Keeping cancer conquered
Penn Medicine research is bringing the “sleeper” phase of cancer to light—creating hope that more cancers could be wiped out for good and never come back.
Illeana Casiano-Vazquez meant to get a mammogram right after her 40th birthday in 2019. But she was busy with her financial services career and her two young boys, then ages 8 and 10. Before she’d gotten around to making the appointment, she found a lump. “I assumed it was probably nothing. I was way too young,” she recalled. “But after I got the mammogram, things escalated quickly.”
Casiano-Vazquez was launched headlong into a treatment journey familiar to many women with breast cancer. There was a biopsy, then what felt like “a million different tests,” and finally the shock of diagnosis: triple negative breast cancer, an aggressive cancer that tends to grow quickly and responds to fewer treatments than other types. Next came eight rounds of chemotherapy, followed by a double mastectomy. The treatment was difficult but successful, ending with those sought-after words: “no evidence of disease.”
Still, Casiano-Vazquez felt a cloud hanging over her head. She knew that for many people, the story doesn’t end there. “Recurrence was and continues to be my biggest worry,” she said. About 30 percent of breast cancer survivors will experience a relapse, often in other parts of the body. For most types of breast cancer, including triple negative breast cancer, the risk of recurrence is highest within the first five years. But it can return at any time, even decades after remission. Once it has returned in other parts of the body, recurrent metastatic breast cancer is not curable.
“So often I’d sit with a patient at the end of treatment and they’d ask, ‘How do I know it’s gone?’ I had to tell them I don’t really have a way of knowing. That feels terrible, and it really weighs on patients,” said Casiano-Vazquez's medical oncologist, Angela DeMichele, MD, MSCE, the Mariann T. and Robert J. MacDonald Professor in Breast Cancer Care Excellence and co-leader of the Breast Cancer Research Program at the Abramson Cancer Center at the University of Pennsylvania. “There are millions of breast cancer survivors, and they are all worried about recurrence. They’re just waiting for the other shoe to drop.”
The ‘hibernation phase’ in cancer
Cancer isn’t an event, but a process. A healthy cell develops mutations, transforms into a cancer cell, grows, and spreads. Cancer researchers have made great strides targeting cancer at nearly every stage of its life cycle. On one end of that spectrum are new approaches to intercept pre-cancers before they take root. At the other end are game-changing treatments to defeat advanced cancers. But even after treatment is an apparent success, the cancer can rear its head again years later. That last stage in the cancer process has been shrouded in mystery.
“There’s this time lag from the end of initial treatment to the point when recurrence happens. The cells have to be there somewhere, but the lag suggests they aren’t actively dividing and growing,” DeMichele explained. “We think of this as a sleeper phase, where the cells are sitting in suspended animation, like a bear hibernating in a cave through the winter.” This is known as a state of “cancer dormancy.”
“There’s this time lag from the end of initial treatment to the point when recurrence happens.... We think of this as a sleeper phase, where the cells are sitting in suspended animation, like a bear hibernating in a cave through the winter.”
Yet no one knew where those hibernating cells might be, or even what they looked like. Now, Penn Medicine scientists are aiming a spotlight on this dark phase of cancer dormancy. It’s a line of research that could have huge implications for millions of cancer survivors, said Lewis Chodosh, MD, PhD, chair of the Department of Cancer Biology at Penn Medicine and associate director of basic science at in the Abramson Cancer Center. “Recurrent breast cancer can be treated, but it can’t be cured. If you want to keep people from dying of breast cancer, you have to prevent the tumors from recurring,” he said.
Years ago, he created a mouse model of breast cancer to study a different topic entirely. A targeted treatment made the mouse tumors disappear. But in some animals, months later, the cancer came back. “That told us there had to be residual tumor cells that survived, maybe in a dormant state,” he said.
While dormant cells were nearly impossible to study in humans, mice offered an opportunity. Chodosh went on to find that the dormant cells hid out in multiple organs in mice, including the bone marrow, where they behaved very differently from active cancer cells. Probing further, he and his team identified multiple pathways that sustained the cells in their sleeper state. And crucially, they showed that medications could take away those protections and destroy the cells, reducing the risk of recurrence.
It was a whole new way of thinking about cancer treatment. Chodosh recalls having a conversation early on with a scientist at a major pharmaceutical company, where he laid out his vision of treating dormant cells to prevent recurrence. “The guy said, ‘You’re living in a fantasy world.’” Chodosh said. “I spent a lot of years trying to convince people that this isn’t crazy.”
A translational team finding cancer where it’s lying in wait
Fortunately, his colleagues at Penn Medicine didn’t need convincing. Chodosh had worked with DeMichele and knew of her expertise in treating advanced breast cancer. Teaming up, they applied for support through the Abramson Cancer Center’s Translational Center of Excellence program, which brings together experts from diverse fields to address major challenges in cancer treatment—the big goals that come with big risks, but also the possibility of great rewards. In 2014, Chodosh and DeMichele became co-directors of a newly launched 2-PREVENT (Secondary PREvention through surVEillance and iNTervention) Breast Cancer Translational Center of Excellence (TCE).
“Our goals with the TCE program are first to change paradigms in science, and then to change practice. And 2-PREVENT is a great example of that,” said Ravi Amaravadi, MD, the associate director of translational research at the Abramson Cancer Center. “This research is changing the paradigm on dormancy. We’re not quite at practice-changing yet, but that takes time—and the early research is showing high rates of success.”
The support from the cancer center was just one example of Penn’s commitment to translational research and a culture of collaboration, Chodosh said. “In many institutions, there’s a fundamental barrier between clinical researchers and basic researchers. But Penn turns that whole thing on its head,” he added. “Nobody sees it as us vs. them. It’s all us. We’re all Penn Medicine, and that allows us to do translational medicine as well as, or better than, anyone.”
“In many institutions, there’s a fundamental barrier between clinical researchers and basic researchers. But Penn turns that whole thing on its head,” said Lewis Chodosh, MD, PhD. “Nobody sees it as us vs. them. It’s all us. We’re all Penn Medicine, and that allows us to do translational medicine as well as, or better than, anyone.”
Building on the support from the TCE program, DeMichele and her colleagues have completed proof-of-concept trials in patients, demonstrating that they can detect and target the dormant cells, with the goal of reducing the chance of recurrence. Now two larger clinical trials aim to confirm and extend those findings. The research offers hope for breast cancer survivors who want to do more than wait to see if their cancer will return.
The powerful investments stopping breast cancer in its tracks
Groundbreaking breakthroughs in breast cancer research at the Abramson Cancer Center are fueled by both public and private funding sources, including generous philanthropic donors playing a critical role in advancing science and care. Lewis Chodosh and Angela DeMichele’s work to understand and prevent breast cancer recurrence has been made possible through multiple grants from the National Institutes of Health and other federal government agencies supporting every step from fundamental science through biomarker identification and clinical trials. Additional support comes from foundation grants and philanthropic donations from supporters who recognize the value of such crucial translational research at an academic medical center.
“This research would not be done by a pharmaceutical company because the drugs are off patent,” DeMichele said—meaning that generic versions could be available to patients at low cost if they became approved treatments. “This distinguishes the work we do at Penn and academia as a whole from work done in [the pharmaceutical industry]. We can focus entirely on what is right for current and future patients, without the pressure of maximizing profits. Many such studies at Penn and elsewhere are focusing on how to use existing drugs in better ways, or how to use biomarkers to identify which patients will benefit from a drug and which will not, and can therefore be spared the side effects and cost.”
Sustaining this important work is also a testament to the visionary support of a steadfast community, including Sara and Jim Gowing, Rhoda Polly Danziger and Michael Danziger (a 1980 Wharton alumnus), and the Dietz & Watson Family. For Andrea Orsher, VMD, and Robert Orsher, VMD (both Penn Vet graduates from the class of 1979) and Jerry S. Rosenbloom, PhD (a 1965 graduate alumnus), in particular, these commitments resonate with Penn connections.
For Rosenbloom, supporting breast cancer research at Penn is deeply personal. The Frederick H. Ecker Professor Emeritus and former chair of the Insurance and Risk Management Department at The Wharton School, Rosenbloom has dedicated much of his life to Penn and spent decades shaping its next generation of leaders. However, his connection to Penn extends beyond the classroom. His late wife Lynn was treated for her breast cancer at the Abramson Cancer Center by Kevin Fox, MD, now an emeritus professor, and throughout her experience, Jerry and their three daughters—all Penn graduates—witnessed firsthand the impact of leading-edge care. His philanthropy is both a tribute and an investment in the future, affirming his wife’s memory and his belief in the power of giving, while ensuring that other families have access to the most promising innovations in care at Penn Medicine.
Andrea and Robert Orsher also found purpose in supporting breast cancer research. After losing their daughter, Rebecca Kate Orsher Stemplewicz, to the disease, they channeled their grief into action, making a gift to support DeMichele’s work. Their generosity also established the ACORN (Access, Community Outreach, & Research Navigation) Program, which increases access to lifesaving clinical research in the community while expediting the pace of discovery for breast cancer research. In addition, their philanthropy has also funded critical research to identify microscopic residual tumor cells in the blood and bone marrow, and to develop methods of eradicating them—along with the risk of recurrence. With their support, the Abramson Cancer Center can ensure that new, more effective treatments continue to emerge, offering hope for a future where fewer families experience the same loss.
Thanks to our community of supporters, Penn Medicine researchers are pushing the boundaries of what’s possible in breast cancer treatment—transforming lives and shaping the future of care. If you would like to learn more about advancing the efforts of DeMichele, Chodosh, or any of the Abramson Cancer Center’s investigators in breast cancer research, please contact Maddie Hansen, Senior Associate Director of Development, at madd@upenn.edu or 215-898-9174.