Precision Medicine Pioneer Targets Earlier Cancer Detection

; Brian J. Druker, MD


April 17, 2017

A Precision Medicine Pioneer Talks Precision Cancer Detection

Eric J. Topol, MD: Hello. I am Eric Topol, editor-in-chief of Medscape. It is a special treat today to have Dr Brian Druker from Oregon Health & Science University (OHSU) with us to talk about what he has been doing in the field of cancer, both the science and the treatment of cancer. We are talking to a real pioneer. Welcome, Brian.

Brian Druker, MD: Thank you, Eric. It is a pleasure to be here with you.

Dr Topol: Here we are in La Jolla, San Diego. You did some of your education here, right?

Dr Druker: Yes. This is where I got started. I remember sitting just up the hill in a classroom listening to the history of the cure of childhood leukemia and chemotherapy drugs. I was daydreaming about how barbaric it was. I thought, "There has got to be a better way." Some of my teachers were talking about understanding the molecular basis of cancer. That just stimulated my enthusiasm and curiosity. Is there a better way? Could we treat cancer more intelligently by understanding what is driving the growth? Here we are in a genomic era and that is exactly what we are doing.

Dr Topol: You went from the University of California-San Diego to Washington University for your residency and then to Dana-Farber for oncology. How long have you been at Oregon?

Dr Druker: I have been there 23 years now.

Dr Topol: Relatively recently, you got Phil Knight of Nike, together with other donors, to donate a billion dollars?

Dr Druker: There is a story behind that. We had an event and Phil Knight, the co-founder of Nike, which is based in Oregon, was introducing me. We had a proposal in front of him for an ungodly amount of money—like a billion dollars, but he had not kicked us out. He was introducing me at this event. To everybody's surprise, including me, he got up and said, "Penny, my wife, and I will donate $500 million for cancer research if you raise a matching amount in 2 years, and it's all or nothing." You have to realize that the baseline of fundraising for cancer, at my institution, was about $10 or $15 million a year. That was an enormous challenge. We stepped up to it, and within 22 months we met it.

We are now in the process of building an entire program on what I call "precision early detection of cancer"—trying to move it back earlier and get out of this conundrum of mammograms and prostate-specific antigen tests, which we think overtreat; or for pancreatic cancer, which we never detect early. We are trying to be more accurate in taking the same precepts of precision medicine for advanced cancer and using them earlier. Ultimately, that sets the stage for precision prevention, which you do so well in cardiology but which we have a lot to learn about in oncology.

Lessons From Gleevec: Start Treatment Early

Dr Topol: I wish we did it even better in cardiology. Before we get into where things will head in the future, I want to go back to Gleevec (imatinib). One can't think of Gleevec without thinking of you. Obviously, you have been recognized with the Lasker Prize and the Albany Medical—which are pre-Nobel prizes—for that discovery. What was going on when you made the discovery of Gleevec?

Dr Druker: As with everything, there was a lot of skepticism. The view of the community was that single-agent therapy for cancer will never work. Kinase inhibitors will never work because ATP is ATP and you will shut down every kinase in the kinome. There are going to be at least a thousand of them, so they are going to be incredibly toxic. They won't work. And for a rare disease, it will never make enough money for a drug company.

There were some small hurdles. We ultimately identified a compound and got it into clinical trials. It pretty much worked for everybody with chronic myeloid leukemia that was driven by the BCR-ABL oncogene. When you have essentially a 100% response rate with minimal toxicity, it is actually pretty easy to get it through the US Food and Drug Administration (FDA).

When people said, 'Targeted therapy is going to work for all advanced cancers,' they forgot that simple precept: You have to start earlier.

When I give a talk about this success, it's about understanding the critical drivers of disease and matching the right patient with those treatments, but it's also about starting early in the course of the disease. We know that as cancer advances, it becomes much more heterogeneous. That is actually something that people forget. When people said, "Targeted therapy is going to work for all advanced cancers," they forgot that simple precept: You have to start earlier.

When we think about what is happening in the immuno-oncology space, we have to understand those rules. We need precision immuno-oncology. Who is responding? Why are they responding? How do we combine these drugs? That is how we are going to attack advanced cancer. I am trying to move it earlier to what we have learned with Gleevec, which is to treat early in the course of the disease before it progresses to an advanced malignancy.

No One-Size-Fits-All Screening Test or Cure

Dr Topol: What have been sobering recently are the reports that cancer can spread very early. This is against the dogma. It used to be thought that it would take 10 or 20 years. For many solid tumors, it looks as though this is an issue. Is this perhaps the reason that screening has failed, because it doesn't capture the people who are already advanced?

Dr Druker: We often get locked into this one-size-fits-all thinking. We will screen for all cancers, and all cancers progress through a very simple stage. Some cancers clearly do, some cancers don't; and for those, the types of screening we do probably will not work very well. For other cancers, screening and early detection will work. I wouldn't throw the baby out with the bath water just because for some cancers [screening] won't work. Clearly, there are others where it will work. We have to be very careful about not overpromising what we are trying to deliver.

Dr Topol: There is a lot of interest these days in plasma tumor DNA as a way to track the earliest stage of cancer. What are your thoughts about that?

Dr Druker: It's incredibly exciting to think about a blood-based detection technology. I don't think it's going to be the only way to detect cancer, but it's going to be one of the tools. There will be some cancers, or maybe some subtypes of cancer, that progress relatively slowly and that release DNA or RNA into the circulation, where detecting circulating nucleic acids will absolutely work. There may be other cancers in which that won't work. Maybe we need some new imaging technology. Maybe we will need a chip that we can implant which will detect cancer.

Dr Topol: Constant surveillance?

Dr Druker: Think about it as a surveillance network in which we could detect something that triggers a more thorough evaluation. There are all sorts of ways we can think about early detection. Nothing is going to be a one-size-fits-all cure.

Dr Topol: With chronic myeloid leukemia and Gleevec, there was an incredible result. As we have seen with many of these other genomically guided drugs, there can be an extraordinary response, almost magical. Then, 9 months later, the badness comes back. This is a real problem. Some people have said, "That is when you have to get the immunotherapy going." How are we going to deal with this issue of delayed unresponsiveness or recurrence?

Dr Druker: First of all, when we talk about chronic myeloid leukemia and Gleevec, the 10-year survival rate is close to 85%-90%. The relapse rate for that disease is pretty low, but resistance does occur. We know that in more advanced cancers, the typical response rate to a single-target agent is 6-12 months. We take the same approach. We have to understand why people become resistant. What we have learned is that some of it is on target. Much like HIV, the cancer has evolved mutations so the drug no longer binds to the target. We understand that that is one element of resistance. We also understand that there is off-target resistance. The drug still binds and shuts down its target, but there is an escape pathway inside of the tumor. There are also tumor extrinsic [factors]—the microenvironment, the tumor immunology. That is where immune therapies can work.

We take that same path of understanding the elements of resistance and use that to preempt resistance before it occurs. That is really simple, and what I have always believed in is that you have to understand something if you are going to fix it. We have to understand all elements of resistance.

Dr Topol: Do you think we will see, in our lifetime, vaccines based on neoantigens and an entirely different type of immune-based prevention or treatment?

Dr Druker: I am absolutely hopeful. We are seeing some evidence that neoantigen-directed immune therapies are working in advanced cancer patients. There is every reason to believe that those can be moved earlier to treat patients who have emerging cancers and prevent them from becoming advanced cancers.

Cost and the Cancer Treatment Economy

Dr Topol: Let's move from the science to the practical. You have these very expensive drugs—in fact, even Gleevec has become much more expensive. You have immunotherapies and all of these new cancer drugs. Everything is like $100,000 or more per treatment. How are we going to deal with this? There is an economic crisis in oncology.

Dr Druker: It's a difficult problem, Eric. What I have said is that we have to support the drug companies because they are developing most of the drugs. If they go out of business, we do not have lifesaving medications. As an economy, we can't continue to afford the high prices. We have to find a middle ground somewhere. I wish I had the economic capability to understand how to balance that. Clearly it's a global issue; it's not just the US economy. These drugs are global, these companies are global, and everybody needs to pay for them. We need a healthy business economy. We need to have a sustainable healthcare industry. It's a really tough problem. I wish I had a simple answer.

Dr Topol: Because these drugs are so expensive, should they be guaranteed to succeed or your money back?

Dr Druker: I don't know about a guarantee for success. I'm involved in an acute myeloid leukemia project in which we are trying to help companies accelerate the path to FDA approval. With Gleevec, it took 1000 patients on the trial to get FDA approval. All we learned from patient 100 to patient 1000 was more about the safety. We didn't learn anything more about how effective it was. The response rate didn't change because everybody had the same genomic profile.

If we could have approved that drug after the first 100 patients—a quick path to FDA [approval]—the company starts to recoup their investment more quickly, and maybe they don't need to price it quite so high in the long run—as long as there are incentives for them not to price these drugs too high, or it's not a market-driven economy.

Dr Topol: That is a really good idea. Hopefully we will see something like that. You have done such exceptional work—the leadership that you are providing in Portland, at OHSU and at the amazing Knight Cancer Center. You have opportunities now because this is the most exciting field in medicine. There is so much going on. The science is advancing. There are so many new ways to approach this, with respect to early diagnosis as well as these advances in therapy at multiple dimensions. I want to leave with a sense of what cancer treatment and prevention will look like in a decade.

Dr Druker: The analogy I use is, what if we turned the clock back 100 years and looked at infectious diseases? Over the past century, the 1900s, we had public health measures like chlorination of water and pasteurization of milk. Those are preventive [strategies]. We brought along antibiotics, which are targeted therapies. We brought along vaccinations, and polio and smallpox were eradicated. If people took vaccines, then mumps, measles, and many other infectious diseases would be essentially eradicated. That's immune therapy. Zika comes along, HIV comes along—certainly we have not completely eradicated infections, but we do not fear them. If you go to the doctor with pneumonia, [it’s] "what antibiotic do I take?" In 1900, that was a death sentence. That's what I see for cancers. It's a broad-based approach. It will be more genomically based therapies. It will be prevention and early detection, in a precision-based way. It will be immune therapies in a precision-based way. Then cancer will no longer be a feared, dreaded disease.

Dr Topol: Wouldn't that be wonderful? It may not have to be cured, necessarily, but it could be managed and not take one's life.

Dr Druker: Exactly the same paradigm that we have for infectious diseases. Cured, managed, and prevented—that is where we want to be as soon as we can.

Dr Topol: Brian, thank you. This has been a great discussion. I could talk to you for hours. I want to thank all of you for tuning in to this Medscape One-on-One with Dr Brian Druker, who has been a pioneer in cancer treatment. It has been great to have him. Thank you for joining us.


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