Huiping Liu, MD, PhD, associate Professor of Pharmacology and of Medicine in the Division of Hematology and Oncology, who was a co-author of the study.
A little-studied group of cancer cells circulating in the bloodstream may play a bigger role in breast cancer progression than previously thought, according to new research published in Science Translational Medicine that sheds light on how the disease spreads and why some patients fare worse than others.
The study offers new details on circulating tumor cells, or CTCs — cells that break away from a primary breast tumor and travel through the blood, where they can seed new tumors in distant organs.
CTCs are already known to be a strong predictor of survival in patients with advanced breast cancer, and they are typically identified by the presence of epithelial markers specific to cancer cells and the absence of markers found on white blood cells, said Huiping Liu, MD, PhD, associate Professor of Pharmacology and of Medicine in the Division of Hematology and Oncology, who was a co-author of the study.
“We can cure primary tumors by surgery or radiation. However, when tumor cells start spreading from one place to another, they can get out of control. A lot of times it is devastating and incurable,” Liu said. “It’s a very significant problem in the clinic and also affects patient outcomes and survival time.”
Prior studies have increasingly noted a subset of circulating cells that don’t fit neatly into traditional definitions of tumor cells or immune cells, Liu said. These “dual-positive” cells, or DPcells, display both epithelial tumor markers and immune system markers, suggesting a hybrid or poorly understood role. Until now, little was known about their clinical importance, Liu said.
In the study, investigators analyzed blood samples from 340 patients with advanced breast cancer and found that DPcells are far from irrelevant. Patients with detectable DPcells had significantly worse overall survival than those without them, even after accounting for traditional CTC counts. The effect was especially striking in patients who otherwise appeared to have a lower metastatic risk — those with fewer than five conventional CTCs. In these cases, the presence of DPcells helped identify patients with poorer prognoses who might otherwise be missed.
The impact of DPcells also varied depending on breast cancer subtype, according to the findings. The association with worse outcomes was strongest in patients with triple-negative breast cancer and HER2-positive disease — two subtypes known for their aggressive behavior and limited treatment options. In contrast, DPcells appeared to have less prognostic relevance in hormone receptor–positive disease.
To better understand whether DPcells are truly cancerous or merely benign cells caught up in the disease process, the team conducted single-cell genomic analyses on individual cells isolated from patients’ blood. The results suggested that many DPcells do, in fact, carry cancer-associated genetic changes.
“A big question in the field was why are some of these cells double-positive, and are they really tumor cells or not? Should we pay attention to these cells?” Liu said. “It turns out these cells are tumor cells, but they happen to express some normal blood cell markers.”
Animal experiments offered additional clues. DPcells were detected in the bloodstream of healthy mice, but not in immunodeficient mice. This suggests that the immune system may play a key role in the formation or survival of these dual-identity cells, possibly through interactions between tumor cells and immune cells.
Taken together, the findings challenge existing assumptions about which circulating cells matter most in breast cancer and highlight the complexity of metastasis, the leading cause of death in patients with the disease.
Additionally, incorporating DPcell detection into blood-based cancer monitoring could improve risk stratification, particularly for patients with aggressive subtypes, Liu said.
“In the future, we hope to be able to not only detect these cells, but also to block them from spreading to make new tumors,” said Liu, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “The goal eventually is to help improve patient outcomes, help them have better life quality and also extend the patient survival.”
Future studies will be aimed at better understanding the mechanisms behind DPcells and how they may be used as biomarkers or treatment targets in the future, Liu said.
The study was supported by Menarini Silicon Biosystems and by National Cancer Institute grants CA060553, R01CA245699 and R01CA298232, R01AI167272, and American Cancer Society CSCC-Team-23-980420-01-CSCC.