NEW YORK—The news that cancer has metastasized or reoccurred is news that all cancer patients live in fear of. But what if there was a marker that could indicate if a cancer was likely to recur? A team of researchers at Mount Sinai may have uncovered just such a marker in a protein known as NR2F1. Their work appeared in the journal Breast Cancer Research in an article titled “NR2F1 stratifies dormant disseminated tumor cells in breast cancer patients.”
This study was a collaboration between the laboratory of Bjørn Naume from the University Hospital of Oslo and the labs of Dr. Julio Aguirre-Ghiso and Dr. Maria Soledad Sosa at Icahn School of Medicine at Mount Sinai. Unlike in the United States, bone marrow aspirates are used in Norway to monitor cancer patients. The Naume lab analyzed patient samples from clinical trials for this study.
As the authors note in their paper, “Breast cancer patients may experience relapse and subsequent death from the disease many years after primary treatment. This indicates an ability of occult cancer cells to survive in a non- or slow-proliferating state, retaining a potential for progression and proliferation at a later time point [1, 2]. The window of time represented by such minimal residual disease (MRD) represents a possibility for therapeutic intervention to prevent development of future metastasis rather than treat overt metastasis. However, the biology of the population of residual disseminated tumor cells (DTCs) is poorly understood. Large studies have shown the presence of DTCs in bone marrow (BM) to be a strong predictor of recurrence over the next 5 years [3, 4]. However, about 60% of the DTC-positive patients remained relapse-free until the end of the follow-up period.”
The team measured NR2F1 expression in DTCs using “double immunofluorescence staining of extra cytospins prepared from 114 BM samples from 86 selected DTC-positive breast cancer patients.” NR2F1 is “an orphan nuclear receptor of the retinoic acid receptor family.” They found that of those patients with detectable DTCs, 27 percent presented with 50 percent or greater NR2F1high DTCs, which was the cut-off for a classification of a “dormant profile.” All the patients who saw their cancer relapse within 12 months after bone marrow samples were taken had 1 percent or less of NR2F1high DTCs.
As noted in the paper, “For decades, DTC biology has been relegated primarily to the area of enumeration and subsequent prognosis.” With the confirmation that high NR2F1 levels can render cancer cells dormant, and low or nonexistent levels of the protein were seen in patients whose cancer metastasized and was fatal, this could offer a new way of monitoring cancer patients and guiding treatment decisions.
“This research shows that the survival advantage in these patients is due to high levels of this protein. Tests using this protein marker could further improve curative treatment of breast cancer, sparing patients from unnecessary treatments. Identifying patients with disseminated disease that is not yet symptomatic and characterizing it for potential dormancy or metastatic recurrence is a game-changer,” said lead researcher Dr. Julio Aguirre-Ghiso, director of Solid Tumor and Metastasis Research, director of Head and Neck Cancer Basic Research and Professor of Oncological Sciences, Otolaryngology, and Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at the Icahn School of Medicine. “Improved techniques to assess the population of patients with residual disease and their dormant or reactivating state will be key to identifying the risk of future metastasis despite undergoing standard treatment. This opens the way for testing new treatments that prevent metastasis by inducing dormancy or eradicating the dormant disseminated cancer cells that have not yet initiated metastatic growth.”
The Mount Sinai team isn't content to leave things there, however—they are already looking into NR2F1 as a potential treatment target, and not just in breast cancer. Thanks to funding from the V Foundation for Cancer Research and The Tisch Cancer Institute at the Icahn School of Medicine, recruitment is underway for a trial in prostate cancer patients to determine evaluate two drugs and see if they are capable of inducing dormancy in cancer cells by upregulating NR2F1. A common treatment in prostate cancer is androgen deprivation treatment, which has been associated with higher levels of NR2F1.
The authors reported in their work that NR2F1 levels have been implicated as a marker of dormancy in other cancer types as well. In a patient-derived xenograft model of squamous carcinoma, for example, “NR2F1 was upregulated in the DTCs that entered spontaneous dormancy … DTC analysis in the experimental models indicated that when 40–50% of DTCs displayed nuclear NR2F1, this correlated with quiescence markers, other dormancy markers such as DEC2 and SOX9, and lack of proliferation.” In metastatic and local recurrence samples of head and neck squamous cell carcinoma, those that “clearly escaped dormancy showed less than 5% of tumor cells positive for NR2F1.” When looking at prostate cancer samples, the team noted that “43–47% of DTCs from patients with no evidence of disease after many years of relapse-free follow-up showed NR2F1 mRNA upregulation, compared with 10% of the DTCs in advanced prostate cancer.”
“Altogether, these results support further testing of NR2F1 as a dormancy marker in solitary DTCs from clinical samples, including assessment of cut-off values to classify patients according to NR2F1 expression,” the authors concluded.