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Breaking the Blood-Brain Barrier

Advances in treating brain metastases and reducing their side effects are bringing new hope to cancer patients. By Sue Rochman

​Illustration © Morphart / Canstock/ Watercolor Mixed Media © Thinkstock

As the calendar turned to September 2014, Leslie Falduto was feeling at the top of her game. The cancer survivor was running six miles, three days a week. Her oncologist had recently told her she was doing great. And at work, Falduto, a registered nurse, was returning to her favorite post, the neonatal intensive care unit.

Talking about her diagnosis of stage III breast cancer in September 2008 still made her feel anxious. But in the world of cancer, five-year survival is one of those measures that is supposed to make you think, OK, maybe now I can pop the champagne. And Falduto, a mother of two from St. Paul, Texas, had passed that marker the year before.
But on Sept. 7, when she went to leave the neonatal unit, an odd thing happened. “I couldn’t remember how to open a door,” recalls Falduto, 38. After that, “I couldn’t remember how to walk.” Her right leg started shaking uncontrollably. Then, she passed out. When she awoke, Falduto was in the emergency room, where she was told she’d had a seizure. A neurosurgeon requested an MRI. The scan revealed a tumor the size of a pingpong ball—metastasized breast cancer—deep in her brain.

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Learn about possible courses of treatment for patients with brain metastases.

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Learning that cancer has metastasized, or spread, means coming face-to-face with the reality of an incurable illness. Learning that the cancer has spread to the brain—the place, in essence, that makes each of us who we are—can be even more unsettling.
“I think there are levels of metastasis, and the brain is the one that everyone really fears the most,” says CJ Corneliussen-James, a co-founder of METAvivor, an Annapolis, Maryland–based organization focused on research and support for patients with metastatic breast cancer.
“When you think about brain metastases, you are thinking in terms of: Now my clock is really ticking,” says Corneliussen-James, who was diagnosed in 2006 with metastatic breast cancer that had spread to her lung. “And you are [also] concerned that you will lose the ability to function or think.” For people living with metastatic disease “who have been around people with brain metastases, that is less of a fear. But for [metastatic patients] who have not had any interaction with someone with brain metastases, there is much more fear about what will happen and how they will cope.”
Forging Their Way
Brain metastases are the most common form of brain tumor in adults. No precise statistics are available, but according to the American Brain Tumor Association, between 100,000 and 170,000 cancer patients in the U.S. learn their cancer has spread to the brain each year. A patient’s risk of developing brain metastases depends primarily upon where the cancer started. Lung cancer is the most common source of brain metastases in men and women, followed by breast cancer in women and melanoma in men, and colorectal cancer in both men and women. Overall, though, melanoma is more prone than other cancers to spread to the brain.
Cancer cells can spread to the brain by traveling through the bloodstream, but they must cross a major obstacle: the blood-brain barrier. The blood vessels that make up the barrier are lined with endothelial cells and act like a strainer: They let in small molecules like the hormones and nutrients the brain needs while keeping out larger toxins and bacteria.
Because of the blood-brain barrier, most cancer cells that try to cross to the brain don’t make it, which is one reason that brain metastases aren’t as common as, say, bone metastases. But some cancer cells do get through the barrier. Once a cancer cell gets into the brain, it typically latches onto the wall of a blood vessel, which it can use to fuel its growth.
During the past five years, oncologists have reported seeing an uptick in cancer patients with brain metastases—and it’s not clear why. “One theory is that new treatments are better at controlling disease outside of the brain,” says DeeDee K. Smart, a radiation oncologist at the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland. This is allowing people to live longer, which could be giving more time for brain metastases to develop. “The other theory,” she says, is that as people are living longer, they “are now going through more chemotherapy regimens,” which may lead cancer cells to develop new types of mutations that change how, when and where they spread. This is because chemotherapy drugs typically used to reduce or eliminate metastases in other organs are made of molecules that are usually too large to get through the blood-brain barrier. “The brain becomes a sanctuary site for cancer cells, a place they’re hiding out,” says Smart.
Researchers had hoped that some new smaller-molecule therapies would be able to squeeze through, and their hunch proved correct when studies showed that BRAF inhibitors and checkpoint inhibitors—systemic therapies being studied in patients with melanoma—not only extended survival but reduced the size of brain metastases.
“Now not only do we have drugs that work in melanoma,” says Jeffrey Weber, an oncologist who directs the Donald A. Adam Comprehensive Melanoma Center at the Moffitt Cancer Center in Tampa, Florida, “but they work in the central nervous system—in brain metastases [caused by melanoma]—and that is revolutionary.” And they may do the same for brain metastases caused by other cancers, too.


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