Trials aim to make cancer relapse a thing of the past
“The thought is always in the back of your head: Is it lurking? Will it come back?” Clinical trials are testing methods that may stop cancer from recurring.
When Illeana Casiano-Vazquez was diagnosed with breast cancer at the age of 40, the risk of recurrence was on her mind early on. “The thought is always in the back of your head: Is it lurking? Will it come back?” she said.
Fortunately for Casiano-Vazquez, early in her treatment journey she met 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. “The first thing she told me was, ‘This is curable.’ I’d already seen a number of doctors and nurses, and she was the first person who said that. And I needed to hear it,” Casiano-Vazquez recalled.
But DeMichele wasn’t just the empathetic oncologist Casiano-Vazquez needed. She was also a co-leader of the 2-PREVENT Breast Cancer Translational Center of Excellence, the only research program in the country focused on preventing breast cancer recurrence. Her fellow co-leader, Lewis Chodosh, MD, PhD, chair of the department of Cancer Biology at Penn Medicine and associate director of basic science at the Abramson Cancer Center, had discovered that after breast cancer treatment, stray tumor cells can lay dormant in the bone marrow, even when scans and blood tests show no evidence of residual disease. Known as disseminated tumor cells (DTCs), those cells can reawaken years later, triggering relapse.
At the time of Casiano-Vazquez’s treatment, DeMichele was leading a trial called SURMOUNT, designed to demonstrate that researchers could detect DTCs, in the bone marrow of breast cancer survivors who had no other evidence of disease. If the dormant cells were present, patients could enroll in the CLEVER trial, which was exploring targeted treatments designed to wipe out the dormant cells.
When DeMichele invited her to participate in the trial, Casiano-Vazquez said, “I jumped at the chance. There was no question in my mind.” About six months after her mastectomy, she had her first bone marrow biopsy, with cells drawn from her hip bone. The procedure was painful, but she was feeling healthy and confident that the sample would come back clean. Instead, DeMichele called with difficult news: They’d detected the sleeper cells in her bone marrow.
“It was devastating, but she reminded me, ‘This is why we’re doing this. We’re going to try to get ahead of these suckers before they wake up,’” Casiano-Vazquez said. The positive test meant she was eligible to enroll in the CLEVER trial, a phase II study testing drugs that, the researchers hoped, would stop the dormant cells in their tracks.
Snuffing out the sleeper cells
Chodosh had shown through his lab research that DTCs don’t act like typical tumor cells. During their dormant hibernation state, he found, the cells use a variety of cellular mechanisms to generate enough energy to stay alive. In a stroke of luck, drugs that target several of those crucial cellular pathways had already been approved by the U.S. Food and Drug Administration for other uses.
The CLEVER trial was the first to study some of those drugs in breast cancer survivors who had tested positive for DTCs. For six months, patients randomly received one of two medications that targeted the dormant cells, or a combination of the two. A control group received monitoring without treatment for three months, then began the combined treatment. The results, which have been accepted for publication in a high-impact journal in the spring of 2025, were encouraging. DTCs were cleared from more than 80 percent of the patients, across all three arms of the study.
“And within four years, none of the patients who cleared have relapsed,” DeMichele said.
It's an encouraging result, though the trial was small, with just 15 patients in each arm. Now, DeMichele and her colleagues are conducting two new trials, ABBY and PALAVY, to extend their findings and explore whether additional drugs can eliminate DTCs, alone or in combination with those already tested. The PALAVY study is the first to expand the clinical trial to seven partner institutions beyond Penn Medicine.
As the trials move forward, Chodosh, DeMichele, and their colleagues continue to push forward with a shared sense of purpose. “Instead of watchful waiting, can we actively monitor patients and eradicate dormant cells to prevent recurrence?” DeMichele asked. “Our goal is to get to that point.”
The relief of knowing and moving on
Early on, Chodosh and DeMichele faced more than a few skeptics. One high-level scientist cautioned that a trial focused on preventing recurrence could never get funded. Another argued that cancer survivors would never agree to painful bone marrow biopsies. One of the most worrisome criticisms was that the research to identify dormant cancer cells would make cancer survivors live in fear of recurrence.
DeMichele considered that feedback carefully. She knew how many of her patients already live with the fear of relapse. The last thing she wanted to do was add to their burden. “We thought long and hard about this. What do patients really want to know? Could it be harmful to learn that you have these cells?” she asked.
Having counseled so many patients with advanced breast cancer, she was confident that the research could help survivors. “Patients need to make decisions about their lives, and not having this information makes it hard to move forward,” she explained. One of her patients, for instance, wanted children but was afraid to get pregnant without knowing whether she was at high risk of recurrence.
To be sure the project wasn’t causing harm, DeMichele built into the research an extensive battery of psychological evaluations to assess patient experiences such as anxiety, fear, and intrusive thoughts about their illness. She found that in about 80 percent of the participants, distress levels go down after being tested for DTCs—regardless of the results. “I’m very comforted knowing this is helping to reduce patients’ stress and fear,” DeMichele said.
Of course, knowledge isn’t the only thing DeMichele can offer her patients. For the first time, there is something patients like Casiano-Vazquez can do beyond watchful waiting. Through the CLEVER trial, she received one of the experimental treatments aimed at eliminating the DTCs found in her bone marrow. At the end of her study period, she waited again for the results of the final bone marrow biopsy. This time, the test found no evidence of dormant cells. Now she’s five years cancer-free.
“My biggest fear was that I wouldn’t get to see my kids grow up, and I’m just so thankful to see the young men they’re growing into. I hope to grow old with my husband and meet our grandkids one day,” she said.
This January, Casiano-Vazquez enrolled in the next clinical trial, where for three and a half years she’ll continue to have her bone marrow tested. It’s something she’s committed to doing to contribute to science and help other people with cancer.
“I often say Dr. DeMichele saved my life twice. Without this trial, I don’t know if I’d still be here,” she added. “She really put herself at the center of what it is to be a breast cancer patient without any options, and I’m so thankful she didn’t give up and heed [the skeptics’] warnings. Just imagine if this could stop recurrence of breast cancer, and how many lives that will impact.”