lice, or basically burst. There’s a lot of reasons why CSF cytology is not a reliable measure. It’s also, and I’m gonna, 

[00:32:12] Paula Jane: can you push a little bit on that?

So you said like a blood test, but it’s not through a vein, correct? No, this is drawn through spinal tap?

[00:32:20] Dr. Priya Kumthekar: Exactly. It’s drawn. Yes. Yeah. But the idea is that you draw the fluid from the patient. That that’s the analogy part, not, not, 

[00:32:26] Paula Jane: but as a patient, I assure you there’s a big difference between having a lab straw and having a spinal tap.

And actually it’s another really good point why we don’t love cytology because in order to get to a sensitivity of 90% or greater, it’s three consecutive spinal taps. And I have never done that for one of my patients because. I probably wouldn’t want that for myself when spinal taps need to be done, they need to be done.

And to be honest, if you have in the right hands, they’re pretty straightforward. It’s a 20 minute outpatient procedure. Mm-hmm um, but I don’t wanna deter so much. I’ll pull it back to the other pieces, cuz there’s a whole other podcast and CSF extraction, um, to 

[00:33:10] Victoria Goldberg: hold you to that promise 

[00:33:14] Dr. Priya Kumthekar: yeah, but long story short CSF cytology has its flaws and they’re numbered.

I mean there’s more than one and then comes the imaging. Imaging’s also flawed because we’re talking about looking at changes in the fluid, right? So we can see evidence of lepto but to measure it in a 2d or 3d fashion is very difficult because it’s almost like somebody took a highlighter to the brain or the spinal cord, cuz we’re looking at the fluid around it.

It’s really difficult to, to measures off the bat. The first two are quantitatively almost impossible. And then the last one is clinical symptoms, which you know, for a physician and for patients the most important, right? Like how are you feeling? And the issue is that there’s so many other variables for that last one that can depend on steroid dosing that can depend on what else is going on in the body that can depend on just how you’re feeling something else is going on.

So doesn’t. How always equate to the most reliable, even though of course, what we want from a quality of life perspective is just how our patients are feeling. But in terms of diagnostics and concrete and quantitative, these three measures are lacking. So then enter circulating tumor cells or also cell-free or tumoral DNA that we can capture in the CSF.

So there have been a variety of studies done on this actually all across the world that are smaller studies that are preliminarily showing that there might be more sensitivity and specificity to these measures. And going back to your point on lumbar punctures, we often do lumbar punctures if we’re making that initial diagnosis, but if we’re treating.

In the CSS space, there are reservoirs that we can put in very similar to a port placement that makes blood draws a lot easier. We can do that for our patients. So whether we do that to use as a treatment, or whether we do that to use for serial draws of CSF, it can make life a lot easier for a patient to have a port like that.

And they’re pretty straightforwardly placed. They’re placed by our neurosurgeons the same way that a surgeon would put in a port to your bloodstream, except this time it would be placed to go directly to your CSF stream. There are ways to simplify that. So we are going after that cerebral spinal fluid, but we can do it in ways that are adaptable and not so hard for the patient.

Then when we get CTCs, it allows us to be more precise and more quantitative. So. We can follow actually quantitatively the concentration of cancer cells in, in the CSF. So you can actually almost grade the degree of lepto in a more concrete and followable fashion. So that is really nicely and easily translatable to the clinic setting.

We can use that just like you mentioned to see how patients are doing with treatments to see how they’re responding to treatments, to see if it’s in fact really lepto or not. There’s, there’s a lot of different diagnostic possibilities, but I also wanna bring it back to the clinical trials and, and the diagnostics, because when we have any clinical trial, we have outcomes that we need to measure.

And if our outcome measurement for leptomeningeal disease is response of any sort, the foundation that we’re standing on with our current standard of care diagnostics is a shaky foundation. And so we’re trying to solidify that foundation more with these next generation of diagnostics, definitely for the clinic to be used, hopefully almost right away, but also so that we can be more successful in clinical trials and lepto so that we can have more therapeutics and also help the patient.

So it’s all part of that same ecosystem that it’s gonna. 

[00:37:42] Paula Jane: and, and speaking of the ecosystem, one of the services we like to do on the podcast, because we know lots of our listeners don’t have access to an NCI designated cancer center. So we would like to ask you in a broad sense, what advice would you have to an NBC patient who is newly diagnosed with lepto?

And I, I say that understanding that for them to be diagnosed with their, their medical team has to have a certain level of understanding of it to even get to the diagnosis. I just had a friend pass away that they were never sure whether it was lepto or not. Mm-hmm . And so if there’s even a question, what would your advice be to that patient?

[00:38:23] Dr. Priya Kumthekar: So I would start with going to your trusted doctor and discussing what the possibilities are because. Just like metastases, anywhere else in the body, each individual has different options and those options are based on what else is happening in the body, how the patient’s feeling, what treatments they’ve had.

There’s so many variables that make each patient’s decision making unique. So I would first ask your oncologist what the options are. And also if there is any option to see a neuro oncologist, I think that can be helpful. And doing that with your oncologist consent and, and asking your oncologist about that.

And I, I realize everyone’s geography is a little bit different, but I think in an era of telehealth, Sometimes we can even be helpful in conversations like these over videos and over the phone, since the beginning of the pandemic, I know I’ve had a lot of telehealth visits with lepto patients that I have never met in person, but I think talking them through what to expect based on what their imaging looks like, what to expect in their particular scenario, and even developing that, um, bridge with their oncologist, who’s really the quarterback of their care, right?

Mm-hmm, developing that relationship and communicating with that person is something that an, an outside neuro oncologist or an inside neuro oncologist can do. So it, it can be helpful to have that communication and quite frankly, therapeutic to talk about it with somebody who’s really familiar with it.

[00:40:13] Paula Jane: And I think just given our conversation, the beginning about relationships and, and it’s clear that you care so deeply about your patients, what advice would you give to a patient on how to balance pursuing treatment versus quality of life? 

[00:40:30] Dr. Priya Kumthekar: Yeah, it’s such a wonderful question. And it’s so patient specific based on where they’re at in their journey in their life mm-hmm it’s so multi-layered, I would definitely trust their trusted sources.

So each of these conversations that I have with patients are all unique in their own weights for whatever that patient is bringing to the table in their lives. And so I, what I would tell them is it, for starters, it’s not always a trade off one for another. 

[00:41:00] Paula Jane: Yeah. Agreed. 

[00:41:02] Dr. Priya Kumthekar: I think that is something that is kind of a misconception, the idea of what would I rather have.

Time or quality of life might not actually be the right question. So that’s number one that I would tell them. And then number two, I always tell my patients that at some point or another, I might be talking about. Focusing only on quality of life. We always focus on quality of life in our clinic, but there might become a time that I only focus on that for whatever reasons that I would of course provide.


[00:41:37] Dr. Priya Kumthekar: And so I would have that conversation that that time might come and it may or may not be that moment. Patient that’s really different. I have some patients that can go to through three or four lines of leptomeningeal disease, directed therapies, because they’re functionally doing really well, or they can tolerate the treatment.

Some of my patients, I don’t do that because I feel like I might hurt them. if I do that and potentially even shorten some of those numbers, if someone is not medically suited for that, it’s hard for me to answer this question because it requires a little bit of a blanketed statement, which is sort of the opposite of how I operate.

Fair enough. 

[00:42:17] Paula Jane: That’s an excellent point. I think you’ve done a beautiful job of answering it. I think you’ve brought up a number of points that are completely valid, so thank you. Yeah. And I know that Victoria wanted to, I’ve monopolized our conversation, sitting on edge, 

[00:42:35] Victoria Goldberg: waiting for her to 

[00:42:37] Paula Jane: go for it. Thank you so much.

[00:42:40] Victoria Goldberg: We can go on and on and talk about it some more and we will, as you promise. So we will have you back, but there are two questions that I wanted to ask. I just thought of them while you and Paula were talking, the first one is actually related to leptomeningeal disease. You mentioned that it’s more prevalent in obviously her two positive and triple negative breast cancer, but I have noticed, and I’m sure Paula has as well that there is a group of young women with ER, positive disease who seem to develop leptomeningeal disease pretty quickly.

Yeah. Who start with almost no disease. And then within less than three years been gone. 

[00:43:26] Dr. Priya Kumthekar: Yeah. So one, I, I absolutely see that population as well. These are trends, right? Not rules. And so I agree with you though. I think that there are these populations. We know that there are a few other risk factors for CNS disease in general.

And one is younger age. Another is African American. There are a few risk factors that are outside of those two big ones that I told you. So yeah, there are other risk factors. Yeah. 

[00:43:58] Victoria Goldberg: Thank you. Okay. And the other question, um, It’s actually related to brain Mets and angled. So you were talking about the phase three, that’s going to have a cohort of hundred and 50 who have leptomeningeal disease and they just newly diagnosed with that.

But it also sounds to me that this treatment would be, would work very well for, uh, brain metastasis as well. So are you thinking of expanding the trial to a brain metastasis cohort as well? 

[00:44:32] Dr. Priya Kumthekar: Yes. So the short answer is yes. I, I agree. It would be wonderful to use this drug in many other settings. I think that there’s a stepwise approach that we will need to take just from a logistical financial and even scientific perspective.

[00:44:48] Victoria Goldberg: And how about her two positive patients will they exclude it from phase three?

[00:44:55] Dr. Priya Kumthekar: That’s an excellent question. So yes, the phase three study is for specifically her two negative patients. And the reason for that is to keep the control arm of the study, because this is a randomized study to the compound versus standard of care.

The, her two positive patients in the phase two study did. Actually show seemed like they had benefit. Um, but the reason why the phase three study was limited to her two negative is to really make sure that we keep the control arm as uniform as possible as there are many different therapeutics used in the, her two positive setting, uh, with brain and CNS metastases.

So the goal is definitely to expand to these patients in the future, but for the phase three, to keep it as scientifically clean as possible, we’re limiting it to the, her two negative. 

[00:45:56] Victoria Goldberg: Thank you. 

If the results are as promising as. It sounds like they will be, it’s gonna be a breakthrough job. 

So I have 

[00:46:06] Dr. Priya Kumthekar: to honestly like my life mission yeah.

Can imagine it’s a really long story with this drug. When this study first opened, it was opened for paral Mets only mm-hmm leptomeningeal patients have historically been left out of clinical trials and continue to be, and this is something that for people like me who treat a lot of lepto and a lot of brain metastases patients to me, I find this unfair on so many levels.

Because it doesn’t reflect the real population that we’re trying to treat. And I think the great news is, and the positive piece of that is that the world is taking notice. Friends of ASCO released a statement a few years ago, as you guys know, to push for this, the FDA has made efforts and even our pharmaceutical partners have.

So there is a push to include more lepto and brain Mets patients. Um, 

[00:46:56] Victoria Goldberg: that’s wonderful. That is so wonderful. And you are absolutely right. This has been a big struggle for a lot of patient advocates, the, uh, exclusion of the brain Mets population from the trials. And it does sound like it’s changing now. The, uh, stable disease at least is now considered.

An inclusion criteria, which is amazing. So to cotton him, as far as I know, was the first trial that actually included brain mats patients with an active disease 

[00:47:27] Dr. Priya Kumthekar: for systemic disease. Yeah, it was. And others should follow suit because it was impactful. 

[00:47:33] Victoria Goldberg: Let’s talk a little bit, and I’m not gonna spend too much time on brain metastasis, but I did want to talk about it.

As we said, the, her two population cause a much higher percentage of incidents of brain metastasis, as you said, 40 to 50%. And I did not know that lepto is this high as well. What is it? 15% you said? Yeah, that’s that really shook me up. And so until Tucatinib we really had not that much to work on for her two positive patients.

There was of course radiation treatments and they have improved vastly, but still not quite there. And there is, I think, an ongoing nutrition trial that you are part of a, probably in a principal investigator on that is testing high dose Herceptin with Projeta for brain maths patients. Right. So can you talk a little bit about that because I’m sure it’s very interesting.

Sure. And the 

[00:48:36] Dr. Priya Kumthekar: Patricia study has completed and we actually, it has completed great publish in JCO, uh, journal of clinical oncology this past year. Wonderful. So I think that it’s a good example of us needing to understand the correct endpoints for clinical trials and brain mets. So the primary endpoint of the Patricia study as it was originally built was for the response rate.

And we did not meet the targeted response rate that the study was built for. But that being said, a lot of patients were stable for a long time. Mm-hmm and that is really Paula to your point, meaningful in the clinic setting. And for me, yes, of course. I wanna see things shrink on the scan, but what do I really want?

I want my patients to live a long time, whether it’s one centimeter or half centimeter in their head, I want them to live a long time with low burden of treatment, right? I want them to have a good quality of life. And the patients on the Patricia study had just that their quality of life was not negatively impacted by the treatments and over half, the patients were still stable on therapy.

Six months later. And so that’s meaningful. Right? And I think that’s ultimately why we were able to publish the results in JCO. Cuz I think it did show that there’s probably some impact there. It’s hard to show biologic effect when things stay stable, but when our patients are progressing and they come on the study progressing and then you’re able to put the breaks on that, I’m certainly bias

But to me that’s meaningful. It’s something that we need to look into more on a few different levels, both on the Patricia therapies themselves. So the high dose, right. Um, Herceptin and Projeta, but also with how we’re designing our studies are we setting our bar at the right place, basically. 

[00:50:31] Victoria Goldberg: That’s so true in real life in clinic, a lot of oncologists would tell you that being stable is good.

So there we go. So the trials, in my opinion have to reflect the reality. exactly. 

Yeah. So I wanted to ask you just one last question and that’s something that I’m really interested in. And this is a question about immunotherapy. We know anecdotally that for some type of cancers, like, um, melanoma, for example, and president Carter, we know that he had been treated by K Truda with brain Mets, and those brain met who the melted away or were stable and he was basically considered cured.

So the question I have in the triple negative space, we now have some checkpoint inhibitors that had been FDA approved. So. Is there potentially a treatment that would include immunotherapy or checkpoint inhibitors more specifically in the treatment of, uh, triple negative, uh, patients with brain meds?

[00:51:44] Dr. Priya Kumthekar: Yeah, I think the, the short answer is yes, absolutely. We, we have seen for patients and I’ll just say in general, patients whose systemic disease is amenable to immunotherapy. Whether it’s melanoma, lung cancer, triple negative breast. And the list of course is being added to every year for patients with systemic cancers that have response to immunotherapy.

There’s probably a role for it in their brain met as well. And whether that’s for primary treatment for asymptomatic Mets, pre radiation, whether that’s for longer term disease, free survival after treatment, where that is placed and how it’s set down is up for some very logical debate suffice to say that for those cancers, there, there probably is a role.

And for some that’s been more definitively placed than others. So for melanoma brain Mets, there’s no doubt that immunotherapy has a role that’s. Not anecdotal. That’s been shown in trials and then for others, there’s still a little bit more clinical trial work to be done. But I would say as a whole, certainly if their systemic cancer is responsive to immunotherapy, it’s certainly gonna help their brain as well.

[00:53:09] Victoria Goldberg: And it’s is it being done right now? 

[00:53:13] Dr. Priya Kumthekar: There are clinical trials at the right now 

[00:53:17] Victoria Goldberg: we’re running out of time. And I will ask the last question that we’re, we’re both very interested in. I usually don’t ask this question, but in your case, I’m going to, the specialty that you went into is obviously incredible and we are so grateful that you are in it, but there is no question about it.

It’s emotionally and professionally. One of the hardest. Areas to be in because of the, uh, response rate that’s so bleak and your patient’s prognosis is not great. So what do you do to keep your mental health intact? Mm-hmm what do you do to, to continue to avoid the burnout and stay sane 

[00:54:06] Dr. Priya Kumthekar: well, a lot of it is mindset.

So for me, it’s the, I, I, I get to not, I have to mindset and that you might make me cry um, but in all seriousness, it, it is like you get to, you don’t have to. And so for me, that’s my whole. Is that I get to, I don’t have to. And then there’s the concrete stuff that, that makes me really happy and gives me that balance in my life.

I, I like the people I come home to I have a husband and two boys. And, um, they’re awesome. So it adds so much levity and joy to my life. Um, I am a runner. That’s a lot of my release, meditative time and happiness. Yeah. There’s so many elements. And for me, again, my friendships in my family are, are so central in my life.

And so therapeutic to me. So for all of it, does it get taxing sometimes? Sure. Does. It hurt me when I see patients who I love have outcomes that I would not want or have outcomes that we expect. Um, yeah, it does, but the moment it stops, I shouldn’t do this job anymore. It does. Cause I’m the moment that I stop feeling, I think is probably my moment to go for plan B, but I’m all in because I get to right. Not cause I have to. 

[00:55:37] Victoria Goldberg: So, um, a follow up question a quick one. I promise . So I have two sons as well, and I had a very stressful career before I got this diagnosis and I had a very hard time leaving my job at work. So I used to bring it home. So how do you manage to separate your 

home life with your, I, I also bring it home.

Let’s just be all right. Good. 

[00:56:06] Dr. Priya Kumthekar: and I think it’s, but I think it’s like, um, I think it’s how you bring it home. Do I bring it home in ways that are wonderful? A hundred percent of the time? No, I would be lying. Right. There’s certainly times where. I’m working late or working early. And I might not hear what my son says, cuz I’m returning emails.

I’m absolutely guilty of all normal people, vices . But I also get to bring it home in a lot of good ways. So my kids know what I do. They’re really young, but they know what mommy does and they respect it. They know that on my clinic days I might be late and it’s not like, oh, mommy’s late, but it’s oh, mommy’s late.

Cuz she’s gotta take care of the patients. So I think there are really healthy ways to bring it home. And I think bringing home the gratitude is a really, really big piece of it. So we actually have a family motto. That’s like etched out on wood in our family room with four words, a lot of. Comes from my work experience and, and all of our life experiences glue together.

So yeah, I, I bring it home sometimes in not so great ways, but I think a lot of times in ways that I want to bring it home, I want my kids and my husband to know that we should be grateful for every day. And that three months of time in life is yes, important to a patient with lepto, but it’s also important to just people like us.

It’s important to everyone every, every month of it, every day of it, every week of it, you know, that’s 

[00:57:34] Victoria Goldberg: wonderful. I’m so thrilled that we’re able to spend this time with you. And thank you so very, very much. And please come back. There are so many more questions we have 

[00:57:45] Dr. Priya Kumthekar: it was so great to both. Absolutely take care.

[00:57:48] Paula Jane: Thank you. Thank you very 


[00:57:51] Victoria Goldberg: Paula and I conducted this amazing interview with Dr. Kumthekar at the last year, but before the 2021 San Antonio breast cancer, symposium it is March now. And two days ago, I sat down with Dr. Nancy Lynn to talk about the latest development and treatments for brain metastasis. And of course, I asked her about the leptomeningeal disease as well.

Here is what she had to say. And in my opinion, it is a good way to end this episode on a hopeful note. 

[00:58:27] Nancy Lynn: So my colleagues, uh, Rashme me and Erica stringer, razor led a trial in the translational breast cancer research consortium. It’s a bunch of academic, uh, centers getting together and cooperating on trials, which is nice.

So in patients who had her two positive leptomeningeal disease and received the hertu climb regimen. So that’s to Tucatinib, chemo plus Herceptin, they found that, although, still not what we wanted to be on average, their survival was actually longer than we would normally expect for patients who have leptomeningeal disease.

And there were some patients who were able to stay on the treatment for a pretty good period of time. It’s very promising. The other thing that they actually measured the drug levels when people had spinal taps. And found that they got really good levels of tib, even in the spinal fluid, which is harder actually to get into than brain Mets, where the blood brain barrier is often quite disrupted. So to see drug levels in the spinal fluid is, is pretty unusual for most drugs, which is really supportive of the fact that this is likely a regimen that has activity in patients with leptomeningeal disease. And then on the topic of leptomeningeal disease, there have been at least two studies to look at using Herceptin, actually given directly into the spinal fluid.

And those have been presented and we’re just waiting for the official papers to come out, which I expect will probably be sometime this calendar year. So it’s still slower, the progress for leptomeningeal disease. And when you start to see something. work. I think it really makes people excited to include patients with leptomeningeal disease in more clinical trials. And so I hope that that will continue to expand over time. 

[01:00:19] Lisa Laudico: This podcast was produced by Victoria Goldberg. The brilliant road to a cure episode team members are Martha Carlson. Dr. Paula Jane, Dr. Ellen Landsberg, Kate Pfitzer and Lynda Weatherby expert sound design by Bill Smith. Our executive producer is Christine Benjamin senior director of patient services and education at share cancer support.

You can find more episodes of our MBC life, wherever you get your podcast. Be sure to subscribe, rate and review us and look for a new episode every week. Check out our blog and full episode notes on our website@ourmbclife.org. We’d love to hear from you.