While our culture and media often reduce scientific brilliance to individual minds, great advances are accomplished through collaboration.
Over recent decades, innumerable scientific accomplishments illustrate the impressive capacity of researchers, clinical scientists, and of course, their patients. But to operate well, these networks can’t just be pointed in the same direction; they need to be speaking the same language and working together.
This is where translational investigators like Dr. Ian Krop come in. His efforts, insights, and understanding not only connect labs to clinics—balancing resources, research, and opportunity—but they also underscore the importance of centering patients in research.
A BCRF investigator since 2017, Dr. Krop is the chief clinical research officer and associate cancer center director for clinical research at the Yale Cancer Center. Dr. Krop also currently serves as chief scientific officer for the BCRF-supported Translational Breast Cancer Research Consortium. He is a member of the National Cancer Institute’s Breast Cancer Steering Committee and co-chairs its Immuno-Oncology Working Group. He is also the co-vice chair for correlative science for the Alliance for Clinical Trials in Oncology.
Chris Riback: Dr. Krop, thanks for joining me. I appreciate your time.
Dr. Ian Krop: I‘m happy to be here. Thanks for asking me to talk about this.
Chris Riback: Before we start with your area of focus, I‘d like to better understand how you think and how you see the world. What is a translational investigator?
Dr. Ian Krop: So that‘s a really good question, and this idea of a translational investigator is certainly not a one-size-fits-all kind of moniker. But essentially, we have a large number of very smart scientists in laboratories trying to understand the basic mechanism of cancer, what drives a cancer, what are cancer’s vulnerabilities? And we have equally smart people in the clinic who are doing clinical trials to test new drugs and take care of patients with cancer. But for the scientific discoveries to become useful drugs, there needs to be somebody to bridge the gap between these two groups of investigators. And that’s essentially what a translational investigator does, is it basically translates the basic laboratory scientific discoveries about cancer into useful information, useful drugs, so that we can actually help patients. And so what that means is helping develop drugs from the, taking advantage of insights from the laboratory and figuring out how to best use those drugs.
And it goes the other way, too. It means looking at the results of a clinical trial, looking at the tumor tissue that was obtained as part of that trial and trying to understand why a particular drug works well in one patient but doesn’t work so well in another patient. And so looking at, are there molecular features of a cancer that allow us to figure out why a drug worked in one person and not another? And then take that back to the laboratory people and say, “Okay, here’s what we think is going on. Can you help us figure out a way to overcome this particular obstacle for this particular type of tumor so that the drug works in more people than it did originally?” And so that we don’t treat patients with drugs that don’t work, identify which patients are going to benefit upfront and which ones aren’t. So that again, we can personalize our therapies for the people for whom they’re going to have the most benefit.
So that’s really the role of a translational investigator, to help the laboratory discoveries get into the clinic and help the clinical discoveries get back to the laboratory so they can be further improved for the next generation of drugs.
Chris Riback: So, among your chief scientific skills is the fact that you’re multilingual, you speak laboratory and you speak clinic fluently?
Dr. Ian Krop: Yes. Unfortunately, I don’t speak other languages. So, when I travel it’s not very useful. But I do speak both the lingo of basic science and the lingo of clinical research of clinical trials. And I think that’s, and that’s really a prerequisite for doing this kind of job because you really are the conduit between these two groups.
Chris Riback: I was going to joke and say, well, that’s why Google Translate exists to help you with your travels. But then I started to think, well, in a way you, people like you, are kind of the Google Translate between the labs and the clinics. I’ve had the privilege, the benefit of getting to speak with other researcher scientists who are involved in translational medicine. And the conversations really are fascinating because each time and each scientist, in their own way, what they learn from the clinics and then bring to the labs, but then what they do in the labs and then bring to the clinics. And I understand the unique role that you have, but there is those two, bringing those two parts together is just central to making progress holistically. But also, as you were just saying individually and making sure that you’re helping folks one patient at a time.
Dr. Ian Krop: Not all translational investigators are actually taking care of patients, but it certainly makes my life much more satisfying and enjoyable to be able to meet with patients on a regular basis and see the impact of all of our work, all of us who are doing involved in cancer medicine and cancer research, to see how much impact there’s been. Because there really has been a tremendous amount, I’ve been doing this for about 24 years or so, and just in my professional lifetime, what’s happened is really extraordinary in terms of where we were when I started and where we are now. And obviously, we still have plenty of room to go and everything always is slower than we would like it to be. But objectively, if you look at where things were 20 years ago compared to now, it’s really night and day.
And in fact, 20 years ago, there probably wasn’t a real need for translational investigators, or at least we didn’t really appreciate that because the state of science was such that there wasn’t so much to translate. It’s only been more recently where the way we developed drugs is so much more rational. It’s not just, “Here’s a thousand different chemicals, let’s try each one on a Petri dish cancer cell and see what kills it.” Which is in some extent the way drugs, cancer chemotherapies were developed back in the day. And so, there wasn’t really a need to translate that. It was just, “Okay, this drug seems to work, let’s go try it in patients.” Now that virtually never is the way we develop drugs. Now, almost everything is, “Okay, someone identified, someone in a laboratory identified a particular pathway into cancer that seems like it’s a potential vulnerability. Let’s design a drug that hits and inhibits that pathway and then we’re going to take it into the clinic.”
And so, there’s a much more rational, science-driven approach to drug development. And because it’s so much more sophisticated there, it’s basically necessitated the need for us translational investigators, to do the translation that you just alluded to because it’s just so much more complicated. In a good way. But again, it requires this type of person, whereas before there wasn’t so much of a need. And unfortunately, I mean because this is a relatively new profession, there has needed to be a lot of work in medical schools and in cancer centers to develop this role because these people didn’t exist before.
Chris Riback: With the added complexity that you are describing though, I assume that the partner of that complexity is greater precision, greater customization. Perhaps, you correct me if I’m wrong, maybe less, I’m hesitant on the word guesswork, so I would absolutely put it in quotes, but more precision with individual patients with, there’s more complexity involved, but that is resulting in better opportunities. Again, you correct me if I’m misinterpreting this.
Dr. Ian Krop: No, I think they’re exactly right. When I started, the number we tossed around in terms of the percentage of early-stage clinical trials of a drug that actually worked was less than 5 percent. So, in other words, 95 percent of drugs flamed out early on because there was a lot more guesswork involved back then. Now we’re surprised when drugs don’t work because they’re just designed, as you were pointing out, they’re just designed in such a more targeted way for the particular patient’s tumor that they tend to work now. And we still need to tweak things and there may be unexpected findings, but we’re starting in such a better place now because of all the work that was done to get the foundation that was built to that, were now just doing everything in a more sophisticated way because under our scientific understanding, our scientific tools are just so much more effective than they used to be.
Chris Riback: So I want to get into one of maybe your particular area focus, HER2-positive breast cancer area. But before I do, just in listening to you and your use of the word, a couple of times—impact—and it’s feeling evident to me that that’s an important result for you, feeling both factual and tangible, but also on some level emotional or a feeling, a positive feeling that you get. And I mean you lead clinical research initiatives at Yale, and on the one hand, what an incredibly inspiring opportunity to have such potential impact on such important work. And yet at the same time it must be very intimidating because any organization has a limit at some point on its resources and you have to help make very hard decisions. How do you think about that balance?
Dr. Ian Krop: Fortunately, we’re in an era where there are resources available to do good science and that’s resources from biotech companies, from NIH, and the Natural Cancer Institute, which funds a lot of research. And then we have foundations and I’d certainly be happy to talk about how BCRF has impacted my research and allowed me to ask questions that I wouldn’t have been able to ask otherwise. But I think the question of just what is the scientific strength of a particular question now is really the strong driver of what goes forward. I mean, there’s always going to be some guesswork because none of us have crystal balls. But now because science is driving things so much rather than more random kind of, as I said, choice of chemical one versus chemical two as a drug candidate, because science is driving things, you can really be objective.
Actually I just spent the last two days reviewing grants for trials, proposals, and you can sit around, and you can objectively say, “Hey, this science is really strong, and I think this is going to therefore have a very good chance of helping patients. So, I’m going to fund that. This one really needs more work and I’m going to send this back for revision.” Now we’re at a point where we can adjudicate things based on the strength of the science and allocate our resources that way. Again, because everything is just being done in such a more rational way than it had been before. And of course we also can are influenced by the need. There are cancers where the unmet, unfortunately, there’s a huge still unmet need and we need to devote more resources there. And so that factors in as well when we review things, is this going to be the seventh drug for a particular cancer context or is this the first? And obviously that should factor in as well.
Chris Riback: What is HER2-positive breast cancer?
Dr. Ian Krop: Well, I’ll start from the beginning. So HER2 is a protein that sits on a vast, a large number of our normal cells. And its job is to tell that cell under situations of stress, “Hey, we need to toughen up and we need to grow faster, and we need to be resistant to toxins and we can’t afford to die.” So, it’s kind of a stress response protein is what we call it. And again, it’s a normal protein. Usually a cell has a thousand or a few thousand of these guys sitting on surface sensing situations of stress. But in about 15 or 20 percent of breast cancers, as they’re forming, there’s an alteration in their DNA that leads to duplication of the gene, the of the DNA that codes for this HER2 protein.
Normally every protein has two copies of a gene in these subsets of cancers because of this. What this mutation essentially that happens in the DNA, they end up with 20, 30, 40 copies of the HER2 gene and the genes are the blueprints for the protein. So now instead of the cell working off two copies of the blueprint, they have 20 and each blueprint is making protein. So what happens is you get way too much of this HER2 protein. So, in these 20 percent of cancers of breast cancers, they have instead of a few thousand copies of HER2, they have a million or 2 million copies on each individual cancer cell.
Now if the job of that HER2 protein is to tell the cell to get more aggressive and grow more quickly and not to die, and you’ve got now millions of these guys each telling the cell to do that, it’s not a surprise that these cells start growing more aggressively and become resistant to death and can become very problematic.
So, when I first started as an oncologist around 1999 or so, having a patient be identified as having HER2-positive breast cancer was a scary thing because we knew those cancers were going to grow more quickly and they were at a much higher risk of recurrence, and they were tended to be resistant to standard things like chemotherapy. So we all dreaded finding out that a patient was HER2-positive.
But right around that same time, it was recognized by several individuals, laboratory scientists, and probably one of the first, one of these early translational scientists, a guy named Dennis Slamon, that the reason these cancers were behaving this way was because of this over expression of this HER2 protein. And once that realization was made, it led to the development of drugs that blocked that HER2 protein. And the first one of those was a drug called trastuzumab or known as Herceptin®.
And that was one of the first demonstrations because when they took the AT protein and they injected it into patients with HER2-positive breast cancer, along with chemotherapy, it dramatically improved the effectiveness of the chemotherapy, and the survival increased dramatically. And it was one of the first demonstrations if you can identify what’s driving a cancer, you can make drugs to block that driver and that can have really dramatic effects on your ability to kill those cancer cells. So, it’s one of the first examples of targeted therapy that really kind of changed our mindset of what understanding the driver of a cancer can do in terms of leading us to effective therapies.
And in HER2-positive disease, this Herceptin really changed the outcomes of patients for the better. Not only did it treat people with advanced HER2-positive breast cancer and extended their survival, but it markedly, by half, cut the number of patients who had early disease after they had their lumpectomies or their mastectomies for their cancer cut down the number of patients who had recurrences down the road by about half. So it really revolutionized the treatment for HER2-positive breast cancer and led to many other HER2 directed therapies. But it also kind of really opened the door to this idea of targeted therapy, not only in breast cancer but in other cancers. So that’s kind of the very quick high-level summary of HER2-positive breast cancer.
Chris Riback: It’s a terrific summary and the visual of those HER2 proteins—millions of them communicating and over-communicating and over-communicating to negative cells, cells doing bad things. Yes, that’s a very powerful and upsetting visual, obviously. However, as you just described, there’s been the work with the Herceptin and chemotherapy. And now as I understand it, and you’ll correct me please if what I have wrong, your clinical trials are testing the benefit of immunotherapy in combination with Herceptin and chemotherapy in advanced HER2-positive breast cancer.
What is your hypothesis? What is the status of the trial? I understand you may be seeking or were seeking a total of a hundred patients for the trial. Have you gotten there yet?
Dr. Ian Krop: Yes, so you’re spot on in terms of what we’re doing in this particular trial. So, you know, you could say, well if we’ve got this great drug Herceptin and we’ve got other drugs, second and third-generation drugs like it, are we done with HER2-positive breast cancer? And in fact, it’s now in many ways better to have HER2-positive breast cancer than almost any other kind of breast cancer because now with the advent of HER2-directed therapy, people do extraordinarily well, and recurrence rates are way down and people with advanced disease are living much longer.
But in patients with metastatic disease, which is when cancer spreads beyond the breast, even in HER2-positive disease in most patients, unfortunately, eventually the cancers become resistant to all of our therapies. We have eight or nine of these HER2 therapies now. But in most patients, eventually the cancer learns to be resistant to all of them. So, there’s still a need to do better even in HER2-positive disease. And there’s a lot of different approaches being tried.
But the one that we had been working on recently, and the one that BCRF is most correctly helping us with, is asking this immunotherapy question. And many people have started to hear about immunotherapy, but just so we’re all on the same page, what immunotherapy from a cancer context anyway is, is trying to teach our own immune systems how to fight a person’s cancer. It turns out actually that while we think of the immune system as fighting off strep throat and the flu and COVID, bacteria and viruses, it’s also designed to fight off cancers and there’s the idea that people develop cancers, little microscopic cancers all the time, but most of the time our immune system recognizes that they shouldn’t be there and the immune system just goes in and wipes them out before they ever amount to anything.
So, our immune system is designed to kill cancer cells, but for some reason, and we don’t completely understand this in some patients, at some time, the immune system doesn’t recognize a budding, nascent cancer as being foreign and for whatever reason doesn’t attack that and allows the cancer to grow. So essentially when a person has a cancer that’s diagnosed, it means that for whatever reason, that person’s immune system wasn’t able to effectively kill off that cancer cell. So, the idea is of an immune therapy is to help that person’s immune system recognize and effectively kill off the cancer. Like it was essentially originally designed to do.
And we’ve made enormous strides in that area. We’ve identified some of the ways that the cancers suppress the immune system, and the field has developed drugs that prevent the cancer from suppressing the immune systems. It’s kind of like a double negative there. But by using these drugs, it allows the cancer basically, I’m sorry, it allows the person’s immune system to wake up and start attacking the cancer because the cancer can’t suppress the immune system anymore. And that’s really when we talk about immune therapy right now, that’s what we’re talking about. We’re talking about drugs that allow, that prevent the cancer from suppressing the immune system so the immune system can reactivate and attack the cancer. And those have been extraordinarily effective. Extraordinary effective in a number of cancers where there really were very few options in the past, like certain kinds of lung cancer and melanoma and kidney cancer, those have just been revolutionized by the development of immune therapies.
In breast cancer, immune therapies have been a little bit harder to develop, but there are now several that are approved in a kind of cancer called triple-negative breast cancer, but so far not so in HER2-positive breast cancer. Which is in some ways a little surprising because in fact we’ve known now for years that one of the ways that Herceptin, the first drug to target HER2, not only does it block HER2’s function to some extent, but it also kind of alerts the immune system that this cancer is there and kind of attracts the immune system to attack the cancer.
But very, it turns out it’s a pretty weak stimulant of the immune system, but we know that there is some ability there for the immune system to work against HER2-positive cancer cells, but it’s quite weak compared to other immune effects. And so, our hypothesis was, “Okay, there is some ability of the immune system to attack a HER2-positive cancer, but what can we do to build that up so it becomes more effective and have a bigger impact. Especially in these patients whom for whom our regular HER2 directed therapies have stopped working.” So that’s kind of the general idea of this.
Our first hypothesis was what can we do to stimulate the immune system beyond where we already are? And the way we tried to address that hypothesis was to say that there already, as I mentioned, there are approved immunotherapies that stimulate the immune system. Those had been shown to have a pretty modest effect if maybe even less than modest effect, in HER2-positive disease. But what we wanted to do was combine Herceptin with these immune therapies because we said Herceptin already has a little bit of an immune effect. Let’s add these approved immune therapies or at least approved for other cancers. Let’s add that to Herceptin and chemotherapy.
And as a further way to push the needle, take completely a very novel immune therapy, a drug that hasn’t been approved, only just recently developed, which is targets a slightly different part of the immune system; let’s test that too, because there’s a number of laboratory studies saying that that could be particularly valuable in HER2-positive disease.
Chris Riback: Is that AVIATOR?
Dr. Ian Krop: So the trial is called AVIATOR. The central question in AVIATOR was can we take patients who had HER2-positive metastatic disease that had already developed resistance to pretty much all of our usual therapies and compare what was available at the, what was standardly available, which was a different chemotherapy with Herceptin, to that same chemotherapy and Herceptin, but add the more standard immunotherapy or add all four drugs. So chemotherapy, Herceptin, and both the older immunotherapy and the newer immunotherapy. So fortunately, these immunotherapies are pretty targeted. So, you can use four different drugs together without making it have too many side effects. If you tried to do that with chemotherapy, that wouldn’t work. But we’re adding, we’re testing basically three targeted therapies and one chemotherapy, and so you can combine those safely.
So that was idea of the AVIATOR trial was to randomly compare a standard regimen with one plus against standard therapy plus one immunotherapy or both immunotherapy. So it was a pretty ambitious approach, but we felt that it was, this was the right time to try that, given all of the science behind it, saying that in the laboratory, this kind of four-drug combination could work really well in patients with this HER2-positive kind of breast cancer.
Chris Riback: And where are you in the trial now?
Dr. Ian Krop: So funny you should ask that. So you were correct that we needed to enroll a hundred patients, 40 patients got one immunotherapy, 40 patients got two immunotherapy and 20 patients just got the chemotherapy and the Herceptin. But if in those patients, if that didn’t work, they could then get immune therapy. So, it was a hundred patients, and literally yesterday I got the notice that the final hundredth patient was enrolled.
Chris Riback: Wow.
Dr. Ian Krop: So your timing is impeccable. We are now finished enrollment, and so we now are waiting to allow patients to see how they’re doing on these three different kinds of treatment.
Chris Riback: Wow. Well you want to break any news here?
Dr. Ian Krop: We need to wait to see how these drugs work. We haven’t analyzed the results, but we’re very excited to finish enrollment. And now we’re hoping that patients stay on these therapies for a very long time. And it’s going to take, we hope that it takes us 10 years to analyze it because that means that patients stayed on these therapies for a very long time. But anyway, it’s excited to have finished enrollment and we will hopefully have the results in the not-too-distant future.
But I would say that not only one of the nice things about a trial like this, and with BCRF support we’re allowed, we’re able to do this, which we wouldn’t have been able to do if this was just us [and a] company, a study that would be supported by a pharmaceutical company. What we’re able to do is do biopsies of the patient’s tumor before and during the treatment.
Dr. Ian Krop: And by doing that, and we’re very appreciative that patients are willing to undergo these biopsies because they know it’s going to help the science and help us make progress, but what we are able to do with those biopsies is really understand at the molecular level what these different drugs are doing, how the immune system is being stimulated, how is it being stimulated in one patient and not in another patient? And does that help us understand how all these different drugs are working together and hopefully give us clues on if they’re not working in each patient, what we can do to supplement that so that they do work.
It also allows us to understand how the cancers could become resistant, either to the particular therapy that we’re giving or by looking at the biopsy before they even start, why did the patients be developed resistance to the last two or three drugs that they were on? So, there’s a lot we can learn. And this is that translational aspect of, yes, we’re testing a drug, but we also want to learn as much as we can about how the tumor’s behaving so that we can then develop the next drug.
Chris Riback: You just touched on yet another point that runs true through these conversations that I’m so fortunate to get to have, and that just is the courage and selflessness of patients who enter trials, literally give of themselves. And it is to help folks like you be able to help them and help unfortunately the people to come. And yes, you just phrased it so well about what the patients in your trial are doing and their courage is always very, very inspiring to me.
Dr. Ian Krop: Yes, and to me too. I mean, it’s one of the most satisfying aspects of this job and why I feel so very fortunate to be able to work in the clinic as well as in the office, is to see the heroism of women who are—[and it’s] mostly women—who are dealing with very difficult circumstances. And yet almost always ask, “Well, what can I do to help figure out how we can beat this thing, not just for me, but for all the patients who are going through this.”
Chris Riback: What role has BCRF been able to play in your research?
Dr. Ian Krop: Biopharmaceutical companies spend an enormous amount of money developing drugs. They’ve helped us make great progress, but their job is to develop drugs as quickly as possible. And when they design their trials, they’re usually fairly straightforward. What do we need to do to get to the next step of drug development? And we partner with them all the time. We do trials with pharmaceutical companies support all the time because it really has led to a lot of breakthroughs, but it’s harder to ask the kind of questions that we’re asking in this trial. Again, not only does drug A help versus drug B and whether one immunotherapy or two immunotherapies, but as we’ve kind of talked about, by looking at these biopsies, can we understand more fundamentally why one drug is working and another is not working in a particular patient but may work in another patient.
Why does the cancer respond initially, but then six months or a year later, stop responding? Those are questions that if we’re really going to make progress in the big picture and long term, we need to get at that. And that takes both contributions from the patients allowing us to obtain these biopsies. And it costs money to do the biopsies, it costs, the sequencing the DNA of these cancers is expensive. All those things cost a lot of money, but it’s the way to really understand fundamentally what’s going on. And that’s something that BCRF was incredibly generous in supporting, not only this pretty large trial that took several years to carry out, but add on these additional fundamental tests that we are doing to both to help figure out how to use these particular immunotherapies, but also hopefully learn more about how breast cancer’s behaving in general.
So that’s something that BCRF has allowed us. I mean, they allowed us to do the trial at all, but really went beyond that to say, “Okay, you can also to learn as much as possible from this trial from our patients. Do these extra biopsies, do the extra molecular testing that’s going to yield hopefully the really key information that we can use to make progress.”
Chris Riback: Dr. Krop, thank you. Thank you for your time. Thank you for the work that you do.
Dr. Ian Krop: Sure, my pleasure. Thanks for giving me the opportunity to spread the word.
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