Dual-positive hybrid cells linked to shorter survival in advanced breast cancer

An enigmatic type of circulating tumor cell called a dual-positive (DP) cell is associated with shorter survival time in patients with advanced breast cancer, according to a study led by investigators at Weill Cornell Medicine and NewYork-Presbyterian. The findings highlight the potential importance of these under-studied cells in breast cancer progression.

Circulating tumors cells are breakaway tumor cells that can seed secondary tumors (metastases) and are commonly detected in the blood of patients with cancer. Dual-positive cells are circulating cells that bear both tumor-cell and immune-cell markers, and are thought to be hybrid cells resulting from rare fusions of tumor cells with immune cells. Recent studies have linked DP cells' presence in patients' blood to worse outcomes in melanoma and pancreatic cancer.

In the new study, published March 11 in Science Translational Medicine, the researchers linked DP cells to shorter survival times in patients with advanced breast cancer, especially the aggressive "triple-negative" breast cancer subtype. The team also showed with animal models that DP cells can seed breast cancer metastases.

A better understanding of the role of these unusual cells in triple-negative breast cancer might help us devise better treatments and methods for predicting and monitoring treatment responses."

Dr. Carolina Reduzzi, study co-first author, assistant professor of cancer biology research in medicine at Weill Cornell Medicine

Dr. Eleonora Nicolò, instructor of cancer research in medicine at Weill Cornell Medicine is the other co-first author of the study. Drs. Reduzzi and Nicolò are members of the laboratory of study senior author Dr. Massimo Cristofanilli, professor of medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine and an oncologist at NewYork-Presbyterian/Weill Cornell Medical Center.

The team initially analyzed blood samples from 340 women with advanced breast cancer who had agreed to participate in the research study when it began at Northwestern University, where Dr. Cristofanilli was originally located. DP cells tended to be less numerous than ordinary circulating tumor cells, which are a known risk factor for metastasis and shorter survival. However, the researchers identified at least one DP cell in 152 (44.7%) of the women. Patients with three or more detected DPs had median survival times of just 23.5 months, compared to 33.6 months for patients with less than 3 detected DP cells. The association between more than 3 DP cells and shorter median survival was validated in an additional group of 51 patients with advanced breast cancer who agreed to participate in the study at Dr. Cristofanilli's clinic at NewYork-Presbyerian/Weill Cornell Medical Center.

Comparisons of different breast cancer subtypes indicated that the shorter-survival risk from DP cells was concentrated mainly among patients with triple-negative breast cancer, a subtype in which tumor cells lack the three most common breast tumor markers: estrogen, progesterone and HER2 receptors.

Supporting the hypothesis that DP cells originate from tumor-cell/macrophage fusions, the researchers found that 60% of analyzed DP cells from patients bore a standard macrophage marker. Moreover, the team were able to detect DP cells in breast cancer mouse models only when the mice had intact immune systems.

About 29% of patient DP cells had genetic abnormalities called copy number alterations, which are commonly found in tumors. Although patients' ordinary circulating tumor cells were more likely to show such abnormalities, DP cells seemed fully capable of seeding metastases in animal models.

The findings underscored the relevance of DP cells in breast cancer and the importance of studying them further. The team is currently conducting a comprehensive characterization of DP cells' gene expression patterns, which should better define their cellular origins.

"Our current therapies target ordinary cancer cells, but DP cells have a different biology," said Dr.Cristofanilli, who is also the scientific director and head of the Liquid Biopsy Platform at the Englander Institute for Precision Medicine and the associate director of precision oncology at the Sandra and Edward Meyer Cancer Center. "We need to understand that better if we're going to target them effectively."