Postdoctoral associate Danhui Ma (left) spent countless hours learning new microscopy techniques under the guidance of Dorothy Sipkins to confirm how breast cancer spreads to the leptomeninges (membranes that protect the brain and spinal cord).
How Breast Cancer Spreads to the Brain
Published
Once cancer gets inside the inner membranes that protect the brain and spinal cord (the leptomeninges), the disease can circulate in the cerebrospinal fluid and spread throughout the central nervous system. The outcome for patients is devastating, with a median survival time of less than six months.
That’s why clinician-scientist Dorothy Sipkins, MD, PhD, and her team at Duke University School of Medicine have kept pushing for nearly 10 years to find out how cancer cells can get inside this vital compartment. Now they have discovered a previously unknown shortcut that some breast cancer cells use to metastasize to the leptomeninges, as well as clues that suggest how to block this path. Their study was published in June 2024 in the journal Science, with an accompanying commentary.
Sliding Down the Fireman's Pole
Physician-scientist Dorothy Sipkins (left) and postdoctoral associate Danhui Ma in the lab.
Sipkins, an associate professor of medicine, and her team showed in mice that breast cancer cells first infiltrated the bone marrow of the skull, then traveled via “emissary blood vessels.” These vessels begin in the bone marrow, pass through normal openings or “windows” in the skull, then become part of the leptomeninges.
“These tumor cells grab onto the outside of these blood vessels and basically shimmy down the vessel like a fireman sliding down a fireman’s pole,” Sipkins said. The work suggests a potential way to prevent cancer cells from taking this shortcut. “The cells in our study expressed a receptor called integrin alpha6 that they use to grab onto a specific protein that encases these blood vessels. Our evidence suggests that this protein, laminin, greases the fireman’s pole,” she said.
Preventing the Spread?
Sipkins hopes these findings will lead to a way to identify which women with breast-to-bone metastases are at highest risk for leptomeningeal disease. “If we can identify those patients by the presence of this marker integrin alpha6, could we prevent the spread?” she said. “And then for patients who already have the spread of the disease, what can we do for them?”
“We haven’t moved the dial in many years in terms of improving treatments for breast cancer patients with leptomeningeal metastasis,” Sipkins said. The disease is rare but is becoming more common as people live longer with breast cancer. “The symptoms that patients experience from this are debilitating. It’s a terrible complication,” she said.
After the team found out how breast cancer cells get inside the leptomeninges, they pushed further to figure out how the tumor cells survive there. Using their tool of choice — confocal microscopy — the researchers peered into the meninges and saw that the cancers cells stuck close to a particular type of immune system cell called macrophages. Then the tumor cells stimulated the macrophages to secrete a protein (glial-derived neurotrophic factor) that is normally used to protect neurons (brain cells). “We demonstrated that in our mouse models, glial- derived neurotrophic factor from meningeal macrophages was important for breast cancer cells to survive and proliferate, and to be successful in the meningeal microenvironment,” Sipkins said. She hopes to use this knowledge to develop new treatments.
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If we can identify those patients by the presence of this marker integrin alpha6, could we prevent the spread? And then for patients who already have the spread of the disease, what can we do for them?
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Dorothy Sipkins, PhD
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Associate Professor of Medicine
Key Donor Support
Sipkins praised her team’s dogged determination to find these answers. For example, post-doctoral associate Danhui Ma, PhD, spent countless hours learning new microscopy techniques and conducting final experiments, Sipkins said.
The initial work that went into this study would not have been possible without a philanthropic gift from David Wells, Sipkins said. Wells’ wife Leslie passed away after a brief battle with leptomeningeal disease, which she fought with the help of the Duke Center for Brain and Spine Metastasis. He made the gift in her honor. As a clinician, Sipkins treats patients with leukemia, and that is her main research focus. But she began studying breast cancer as well several years ago because it often spreads to the bone and bone marrow. This new study was inspired by some of her previous work in leukemia, in which she discovered that acute lymphoblastic leukemia cells can use this “fireman’s pole” method to spread to the leptomeninges.
For decades, a diagnosis of metastatic breast cancer has carried a clear message: while treatments can help control the disease and extend life, the disease is generally considered incurable. As a result, treatment strategies have traditionally focused on managing cancer and maintaining quality of life rather than pursuing a cure.New advances in breast cancer therapies are changing that conversation. Research led by Duke Cancer Institute breast surgical oncologist Jennifer Plichta, MD, suggests that some patients with limited metastatic breast cancer may benefit from a more aggressive treatment approach than has traditionally been offered. The findings, published in JAMA Surgery, add to growing evidence that metastatic breast cancer is not the same for every patient and that treatment decisions may need to become more personalized.Plichta's research builds on years of work focused on improving how physicians classify and predict outcomes for patients with breast cancer. Historically, a diagnosis of metastatic, or stage IV, breast cancer, was associated with poor survival. However, the development of targeted therapies and other advances in systemic treatment have dramatically improved outcomes for many patients."Many women with metastatic breast cancer are now living for years and sometimes even a decade after diagnosis," Plichta said. "We've come a long way in terms of treatment options and survival."At the same time, researchers have discovered significant variation among patients with metastatic disease. Some experience aggressive cancer that progresses quickly, while others have relatively limited disease that remains controlled for long periods.This variability led Plichta and her colleagues to ask an important question: Are there certain patients with metastatic breast cancer who could benefit from treatment strategies typically reserved for patients with earlier-stage disease?The study focused on patients with what is known as oligometastatic breast cancer, a form of metastatic disease in which cancer has spread to only a limited number of sites. Researchers believe this group may represent a distinct subset of patients whose disease behaves differently than widespread metastatic cancer.Using data from the National Cancer Database, which captures information on many newly diagnosed breast cancers in the U.S., the team analyzed outcomes among patients with limited metastatic disease. They examined whether patients received treatment directed at the primary breast tumor, treatment directed at metastatic sites, both treatments, or neither.The goal was to determine whether a treatment approach that more closely resembles care for stage III breast cancer—combining systemic therapy with aggressive local treatment—might improve outcomes for selected patients."What stood out was that removing the primary breast tumor seemed to be the factor most strongly associated with improved survival," Plichta said. "Treating the distant sites did not appear to offer the same survival advantage on its own."While previous studies have explored surgery for patients with metastatic breast cancer, results have been mixed. Plichta believes one reason may be that metastatic breast cancer is often treated as a single category, even though patients can have vastly different disease characteristics and prognoses.One of the most significant implications of this research is how clinicians think about treatment goals. Patients with stage III breast cancer are typically treated with curative intent, meaning doctors use every appropriate therapy available, including chemotherapy, surgery, and radiation, in an effort to eliminate the disease. Patients with metastatic breast cancer, by contrast, are usually treated with palliative intent, focusing on disease control rather than cure.But as outcomes improve, the line between those groups may not be as clear as it once was."We're seeing some patients with metastatic disease living longer than patients with locally advanced breast cancer," Plichta said. "That raises important questions about whether some patients with limited metastatic disease should be approached differently."Because the study was retrospective, the results point to an important association that warrants further study. Several clinical trials are now being developed to investigate curative-intent treatment strategies in specific subgroups of metastatic breast cancer patients, including those with HER2-positive disease. Duke hopes to participate in these multi-institutional studies as the field continues to evolve.As breast cancer treatments continue to improve, researchers are gaining a more nuanced understanding of metastatic disease. For Plichta, the study represents an important step toward that goal."I hope this work encourages further research into which patients may benefit from a curative-intent approach," she said. "The ultimate goal is to find the right treatment strategy for the right patient."
For decades, a diagnosis of metastatic breast cancer has carried a clear message: while treatments can help control the disease and extend life, the disease is generally considered incurable. As a result, treatment strategies have traditionally focused on managing cancer and maintaining quality of life rather than pursuing a cure.New advances in breast cancer therapies are changing that conversation. Research led by Duke Cancer Institute breast surgical oncologist Jennifer Plichta, MD, suggests that some patients with limited metastatic breast cancer may benefit from a more aggressive treatment approach than has traditionally been offered. The findings, published in JAMA Surgery, add to growing evidence that metastatic breast cancer is not the same for every patient and that treatment decisions may need to become more personalized.Plichta's research builds on years of work focused on improving how physicians classify and predict outcomes for patients with breast cancer. Historically, a diagnosis of metastatic, or stage IV, breast cancer, was associated with poor survival. However, the development of targeted therapies and other advances in systemic treatment have dramatically improved outcomes for many patients."Many women with metastatic breast cancer are now living for years and sometimes even a decade after diagnosis," Plichta said. "We've come a long way in terms of treatment options and survival."At the same time, researchers have discovered significant variation among patients with metastatic disease. Some experience aggressive cancer that progresses quickly, while others have relatively limited disease that remains controlled for long periods.This variability led Plichta and her colleagues to ask an important question: Are there certain patients with metastatic breast cancer who could benefit from treatment strategies typically reserved for patients with earlier-stage disease?The study focused on patients with what is known as oligometastatic breast cancer, a form of metastatic disease in which cancer has spread to only a limited number of sites. Researchers believe this group may represent a distinct subset of patients whose disease behaves differently than widespread metastatic cancer.Using data from the National Cancer Database, which captures information on many newly diagnosed breast cancers in the U.S., the team analyzed outcomes among patients with limited metastatic disease. They examined whether patients received treatment directed at the primary breast tumor, treatment directed at metastatic sites, both treatments, or neither.The goal was to determine whether a treatment approach that more closely resembles care for stage III breast cancer—combining systemic therapy with aggressive local treatment—might improve outcomes for selected patients."What stood out was that removing the primary breast tumor seemed to be the factor most strongly associated with improved survival," Plichta said. "Treating the distant sites did not appear to offer the same survival advantage on its own."While previous studies have explored surgery for patients with metastatic breast cancer, results have been mixed. Plichta believes one reason may be that metastatic breast cancer is often treated as a single category, even though patients can have vastly different disease characteristics and prognoses.One of the most significant implications of this research is how clinicians think about treatment goals. Patients with stage III breast cancer are typically treated with curative intent, meaning doctors use every appropriate therapy available, including chemotherapy, surgery, and radiation, in an effort to eliminate the disease. Patients with metastatic breast cancer, by contrast, are usually treated with palliative intent, focusing on disease control rather than cure.But as outcomes improve, the line between those groups may not be as clear as it once was."We're seeing some patients with metastatic disease living longer than patients with locally advanced breast cancer," Plichta said. "That raises important questions about whether some patients with limited metastatic disease should be approached differently."Because the study was retrospective, the results point to an important association that warrants further study. Several clinical trials are now being developed to investigate curative-intent treatment strategies in specific subgroups of metastatic breast cancer patients, including those with HER2-positive disease. Duke hopes to participate in these multi-institutional studies as the field continues to evolve.As breast cancer treatments continue to improve, researchers are gaining a more nuanced understanding of metastatic disease. For Plichta, the study represents an important step toward that goal."I hope this work encourages further research into which patients may benefit from a curative-intent approach," she said. "The ultimate goal is to find the right treatment strategy for the right patient."
