Research in Action: Accelerating Treatments for Breast Cancer Brain Metastases

The first in our “Research in Action” series, BCRF highlights recent research advancements for this difficult-to-treat form and calls attention to the need for more research

Jen Feinberg lived for two years thinking that breast cancer was behind her.

At her second-ever mammogram, she had been diagnosed with ductal carcinoma in situ (DCIS) and opted to undergo a double mastectomy. Afterward, her oncologist told her they had found a one-millimeter micro-metastasis that was a different subtype (HER2-positive) than the DCIS, but by having the double mastectomy, she had pursued the most aggressive treatment. She went on with her life, working as an attorney and raising her two daughters with her husband.

Then, in 2020, she got the gutting news that she had developed HER2-positive metastatic breast cancer (MBC). She soon started on two HER2-targeted therapies, trastuzumab (Herceptin®) and pertuzumab (Perjeta®). Jen jumped into researching future lines of therapy and clinical trials to try to stay one step ahead of the disease and prepare for the day when her first-line treatments stopped working.

Eighteen months after her initial MBC diagnosis, at the end of 2021, she learned that the disease had metastasized to her brain. Brain “mets” are devastatingly common in patients with HER2-positive MBC like Jen: Up to 50 percent of these patients will develop brain mets, and those who do typically experience poor survival outcomes. Brain mets are less common in other types of breast cancer, like hormone receptor–positive disease.

Historically, brain mets were notoriously difficult to treat. And targeted therapies presumably couldn’t cross the blood-brain barrier, the vessels and tissues that “guard” what reaches the brain. The blood-brain barrier is helpful for keeping out things like bacteria and allowing in things like oxygen and water—but it’s an impediment to anticancer drugs.

Because of that fact and their worse survival outcomes, patients with brain mets have been almost universally excluded from clinical trials, compounding the matter. Without clinically testing newer drugs in patients who developed brain mets, patients had limited options and were generally treated with surgery and radiation, often as a palliative care measure.

But in just the last four years, this story has changed—all because of research.

“I was terrified when I first learned that I had brain mets but comforted by the fact that there were approved therapies and clinical trials available to me then,” Jen said.

In 2020, BCRF investigator Dr. Nancy Lin presented results from the groundbreaking HER2CLIMB trial showing that the anti-HER2 drug tucatinib (Tukysa®) could cross the blood-brain barrier and improve outcomes for patients with brain mets when combined with trastuzumab (Herceptin®) and capecitabine (Xeloda®).

HER2CLIMB was one of the first major trials to include these patients—and might not have been possible without BCRF support. In 2013, with funding from BCRF, Dr. Lin was able to launch a phase 1 clinical trial testing tucatinib for brain mets at Dana-Farber Cancer Center, where she runs the Brain Metastases Program.

“We found that patients experienced tumor shrinkage in their brain with this regimen, and we noticed that some patients’ cancer stabilized, both in the brain and in their bodies for up to two years. This gave the manufacturer of tucatinib confidence to include patients with brain metastases in all their subsequent trials, including our HER2CLIMB study,” Dr. Lin said in 2020.

Those early results, Dr. Lin said, were the first to support including patients with brain mets in clinical trials, including the HER2CLIMB trial that ultimately led the FDA to approve tucatinib for HER2-positive patients with brain mets—changing the treatment landscape.

“This exemplifies the best of BCRF and how the Foundation is an incubator for breakthroughs—giving early support to projects and ideas that other funders would consider too risky,” said Dr. Dorraya El-Ashry, BCRF’s chief scientific officer. “BCRF has long prioritized out-of-the-box approaches to breast cancer’s most challenging questions, like how brain metastases happen, how they can be treated, and how they can be prevented.”

Now, two other targeted therapies—both antibody-drug conjugates—have shown promise for these patients. Paradoxically, these relatively large drugs do cross the blood-brain barrier. The first, trastuzumab deruxtecan (T-DXd/Enhertu®) was previously approved for treating metastatic HER2-positive breast cancer. This September, researchers involved with the DESTINY-Breast12 trial, including Dr. Lin and other BCRF investigators, published especially encouraging results showing T-DXd has activity in brain mets: 61.6 percent of patients were alive 12 months after starting the therapy, further supporting its use.

Also in September, Dr. Lin and other BCRF investigators involved in a BCRF-supported, phase 2 study out of the Translational Breast Cancer Research Consortium published results showing that a combination of the antibody-drug conjugate ado-trastuzumab emtansine (TDM-1/Kadcyla®) and neratinib (Nerlynx®) could treat brain mets in about a third of patients. This was the first trial to look at this combination.

T-DXd, neratinib, and TDM-1 were all approved for metastatic HER2-positive breast cancer in just roughly the last decade, with T-DXd only approved in 2022.

The timing of these advancements is not lost on Jen, who was diagnosed with brain mets only about a year after tucatinib was approved.

“Before April 2020 there were no FDA-approved treatments for brain mets. Since then, I have benefitted from all these drugs,” Jen said.

Still, more progress in patients with MBC—including those with brain mets—cannot come soon enough for patients. Although more treatments are being shown to cross the blood-brain barrier, breast cancer patients diagnosed with MBC and brain mets still experience poor outcomes. We still lose more than 42,000 people to MBC each year. That’s why BCRF supports research to find new treatments, understand how breast cancer spreads to the other organs, including the brain, and ultimately to stop the metastatic process entirely.

“There are patients who have amazing responses, but for the majority of patients, cancer eventually gets through—it figures out how to get past the first line of therapy,” Dr. Lin said. “If you’re living with an MBC diagnosis, you know there’s a finite number of treatments that will potentially work. The longer that list, the better because it means people can live longer even with MBC.”

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