From the Duke Cancer Institute archives. Content may be out of date.
Suzanne Wardell
Research that originated in a Duke Cancer Institute (DCI) laboratory contributed to Food and Drug Administration (FDA) approval of the first new endocrine therapy for breast cancer since 2002, and the only drug designed to target mutations in estrogen receptor 1 (ESR1).
Donald McDonnell, PhD, associate director For translational research at DCI and the Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, directed the research team that led to the development of elacestrant (Orserdu, Stemline Therapeutics, Inc).
The new therapy, a selective estrogen receptor down-regulator (SERD), is indicated for the treatment of postmenopausal women or adult men with estrogen-receptor-positive/HER2-negative ESR1-mutated advanced or metastatic breast cancer who have been treated unsuccessfully with at least one previous endocrine therapy.
The FDA approved the therapy in January 2023.
Meeting a Need
Erik Nelson
The drug is the only SERD that can be taken orally, which makes it more convenient for patients. McDonnell said it fills a significant unmet need because up to 40% of patients diagnosed with ER-positive/HER2-negative breast cancer will acquire ESR1 mutations as the cancer advances. In most cases, these mutations will trigger resistance to standard endocrine therapies.
During the past decade, the McDonnell Lab has been focused on identifying and developing new endocrine therapies to treat advanced ER-positive breast cancer. This initiative has included revisiting older hormone therapies originally developed to treat osteoporosis or menopause symptoms.
Elacestrant, for example, was developed initially to treat hot flashes in post-menopausal women but was never approved for that use. Clinical trials demonstrated that RAD1901, as the therapy was known, stopped hot flashes at low doses but increased them at higher doses. McDonnell and researchers in his lab were intrigued by the pharmacology. “It turns out that the reason for RAD1901’s failure as a treatment for hot flashes was a useful property for a breast cancer drug,” McDonnell said.
Investigators who were trainees in the McDonnell Lab at the time, Suzanne E. Wardell, PhD, and Erik Nelson, PhD, determined that RAD1901 was effective at blocking the estrogen driving cancer cell growth by binding to its receptor, like a selective estrogen receptor modulator(SERM), and degrading the estrogen receptor, like a SERD.
Wardell and Nelson went on to demonstrate that RAD1901 inhibited tumor growth in mouse models. This was the springboard for continued investigations worldwide; culminating in the successful multicenter phase 3 clinical trial (EMERALD 2018–2022) that led to FDA approval. Wardell is now an assistant professor of pharmacology and cancer biology at Duke, in McDonnell’s lab. Nelson is now a professor of molecular and integrative physiology at the University of Illinois Urbana-Champaign.
“We’re already prescribing elacestrant for our patients,” said Heather Moore, CPP, PharmD, a clinical pharmacist with Duke Health, noting that the drug is currently being distributed nationally by two specialty pharmacies.
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."
