The Blood-Tumor Barrier Is Critical in Brain Metastasis Control

Mark G. Kris, MD


February 14, 2019

This transcript was edited for clarity.

Hello. This is Mark Kris from Memorial Sloan Kettering, speaking today about a common and really difficult problem in the care of patients with lung cancer, which is the treatment of brain metastasis.

There has been much recent activity discussing how drugs can be used to treat brain metastasis and some of the difficult decision-making that ensues, including whether to use drugs or to use a local measure, either surgery or radiation, which by and large has been our standard when we face patients with brain metastasis.

I will talk more about the selection in a subsequent video, but today I would like to discuss the problem itself. The first thing is that brain metastases are tremendously common. My research group—myself, Bob Li, Michael Offin, and Alex Drilon—has recently been looking at the incidence and course of brain metastasis in patients with oncogenic targets.[1]

We found that they are extraordinarily common. I obviously think I always felt that, and you may know that too. I was really surprised to see that for EGFR- and HER2-[positive lung cancers], as an example, 47% of patients develop brain metastases during the course of their illness.

Second, if you develop a brain metastasis, at least in an analysis of having it or not, your survival is clearly lower. In fact, in the EGFR cohort that we looked at of about 200 patients, the survival of people who ever developed a brain metastasis was half of that compared with people who never developed a brain metastasis.

It's interesting that, even in that group, the people who lived a very long time and did not develop a brain metastasis lived the longest. I think many people have felt that the incidence of brain metastasis goes up over time. In our cohort that had the best survival, they didn't develop brain metastases as time went along.

The other important things to consider are the different issues related to brain metastasis. The first issue involves existing brain metastases—brain metastases at diagnosis. The second issue involves brain metastases developing in and during treatment. Please try to separate these two because they are distinctly different conditions and require different therapeutic approaches.

One common misconception is that there is a blood-brain barrier that always keeps cancer drugs from going into the brain. Now, indeed, it is true that there is a blood-brain barrier and it is a source of resistance to drug penetration and to the central nervous system (CNS). However, when a tumor is present, again, those patients who have a brain metastasis when they present or they develop one during the course of their illness—and you have to treat the brain metastasis that's there—there is no blood-brain barrier. This barrier has been replaced by the blood-tumor barrier.

For people with brain metastases, the blood-tumor barrier is most important. The blood-tumor barrier is probably not site-specific. There is not much research on this, but whether you have a tumor in the lung or in the brain, the barrier between the blood and the tumor is very similar.

The general observation is that whatever the rate of response is for a drug in a primary site or in a non-CNS metastatic site, the rate is virtually identical to the CNS in patients with existing CNS metastases. I urge you to look at various papers, and you'll notice that, over and over again, the rate of benefit in the brain is virtually identical to the rate of benefit throughout the body.

Again, the issue there is the blood-tumor barrier, not the blood-brain barrier. The blood-brain barrier is important; in trying to prevent the emergence of brain metastasis, it is all about the blood-brain barrier.

I'll share a few words about the prevention of subsequent metastasis and where the blood-brain barrier is critical. First, control of the primary tumor is absolutely essential. Whatever can be done to lead to control of the primary tumor is going to cut down on brain metastasis. The most successful surgery, radiation, multimodality program—if it cures the cancer, you're not going to get a brain metastasis.

Here, the potency of the drug is important. The more potent the drug, the more likely it is to kill the cancer in the first place. This is where CNS penetration becomes important. If you're trying to prevent recurrence or progression in the brain, then drugs that can cross the blood-brain barrier are critical.

I think that's very important in drug selection. There is ongoing discussion about what is the best drug to give up front, particularly in the EGFR and ALK space. To me, there is no question. You should give osimertinib or alectinib. In the literature, the more potent drug and the more CNS-penetrant drug is more successful in preventing metastasis. This is another reason to give those drugs first, to always give them up front, and not to reserve them, as some people feel is a strategy.

Please remember that there is a difference between the blood-brain barrier and the blood-tumor barrier. Different situations require different processes and plans of treatment. Always, the best drug is the one that is most likely to treat and/or prevent brain metastasis.

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