When Dr. Lewis Chodosh started working at the University of Pennsylvania over thirty years ago, he came prepared with a theory: As an endocrinologist, he was interested in better understanding the observation that women who have their first child when they are young tend to have a lower lifetime risk of breast cancer. He created an animal model and began testing his hypothesis about pregnancy hormones.
After about eight years, though, the results didn’t back up his theory. “We were incredibly disappointed,” Chodosh says.
Still, the project was anything but a waste of time. In fact, it has helped spawn what could become the next frontier in saving the lives of recovering breast cancer patients. “This is a classic example of the sort of serendipity of science,” says Chodosh.
During their initial research, Chodosh and his team noticed that the tumors on the animals were shrinking, then disappearing. Curious if they had come up with a new treatment for cancer, they kept a close watch on their animal patients.
“Months later in these animals’ lives, their cancers came back spontaneously,” Chodosh says. The recurrence meant one thing: “There must have still been cancer cells in the animal that were not eradicated.”
The group had opened the door to studying dormant sleeper cells, which have the same molecular structure as the original cancer and somehow broke off during treatment. Normal cancer cells are constantly growing and dividing; that’s why cancer spreads. But these sleeper cells remain inactive and undetectable in the body for years before growing.
Roughly 30 percent of breast cancer patients who enter remission after treatment later experience a recurrence. Sleeper cells are responsible for many of these recurrences. For some patients, the new cancer can appear in an advanced or incurable stage.
“I think of it like a dandelion in your lawn,” says Chodosh. “The seeds blow across your lawn and individual seeds just settle into the grass.”
Chodosh and a team of researchers at Penn are working to change that through a large-scale breast cancer clinical trial testing different drug combinations to keep sleeper cells at bay. Since 2017, Chodosh and Penn colleague Dr. Angela DeMichele — along with clinical research program director Dr. Lauren Bayne and dozens of researchers, pathologists, nurses, and clinical professionals at the Abramson Cancer Center at Penn Medicine — have worked with hundreds of breast cancer patients from across the nation with promising results.
As they work towards a final, large-scale trial, their work raises the question: Could we see the end of breast cancer recurrences as we know them?
Cancer cells hibernating
Over years of work, Chodosh and his team discovered that the sleeper cells often end up in a patient’s bone marrow and that traditional chemotherapy treatments seemed to have little power against them.
Most importantly, they figured out how the cells survive: in part by “eating themselves” through a process called autophagy to get energy. DeMichele, co-leader of the Breast Cancer Research Program, describes autophagy as, ”Like how a bear hibernating for winter does not need to go get food, but instead uses its own fat to sustain itself; the cancer cells do that too.”
The dormant cells also utilize the body’s mTOR pathway, which controls how cells grow, metabolize, and survive. With this knowledge, the team could now look for means to destroy the cells or stop them from becoming active, including mTOR inhibitors and other FDA-approved drugs. Their goal, according to Chodosh: Block dormant and “uniquely vulnerable,” cancer cells’ routes to survival.
For the first time, they had a roadmap of what could be done with human patients. “All of this is the result of a failed experiment a long time ago that led us down an unexpected path,” he says.
“We may not cure [cancer], but if we can control it, people can live long lives, even with advanced disease.” — Dr. Angela DeMichele
The trials
While Chodosh was in the lab, DeMichele had been looking for better ways to treat metastatic disease, when the cancer spreads from its origin site to other parts of the body.
“When we got together, it was appealing to her to think, well maybe the best way to treat metastatic disease is to prevent it from ever happening,” he says. His team had also been working on fine-tuning the instrument and testing that searches for the cells in the bone marrow. The instrument they created “can pick out a single dormant DTC among 15 million cells, while also preserving the cell for further analysis,” according to an article by Kirsten Weir for Penn Medicine.
The pair set about creating a clinic trial for people, modeled on Chodosh’s experiments with mice. The first group of patients had completed treatment within the past five years. Those whose bone marrow showed clear scans were monitored, and those whose scans showed dormant cells were eligible to enroll in the Phase II CLEVER clinical trial. Patients in CLEVER (which stands for HydroxyChLoroquine, EVErolimus or Combination for Prevention of Recurrent Breast Cancer) were randomly assigned to receive six cycles of either one of the two study drugs or a combination with both drugs. Trial participants underwent additional bone marrow assessments at three and six months. If they still showed dormant cells after six months, they could keep doing combination therapy for another six. All patients were monitored for three years after their participation ended.
“I use this analogy: You have a gallon of milk. That’s all the bone marrow in your body,” says DeMichele. “Let’s say you have blueberries that represent these sleeper cells. You take the blueberries and you put them in the gallon of milk, and you shake it up and you pour out a glass. You can imagine that if you had lots of blueberries and you pour out a glass, well, you’re going to get some of those. But let’s say you have very few cells. You might pour out a glass, and even though there are blueberries in the gallon, they’re not in the glass.”
In cancer cell terms: DeMichele says the team learned they can’t just test bone marrow once for active cancer cells. They now look up to four times to ensure they are not present.
The CLEVER trial lasted about five years, and included 51 patients. About 3.5 years later, only two patients had a recurrence or a new cancer developed. Per their results released last September, CLEVER successfully proved that these dormant cells can be targeted and treated.
This success led to the expansion of other, bigger trials: more participants, longer timelines, and partnerships with other research facilities — all looking at the multiple ways the sleeper cells can get comfortable and how to block each pathway through different combinations of drugs.
The end goal: Find a combination that blocks all potential pathways.
Currently, DeMichele says, they are in the middle of the bigger studies that will wrap up likely in 2028, with the aim of one final, large definitive tract in the years after that, based on the outcome of the current trials.
The gift of knowing
When Lisa Dutton, a Philadelphia native and a participant in the CLEVER study was first diagnosed in 2016 during a routine annual mammogram, she was shocked. She had already been through two negative biopsies and figured the third was simply routine. Instead, she learned she had stage one, triple negative breast cancer. After receiving treatment in 2017, a friend told her to look into clinical trials so that she could “throw everything you can at it.”
Dutton agreed, did her own research, found DeMichele, and joined the trial soon after. Her first two bone barrow samples were clean, but about three years later, during the coronavirus pandemic, dormant cells showed up.
“I can remember holding the phone, like, one more thing, one more thing,” Dutton says. On the other hand, “what made it feel less stressful than it would have is I had a good relationship with the team, so I felt confident that whatever else was going to happen, I’d be with them.”
She began randomized treatment and received oral medication once a month. Knowing the medications were already FDA-approved helped Dutton feel more at ease taking them. After six months and two bone marrow tests, she was able to choose whether she wanted to learn her results.
“I want to know everything. And fortunately, no cells were found then,” Dutton says. Six months after that, and still no more cancer cells. She has since accepted the opportunity to be followed for 20 years.
Dutton now urges other cancer patients to join clinical trials.
“That’s really the only way that the outcomes will get better over time, whether it’s new procedures, new tests, new supportive therapies — it’s important to get representation from a large group of people,” she says.
According to DeMichele, many patients in the trial feel the same way as Dutton.
“This is research. We don’t know if it’s going to work,” she says. “Many of the patients say, ‘Yes, I want to do this because I want to know, and I want to be proactive. And a lot of patients say, I’m doing this for the next person who gets breast cancer. I’m doing this because I got this and I don’t want it to come back, but I really don’t want the next generation to be dealing with this.’ Working with cancer patients is a very unique and privileged situation, because they are so altruistic, and they are partners, true partners, in this.”
“All of this is the result of a failed experiment a long time ago that led us down an unexpected path.” — Dr. Lewis Chodosh
Moving forward
They still have questions to answer.
“Something fundamentally changes the cancer cell when it gains this ability to go live in another organ. And we don’t know why,” says DeMichele. “It’s a fact. We know it because that’s how the cancer behaves, but we don’t know why.”
It is also unclear how well these studies will transfer to other cancers, though the researchers think it’s likely some of the methods will translate to other cancers, potentially prostate. But the progress they are making brings hope to patients and researchers alike.
“Our bodies can live with cancer in them, so long as it’s under control and it’s not getting in the way of normal functioning of our organs. And so we also are now seeing that many people are living with metastatic breast cancer. We may not cure it, but if we can control it, people can live long lives, even with advanced disease,” DeMichele says. “It may not be our ultimate goal, but it’s a worthy goal in the interim. It really gives them back a life at a time when, in the past, people would say, there’s nothing we could do.”
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