August 14, 2020—(BRONX, NY)—Researchers at Albert Einstein College of Medicine have received a five-year, $5.1 million grant from the National Cancer Institute, part of the National Institutes of Health, to further evaluate novel tests that Einstein researchers have developed for predicting whether primary breast tumors are likely to spread. Such tests can help prevent unnecessary overtreatment and also identify cases that need more aggressive therapy. The principal investigators on the grant are Thomas Rohan, M.B.B.S., Ph.D., D.H.Sc., professor and chair of epidemiology & population health at Einstein and Montefiore Health System, and John Condeelis, Ph.D., professor and co-chair of anatomy and structural biology at Einstein.
Breast cancer is the most common cancer among women worldwide, with a quarter of a million cases diagnosed in the United States each year. While early detection has improved the mortality rate in recent decades, approximately 42,000 American women die annually, primarily because the cancer has metastasized, i.e., spread to other parts of the body.
“Given the limitations of current prognostic tests, new methods to identify tumors likely to metastasize and respond to therapy are needed,” said Dr. Rohan, who holds the Harold and Muriel Block Chair in Epidemiology & Population Health at Einstein and Montefiore.
The test for predicting whether tumors will spread was developed by Dr. Condeelis and his colleagues in the Gruss Lipper Biophotonics Center and its Integrated Imaging program, both of which he co-directs. They had observed that breast cancer spreads to other parts of the body when three specific cells are in direct contact: An endothelial cell (a type of cell that lines blood vessels); a perivascular macrophage (a type of immune cell found attached to blood vessels) that is pro-angiogenic (i.e., encourages blood-vessel growth); and a tumor cell that produces high levels of Mena, a protein that can enhance a cancer cell’s ability to cross the walls of blood vessels and spread via the bloodstream throughout the body.
“We found that where these three cells contact each other a doorway forms that allows tumor cells to enter blood vessels in breast tumors,” said Dr. Condeelis, who also holds the Judith & Burton P. Resnick Chair in Translational Research. “We refer to such a doorway as a tumor microenvironment of metastasis, or TMEM.” Tumors with high numbers of TMEM (i.e., they have a high TMEM “score”) are more likely to metastasize compared with tumors with lower TMEM scores.
In addition to TMEM, the researchers have developed several TMEM-related tests for predicting tumor spread, based on levels of two subtypes of the Mena protein that tumor cells using the TMEM doorways produce. MenaINV drives tumor cell invasiveness and the crossing of blood vessel walls, while Mena11a suppresses these behaviors. The greater the difference between all Mena isoforms and Mena11a—a number called MenaCalc—the greater the number of tumor cells available to use TMEM doorways and the greater the risk of death due to TMEM-mediated spread of tumor cells. In addition, the higher the levels of MenaINV, the more likely that tumor cells will efficiently use TMEM doorways to enter the bloodstream.
Given the limitations of current prognostic tests, new methods to identify tumors likely to metastasize and respond to therapy are needed.
Thomas Rohan, M.B.B.S., Ph.D., D.H.Sc.
In a cohort of patients at Kaiser Permanente, Drs. Rohan and Condeelis, together with their co-investigators, found that TMEM was positively associated with risk of distant metastasis in ER+/HER2- breast cancer. The Einstein-Montefiore researchers will now use the Kaiser Permanente cohort and others to examine the association of three markers—MenaCalc, MenaINV, and TMEM and their combinations—with the risk of distant metastasis in those patients. They will also compare how well these markers compare with current clinical tests for predicting cancer spread, including the IHC4, PAM50, and Oncotype Dx® RS predictive tests.
The grant is titled "TMEM, MENAcalc, and MENAINV as Prognostic and Predictive Markers for Breast Cancer Metastasis.” (1R01CA240646-01A1)