Pinpointing the Onset of Metastasis

 

Wed, 06/24/2015 - 1:43pm by Lindsay Hock, Editor Image: MetaStat Within the oncology community, a debate is raging about two controversial topics. The first is overdiagnosis. According to a recent report in The Wall Street Journal, some leading cancer experts say that zealous screening is finding ever-smaller abnormalities that are being labeled cancer or precancer with little or no justification. Coupled to this is a more serious and potentially more destructive problem: overdiagnosis is leading to overtreatment. Some cancer patients being treated aggressively—with surgery, radiation, chemotherapy and other treatments—all of which is unnecessary, expensive and can potentially bring lifelong side effects. Many women with breast cancer make the dramatic decision to undergo treatment beyond a lumpectomy to diminish the risk of the cancer spreading once a tumor is removed. But in making the decision to perform additional procedures, women and their doctors are, in effect, betting that it’s better to overtreat than to undertreat. This isn’t quite the “it’s better to be safe than sorry” approach because it ignores an important statistic: only 35% of women with newly diagnosed breast cancer have a tumor that will actually metastasize. These patients with an aggressive tumor are good candidates for chemotherapy. However, the majority of women with newly diagnosed breast cancer—approximately 65%—have tumors that are biologically incapable of metastasizing, rendering these extra measures unnecessary. The dilemma of overtreatment has been well-summarized by Otis Brawley, chief medical officer of the American Cancer Society. “I am confident that somewhere between 10% and 30% of women with localized invasive breast cancer would be just fine if we just watched them,” Brawley told The Wall Street Journal. “But I cannot look into a patient’s eyes and say, ‘You’re one of the 10% to 30% that should not be treated.’” Boston, Mass.-based MetaStat Inc., whose Scientific and Clinical Advisory Board is chaired by Oscar L. Bronsther, MD, is aiming to provide more clarity for patients and oncologists when deciding what’s next after a tumor is removed. The company has developed new tests to analyze whether a specific individual’s cancer has metastatic potential, MetaSite Breast and MenaCalc. These tests are intended to potentially allow clinicians to customize cancer treatment decisions by identifying and differentiating high-risk patients who need aggressive therapy, and by possible sparing low-risk patients from the harmful side effects and expense of additional treatment. MetaStat’s researchers have identified the important predictive role of the Mena protein. Mena is found in the developing embryo where it is an important actor in the developing nervous system among other functions. It facilitates and organizes formation, extension and navigation of growing nerve fibers through tissue to link with other neurons, forming the proper circuits needed for a functional nervous system. Its expression decreases from embryonic to adult life. However in metastatic cancer cells, high levels of the Mena protein accumulate and influence a number of intracellular signaling programs. Mena facilitates a dangerous process whereby tumor cells send out a well-organized protuberance that invades surrounding tissue and pulls the remainder of the cell behind it. Mena modulates the strength and direction of this invasive process and steers the migrating cancer cell in the direction of blood vessels through its ability to modulate the metastatic cell’s response to chemical signals that attract it to blood vessels. Mena is present in cancer cells in more than one form. MetaStat has identified the most dangerous isoform of Mena that it has named MenaINV (Mena invasive). Mena11A, on the other hand, is the Mena isoform that seems to exert a much more positive influence on the cell’s behavior, reducing the ability of cells to break away from the tumor and invade and migrate toward blood vessels. MetaStat’s key discovery is that it can predict the metastatic potential of a cancer cell by measuring the relative levels of MenaINV and Mena11A. As the relative levels of MenaINV rise and Mena11A fall, the cancer cell transitions to a more metastatic shape and behavior. These metastasis-promoting behavior changes include increased migratory behavior, changes in shape, loss of adhesion to neighboring cells and up to 100-fold greater sensitivity to the chemical attractant that lures metastatic cells to blood vessels. The company’s MetaSite Breast test is performed on tissue from a biopsy and can identify where metastasis begins in the body. For this to happen, three types of cells must self-assemble in a structure called the “MetaSite”: one type of cell that lines blood vessels; a type of immune cell; and a tumor cell that expresses the Mena protein. MetaStat Breast can identify these cells by a staining process. MetaStat has shown in clinical studies that the density of MetaSites is linked to metastatic risk. Performing the test readily fits into the current diagnostic paradigm and requires no additional surgical procedures. MetaStat’s other test, MenaCalc, measures metastatic risk in breast, prostate, lung and colorectal cancers. The MenaCalc assay requires very little tissue and can be performed on cells from a needle biopsy or fine needle aspiration, allowing oncologists to begin treatment starting from patients’ initial visit. MetaStat expects to initially commercialize the MenaCalc assay for breast cancer, followed by assays for prostate cancer and adenocarcinoma of the lung. With the advent of tests for cancer patients that can determine the likelihood of metastasis, the outlook for cancer diagnostics appears brighter on several fronts. Oncologists will be equipped to offer their cancer patients a much more informed set of options, involving less uncertainty and a better understanding of what additional treatments, if any, are worthwhile. Patients, in turn, can look forward to more personalized care reflecting their individual cancer, and will be assured that they are avoiding unnecessary procedures that can take a toll on the body. Overall, by reducing the rate of unneeded treatments, the cost of cancer care—which currently stands at more than $100 billion in the U.S. annually—may fall: a win-win for everyone involved. rdmag.com