MedBuzz: In this episode of Oncology Unscripted MedBuzz, Dr Marshall discusses evolving rectal cancer data and the growing role of genomic testing. He also reflects on US science policy and concerns about instability, and the need to modernize clinical trials while protecting independent oversight and patient data. Main Topic: In this episode of Oncology Unscripted, Dr Marshall discusses the growing role of precision medicine in oncology and how it is shifting from an optional tool to a standard part of cancer care, including the increasing importance of MRD and ctDNA, and promise of blood-based cancer screening. Interview In this episode of Candid Conversations, Dr. John Marshall speaks with Dr. Marija Balic of UPMC and the University of Pittsburgh about MRD ctDNA testing in early breast cancer.
MedBuzz:
In this episode of Oncology Unscripted MedBuzz, Dr Marshall discusses evolving rectal cancer data and the growing role of genomic testing. He also reflects on US science policy and concerns about instability, and the need to modernize clinical trials while protecting independent oversight and patient data.
Main Topic:
In this episode of Oncology Unscripted, Dr Marshall discusses the growing role of precision medicine in oncology and how it is shifting from an optional tool to a standard part of cancer care, including the increasing importance of MRD and ctDNA, and promise of blood-based cancer screening.
Interview:
In this episode of Candid Conversations , Dr. John Marshall speaks with Dr. Marija Balic of UPMC and the University of Pittsburgh about MRD ctDNA testing in early breast cancer.
Ep 30 Main Topic: Navigating the Expanding Role of Precision Medicine
John Marshall, MD: John Marshall, Oncology Unscripted. Yeah. Episode 30. If you’ve watched all 30, we’ll send you a special gold-plated section of the East Wing that was torn down on the road here in Washington, DC. You’ll want that for your office, or maybe a doorstop or something. All 30, and you get a brick from the East Wing.
I’m, of course, lying. We don’t have that to give you.
We are going to focus, for the next really half year or more, around precision medicine. We’ll do our usual stuff, but we want to drill down on the impact of precision medicine in a variety of ways. You know, we went from having just a few tests: ER/PR. HER2-negative came later because that was a negative, if you will. BRAF comes along. There are some other markers here and there, fusions here and there. But let’s face it: we fronted all of this activity with companies that were willing to do the precision medicine, whether they got paid or not, in a way that collected data that demonstrated the benefit.
And over here, we had drug development going on because we had more and more knowledge about the different markers and the biology of cancer. So we were, in a sense, fronting our success through risk-taking, both by the precision medicine companies and the companies and all of us who are helping to make new therapies possible for our patients. And I think we can all look at each other and say that that was an investment that has paid off nicely, mostly in rich countries, mostly here in the United States. I’ve said before, I’ve been to events at ASCO where we just saw some new cool target and some new cool drug that had a good benefit rate for patients, and I’ll walk out with a friend from Europe or someplace else, and they’ll say, “Well, that’s great, but we are not going to be able to have that drug because of price.” And so, we need to disrupt this in a way so that we have more global access in order for precision medicine to make it to the next step.
But I really want to drill down on a few points that are really here, focused around the US and our own sort of local market.
And the first is: is precision medicine a choice, an option, or is it the standard of care? And we know in health care, we order tests mostly because it’s a hunch. We’re trying to make a diagnosis, this sort of thing. In some cases, we wouldn’t dare treat a patient without precision medicine.
I’m on service this week. We just admitted a lung cancer patient who, all we have is the tissue biopsy and a negative blood sample. So, the ctDNA on the blood is negative, but we still need to know. They might be hiding a fusion or something that’s not showing up in the blood. And so, even though we’re starting chemo because the patient’s sick, we have also gotten a biopsy and are sending that off for next-generation sequencing because there’s no way you’re going to treat a lung cancer patient without knowing the precision medicine results. In that case, we’ve known that to be true for breast cancer, for example. There’s no way you would treat a patient without knowing ER/PR, HER2, or triple-negative. Well, in colon cancer, we’ve talked about this before. Is it a requirement to do HER2 because only so few of them have it positive? What about RAS? Well, maybe soon. How about G12C? Not that common, but you’ve got a drug, right? About RAS mutations predicting resistance, you’ve got to know that, right? What about BRAF? It’s been a slow uptake on BRAF. MSI was pretty good.
So, I actually think precision medicine has shifted from a choice now being the standard of care. The reason that’s a risky thing to say is that if you haven’t done it, or if you haven’t interpreted it correctly for your patient, are you medically liable? Is that malpractice to not have acted on the mutation that exists or doesn’t exist in the patient in front of us? But I actually think that’s where we’re going, pretty much where we are for many cancers. And so, you need to make sure your practice is up to speed on all of this. I think most of us are, but there are still a bunch of times when it’s not being done or not done appropriately. So, we almost have to check on every patient to make sure it’s being done properly.
The second area I want to kind of drill down on is this idea around minimal residual disease, MRD, ctDNA testing, and precision medicine papers that are about to be presented in Chicago at ASCO. Many of them in the colorectal cancer space are this. Many of them are late-breaking abstracts, so I don’t know yet what they’re going to say, but usually late breaks are positive. Somebody knows the answer to what they’re going to say. But the other piece of this that’s really fairly striking is that a lot of these papers are done outside the United States. The research is being done outside the United States. And so, even though we’re getting access to these genetic tests, MRD testing, and stuff kind of free, it’s being paid for or covered by companies or by insurance one way or the other. So, we have access to it. In these other places where they don’t have access to it, that’s where they’re doing the research and generating this kind of data that I think will be practice-changing. So, do look out for the precision medicine, particularly around the MRD testing that we’re seeing increasingly out there in the literature, and yet another bunch of new papers coming up in Chicago in the colon cancer space, but also in other diseases as well. So, keep a nose out for that.
And then the last place I want to go is, you know, where I’m getting more and more questions about using blood testing to screen for cancer. There are only about five cancers we actually screen for officially. Screening is supposed to be cheap. It’s supposed to be noninvasive. It’s supposed to be easy. It’s for those patients who don’t have other risk. And so, you know, mammogram probably fits, Pap smears fit, but colonoscopies are not cheap and not noninvasive. We don’t screen for a bunch of bad cancers like pancreatic and gastric, and we start to screen for lung in the smokers now. But could it shift over to blood testing? And our patients love this idea. This is a very attractive idea to the consumer out there, to think that I’ve gone to my primary care doc, and they did a cancer-screening blood test, and it was negative. And I think that is good news. Let’s not kid ourselves. That is good news, and it’s where we’re going. But we’re going to be in this awkward window when a patient is completely reassured by that negative blood test and therefore is not going to get the normal screening. So, it’s going to take some time for us to demonstrate that that blood test is equal to or more effective than traditional screening that’s out there, and there will be a lot of pressure on us all to incorporate this. So, as you’re thinking about your ctDNA testing in patients with known cancer, think about that technology as it might inform a healthy person coming in in a primary care office and getting a blood test, kind of like a, you know, complete metabolic profile, but let’s throw in a cancer-screening test to see if there are any cancer genes floating around there. It’s where we’re going. I think it’s an important place to go, and I think the loop between treating MRD-positive and treating patients who are screen-positive may actually one day connect back itself. And I’m hoping that’s where all of this science goes. But we are going to work ourselves through this sort of awkward in-between time when we’re not quite so sure of what we’re doing. So, keep your nose up, keep a little bit of skepticism going forward. Embrace the new technology, but know what you know and know what you don’t know. John Marshall for Oncology Unscripted.
Ep 30 MedBuzz: Science, Policy, and the Future of Cancer Care
John Marshall, MD: John Marshall, Oncology Unscripted, believe it or not, episode 30. Here we go, and there’s a whole lot to talk about.
I am a real doctor. I just want to show you that. I’m actually on service this week.
This is a Harvey three-head stethoscope. I actually do know how to use it. This is a mask for when you go into the rooms where you need one of those. Actually, I’ve got one patient right now who has some bedbugs and lice, so we have to be particularly careful there. We even have those here in Washington, DC.
So, real doctor, been on rounds today, but a whole lot to talk about. And where I wanted to start is actually with an article that came from a paper. You remember, I really like paper journal articles. I don’t know if you do, too. This is from the Journal of Clinical Oncology, and there are 2 articles on rectal cancer.
One’s a new data set, and the whole point of this strategy is: can we get rid of radiation in these people with rectal cancers? Because remember, radiation’s in there for bad surgery.
And now that surgery has gotten so much better and our preoperative chemo has gotten better, can we do away with it? And as you’ll see from this article, there is really pretty solid evidence that we need to reduce how much radiation we are giving, giving it less frequently. And what I really like about what JCO did with this is that they then brought forward a review article by Barbara Noiret et al, who kind of looked at all the data that’s been coming forward over the last 10 years and really kind of sliced and diced where the tumor is—very low down by the sphincter, up higher by the sigmoid colon, in the middle—and really gave us some nice overview about how best to proceed in patients with newly diagnosed rectal cancer.
We’re going to review this article in our fellows’ journal club this Friday, so I think it’s pretty important. I think any of you out there who take care of rectal cancer—surgeons, radiation oncologists, or oncologists—ought to make sure and review this new data. I think it’s important, and I think practice-changing even immediately as we go.
But let’s shift gears a little bit and talk about sort of the business side of oncology, and I know that you see lots of mergers and acquisitions, but one that I’m particularly interested in is that Abbott has recently acquired Exact Sciences. And you know Exact Sciences because of Cologuard and Oncotype DX.
They’ve made all of these genomic tests available, whether it’s for screening or risk analysis out there, and we’re all using them more and more. There are ads running on TV for that box, you know, for screening for colon cancer. That’s Exact Sciences. But this merger really does put together 2 companies that I think will serve each other well as they go forward in trying to help revolutionize the management of cancer in general and the incorporation of genetic information into our decision-making day in and day out. So keep an eye on that.
Second, you probably saw just within the last day or 2 that the National Science Board, the National Science Foundation that was founded by Congress back in 1950, actually the entire board of this was fired. Donald Trump sent them all an email. He’s so nice about how he fires people.
Sent them an email and basically said, “You’re fired,” and doesn’t really explain why. There is some spokesperson who kind of dances around the issue. They say, “Well, if they’re not really in line with what the current policies are, we can do whatever we want.” But as I thought about this, what’s the job of the National Science Foundation and the National Board here?
Well, it was brought on by Congress to be an advisor to the president, executive branch, as well as to Congress about what we need to know from a science and engineering perspective so that we can incorporate that into our own policies. And so, by firing all of that board, the suspicion is he’s going to put in people who think like he does. And so what that board will then make are formal, government-funded recommendations that basically agree with the current administration. And, you know, I keep shaking my head about this. His policy is, “If I don’t want to hear what you have to say, well, I’ll just fire you, and I’ll bring in people who do say what I want to be said.”
And so, I’m very anxious about this. I do think it represents one more level of unstableness in our world here in the United States as we think about knowledge and intelligence, those things that we pride ourselves on, getting more and more eroded so that one day we will no longer have the capability to lead in the space of science and technology.
And this also sort of rang true with my next point. And as I started to review the ASCO abstracts, they were just released, and we’re all getting ready for the big meeting in Chicago. And I scanned down what many of the presenters, where they came from, and some of the science that they were coming with.
One, there’s a lot of genetic precision medicine stuff coming. We’ll get back to that later on. But a strikingly high percentage are coming from nontraditional sources, such as China and other parts of Asia. And so, if we’re really trying to make America great again with having the best science and intelligence, at the same time we’re taking away those people who are going to be the best advisors and policy setters that are here today, I don’t see how we’re going to really justify the actions that are going forward.
So, we’re already seeing the shift in science and innovation to ex-US sites and investigators, and we continue to sort of degrade the brain trust that exists here in the United States that we’re paying our taxes to help fund and support. So yes, if you’re unsettled, you are hearing me correctly.
But then my last point on this is around our FDA commissioner, Marty Makary. I think I’m saying that right. Now, Marty is a GI cancer surgeon from Hopkins, originally I think from England, and very, very bright, has written books on many, many subjects, and took on the role about a year ago now as FDA commissioner. Obviously, not an easy role to play in the current administration.
To be a real scientist and to live in this ecosystem is not an easy thing to do, but so far, I think he’s doing okay. He too is disruptive. He too wants to be disruptive, and I’m not against disruption fundamentally. And so where I’m kind of torn, and also a bit bipartisan, by the way, just want to point out to everybody that these are elephants on this tie, so this is my bipartisan moment, wearing the elephant tie and Marty’s—
On one breath, he is saying we should do more with psychedelics. We can talk about that later. It was a great night or 2 I had in Durham, North Carolina, with psychedelics, but that was many, many years ago, actually in the last century, so we won’t talk about that. But what he’s really talking about in terms of disruption is improving clinical trial efficiency, and I am so into this concept. We’re working on this with some colorectal stuff that we are doing on a national level. Can we actually alter traditional drug development so that we can find the right patient, right drug, high bar, don’t need control arms, reduce cost, speed, accelerate the clinical benefit for that individual patient, reduce drug costs, get more therapies out there for our patients more quickly, and not just here in the United States, but everywhere else?
So, this idea of faster readout and different design strategy, disrupting traditional design strategy, I’m very much into. But one thing that he pointed out in a recent video that I saw of his is that he was arguing in favor of direct reporting to the FDA. So, we know that the CROs do take a lot of our finances and time as they process the data for clinical research and then hand it off, prepare it, and hand it off for the FDA and other regulatory agencies.
But what he was proposing is: why don’t we just have some sort of direct line from, say, my electronic medical record that I entered into today as an attending on call, and if it’s a patient on trial, have that feed directly over to the FDA? And I say, on one level, I kind of get that, but that’s when I used to trust our government with our data. And I realize that’s a big thing to say, but I’m uneasy right now of having that go directly to them without some sort of independent review in there.
That’s what the FDA is supposed to be, but I’m not sure they’re still maintaining that or can continue to maintain that at the level we’ve come to expect. So, other than that direct data feed, I like what he’s saying. So, in my bipartisan, elephant-tie-wearing spirit, I do think we ought to listen to what the FDA is saying around clinical trial disruption and evolution, maybe revolution, so that we can drop the price, improve the speed with which we identify the right therapies for the right patient, incorporate precision medicine more readily, and cure more people more of the time.
That should be in the Constitution. John Marshall for Oncology Unscripted.
MRD ctDNA Testing in Triple-Negative Breast Cancer: A Candid Conversation With Dr. Marija Balic
John Marshall, MD: John Marshall back, episode 30, as promised, for Oncology Unscripted. I am always very, very lucky to get to interview the best and the brightest in our field across the country and around the world.
And today is no exception. I am joined by Marija Balic from UPMC, up in Pittsburgh, not too far from where I'm sitting right now. It's a kinda windy road to get there, but you can get there nonetheless. And we are so excited she's joined us because she has been on point of an NSABP study looking at neoadjuvant therapy in breast cancer, of course. But this is specific to triple-negative breast cancer and specific to MRD ctDNA testing. And her data has been so profound that she's gotten, of course, to present it at San Antonio and at other meetings along the way. And we are lucky enough that she said yes. So, Dr. Balic, welcome to Oncology Unscripted.
Tell us a little bit about yourself.
Marija Balic, MD, PhD, MBA: So, thank you. Thank you so much for this enthusiastic introduction. A little bit about myself: I joined, 2 years ago, to lead the breast program here at UPMC at the University of Pittsburgh, and mainly also based on the NSABP that is very close here in Pittsburgh, and the role of NSABP that it has played in my life.
I joined from Austria. I led the breast center at the University of Graz and was vice president of the ABCSG, which was basically built after the model of the NSABP. And, since 2 years, I have joined both and am leading both the program at the university as well as the translational research program at the NSABP.
John Marshall, MD: I'm a good friend of Norman Wolmark's and all the gang at NSABP. Soonmyung Paik used to be here at Georgetown a long time ago. That's a great group with some of the smartest people on the planet, and I know they're even smarter with your being there. So, welcome.
Marija Balic, MD, PhD, MBA: Thank you. Thank you. Well, Bernie Fisher initiated the thoughts of early metastatic spread, so it's the source of all the research we are doing currently.
John Marshall, MD: It is. It's the beginning of it all, isn't it? Right there. So, it's so great for you to be a part of that.
Listen, in GI cancers, and colon cancer in particular, we are in this debate of: should we be doing MRD testing or not? We haven't had the kind of innovations you guys have had in breast cancer, so we're taking anything we will take.
So, we've been fairly early adopters. When I talk to my breast cancer friends, it's more controversial about whether you do it or not, and are there certain kinds of breast cancer where you do it more than others. So, what's sort of your take today on MRD testing in earlier breast cancer?
Marija Balic, MD, PhD, MBA: My take would be that we are closer to demonstrating the potential clinical utility, but we are not there yet compared to GI and colorectal cancers, where we've seen the stage II data and basically the treatment decision contribution based on ctDNA, whether to treat patients with adjuvant treatment or not. I think triple-negative breast cancer may be the first, where we will be able to demonstrate this utility based on our data, based on data that was represented from the I-SPY clinical t rial, and also the summary that was published by Mark Magnanua last year in Nature Medicine. In triple-negative breast cancer, we see a high frequency at baseline. In our own data, 96% of patients were positive.
John Marshall, MD: That shocked me. I mean, that you had such a high percentage of positive. Yes, tumors in situ, right? But almost—
Marija Balic, MD, PhD, MBA: Yeah.
John Marshall, MD: In colon, we have a pretty high percentage that aren't positive even with tumor in situ. So, that's a difference right there, a biology difference.
Marija Balic, MD, PhD, MBA: Definitely, and we see differences across the subtypes at baseline. Triple-negative breast cancer is probably with the highest percentage of positive cases. The greatest challenge is in hormone receptor-positive cases, both at baseline and throughout the treatment. And then, somewhere in the middle, based on its mixed biology, also HER2-positive breast cancer, depending on whether it's hormone receptor-positive or not.
John Marshall, MD: What is your all sort of theory on that? The answer I give patients on this is that the faster your tumor is moving, the more likely the ctDNA will be positive. If it's slower, maybe—well, you know, for us it's peritoneal, but slow turnover, we see fewer uptake. Is that sort of your take on it too?
Marija Balic, MD, PhD, MBA: There seems to be a correlation with the cell cycle and the speed of the cell cycle and the release of ctDNA, of course, and the high turnover of the triple-negative breast cancer seems to correlate with the ctDNA positivity at baseline. Which, we have also very nicely shown, is the clearance through the treatment with effective neoadjuvant treatments.
We do manage to clear 90% of those patients even before surgery.
John Marshall, MD: We'll get back to the high-level results, I mean, which were just so impressive. But before we go there, I want to—A lot of us are being marketed the different assays that are out there. And so—but there are 4, 5, 6 major sequencers that we have access to in this country. Some are tissue-based, some are blood-based, some offer both. An evolution in how many genes are picked and how much AI is used, et cetera. There's part of me that feels like, do I care whether my patient's CAT scan was done on a GE scanner or a Siemens scanner? I get the same CAT scan. Versus, no, these are fundamentally different assays and tests, and it is a little bit apples and oranges.
Do you have a sort of mindset about the different assays that are out there?
Marija Balic, MD, PhD, MBA: So, I do believe that tumor-informed assays still allow for higher sensitivity, and we are currently even facing the first generation of ultralow or ultrasensitive assays. So, I am still convinced that the tumor information really generates more significant information. And then not only the way how you sequence tumors and how you get this tumor-informed information, but also how do you generate the approach to analyze blood and plasma? Between digital PCR for selected probes and large scale of selected probes, current assays are even using up to 1000 or 2000 probes. There is definitely a potential to increase sensitivity and thereby be much more prognostic and hopefully predictive as well.
John Marshall, MD: Very helpful and very insightful. Let me give you a chance to tell us the punchline of what we're here to talk about. Your study, maybe a quick overview of the design and what are some of the high-level points that you found.
Marija Balic, MD, PhD, MBA: So, basically what we have performed, that was a subanalysis in the NSABP B-59/GBG 96-GeparDouze study. It was a large study with more than 1500 patients who were randomized into adding immunotherapy to a maximum of chemotherapy backbone. And in a substudy of patients who were enrolled in the NSABP, a little more than 200 patients were available for tumor-informed sequencing, which was based on whole-exome sequencing, a very deep whole-exome sequencing between 400 and 800×.
And basically, after subtraction of the germline information, specific probe sets were identified, and then plasma hybridized to those specific probes. Per patient, we were able to identify between 40 and 200 specific alterations to be generated. And with that, and with appropriate dilatory algorithm to identify who are really positive cases, we were able to identify 96% of patients who were positive at baseline.
Then, before surgery, 10% of patients were still positive, but it went down to 6% after surgery, and that is basically identifying time points for de-escalation or escalation in treatment. And the primary endpoint was post-surgical endpoint and prediction of prognosis. And then, at our recent presentation at AACR, we included this post-neoadjuvant treatment, pre-surgery time point to really associate with long-term prognosis.
John Marshall, MD: Just really, really impressive data. I was wondering, you know, we've been having discussions with regulatory agencies even now about MRD to negative as a regulatory endpoint. And I know you and others in the breast cancer field really helped lead the path CR quick regulatory endpoint in the adjuvant setting. Do you think this is starting to creep in on that? Maybe covariables or co-endpoints, you know, where you have path CR and MRD, that that's an even stronger regulatory endpoint?
Marija Balic, MD, PhD, MBA: So, I think that's the way where this is developing. There will be some changes with sensitivity of the assays. I think that will be really important to define prior to designing clinical trials and really defining the endpoints. But, for example, in our case, when we take into account this post-neoadjuvant but pre-surgery time point, our positive predictive value for non-PCR was 85.7%, which is very high, but it is still not 100%.
So, the question is: can we improve this with better technologies to really be able, potentially at some point, to say, "Well, these patients don't need surgery"? We are close, but not there yet.
John Marshall, MD: I, you know, over 40 years of doing this, I've watched everything from, you know—I didn't actually live during the radical mastectomy or practice during the radical mastectomy years, but we went from lots of surgery to lumpectomies to back to more surgery, prophylactic bilateral mastectomies. So, there's been this swing in the sort of mantra and community think around surgery and breast cancer.
Now, in GI cancers, particularly colorectal cancer, we're increasingly identifying patients who may not need their rectums removed and therefore need a permanent ostomy, you know, just a quality-of-life bonus. And so, we're using a lot of MRD testing to watch and wait those patients. Is this starting to be something you guys are folding in, or is there really not that same pressure for the mastectomy that we have for rectal removal?
Marija Balic, MD, PhD, MBA: Oh, well, there is definitely a pressure, and it very much depends on the part of the world where you practice. The hypothesis that breast-conserving surgery is safe for the patients comes from Pittsburgh and from Bernie Fisher, basically, the first randomized trial that has demonstrated the safety.
I think the pre-surgery time point is also the most important time point for surgeons to really potentially identify patients who may omit surgery, and it may evolve there. But, as said, we are still not there yet. The drop of patients from 9% to 6% after surgery and the hazard ratio of 10 versus 30-fold increased risk after surgery if they remain ctDNA positive does show that there is certain role of ctDNA clearance just based on surgery.
So, we definitely have to work better on optimizing—
John Marshall, MD: Is the answer for that? Is that a pathologist not seeing microscopic disease and therefore calling it a path CR, but it's not really a path CR?
Marija Balic, MD, PhD, MBA: Potentially, potentially that's the reason, and it's definitely the reason. So, what we did see is basically also in a more granular analysis that patients who are ctDNA negative and still have remaining tumor are almost having as good prognosis as those who are ctDNA negative and achieve pathological complete response.
I do think that there is some resistant disease that treatment is still not eradicating that can then be removed by surgery, leading to additional curation of the patient.
John Marshall, MD: Terrific. Dr. Balic, Marija, thank you so much for taking time, what I know is a very busy day, and thank you for sharing the data that you've got with me and with our audience out there. And my guess is we'll see more of this data in Chicago. So, maybe we'll cross paths in the big hallway somewhere along the way.
Thanks for joining us on Oncology Unscripted.
Marija Balic, MD, PhD, MBA: Thank you for having me.
This transcript has been developed using AI and edited for clarity.