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The Development of Diagnostic Assays for Metastasis
Clearly, it would be highly desirable to implement diagnostic assays to positively identify patients with a high risk of metastasis who need aggressive therapy and spare those with low risk from the harmful side effects and expense of chemotherapy. Such diagnostic assays already exist. Two assays, known as MetaSite Breast and MenaCalc, developed by MetaStat, Inc., are designed to accurately stratify patients based on their individual risk of metastasis and to provide physician and patient with clinically actionable information to better customize cancer treatment.
MetaSite Breast is an immunohistochemistry-based test, performed on FFPE tissue from a biopsy, that directly identifies and quantifies the active sites of the metastatic process. In order for breast cancer tumor cells to enter a blood vessel—the first stage of metastasis—three types of cells must self-assemble in individual structures. This structure, termed Tumor Microenvironment of Metastasis or “MetaSite,” is composed of an endothelial cell, a perivascular macrophage and a tumor cell that expresses the Mena protein. It is possible to utilize a triple immunohistochemical stain for paraffin-embedded tissue that simultaneously labels macrophages, endothelial cells and invasive macrophage-associated carcinoma cells. It has been demonstrated in clinical studies that the density of these observed triple-stained MetaSites correlates with metastatic risk. Data from a 481-patient correlative clinical study demonstrated a positive association between MetaSite score and risk of distant metastasis in women with ER-positive/HER2-negative breast cancer.[vii]
The second assay, MenaCalc, relies on the specific properties of the Mena protein and that fact that it is alternatively spliced to create a family of structurally similar but physiologically distinct proteins. Mena is found in the developing embryo, where it is a directional protein that plays a significant role in the maturation of both the central and peripheral nervous system. Postpartum, only small amounts of the Mena protein persist. 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. Mena 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 multiple isoforms. The most dangerous isoform of Mena is named MenaINV (Mena invasive). Another isoform, Mena11A, 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. As the level of the former rises and the latter falls, the cancer cell transitions to a more metastatic shape and behavior. These behavior changes include increased migration, 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. MenaCalc is designed to predict the metastatic potential of a cancer cell by measuring the relative levels of MenaINV and Mena11A. It also has the potential to predict outcome in multiple epithelial-based tumor types including breast, prostate, lung and colorectal cancers. The MenaCalc assay requires very little tissue and is designed to be performed on cells from a needle biopsy or fine needle aspiration. A clinical study suggested MenaCalc may serve as a biomarker for metastasis.[viii]
In April 2015, at the annual meeting of the American Association for Cancer Research, MetaStat presented the positive results of a clinical study demonstrating the MenaCalc Lung score is an independent prognostic factor and predictive for distant metastasis in patients with non-small cell lung cancer. This suggests the assay could provide information to help physicians better understand the metastatic potential of tumors in patients with squamous cell carcinoma. Moreover, these data, combined with earlier data in node-negative and node-positive patients with breast cancer, demonstrate the breadth of the MenaCalc platform and support its applicability to all epithelial-derived tumors.[ix]
Further research is likely to extend the range and accuracy of assays that can determine the likelihood of metastasis. These will allow doctors and their cancer patients to map the best course of treatment for the best possible outcomes, reducing the uncertainty and improving understanding of which treatments, if any, are worthwhile. Next-generation diagnostics could eventually lead to more targeted therapies for specific subsets of cancer patients, as well as to increasing savings for hospitals and patients. Overall, by reducing the rate of unneeded treatments, the cost of cancer care—which currently stands in excess of $157 billion in the U.S. annually[x]—may drop.
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Oscar L. Bronsther, M.D. is Chairman of the Scientific and Clinical Advisory Board at MetaStat, Inc., a molecular diagnostic company focused on developing and commercializing epigenetic-based diagnostic tests for early and reliable prediction of systemic metastasis.
[i] Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell. 2006 Nov 17;127(4):679-695.
[ii] O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005; 10 Suppl 3:20-29.
[iii] Beck M. Some cancer experts see ‘overdiagnosis,’ question emphasis on early detection. The Wall Street Journal. 2014 Sep 14. Available at: http://www.wsj.com/articles/some-cancer-experts-see-overdiagnosis-and-question-emphasis-on-early-detection-1410724838
[iv] Linos E, Schroeder SA, Chren M-M. Potential overdiagnosis of basal cell carcinoma in older patients with limited life expectancy. JAMA. 2014;312(10)997-998.
[v] Ong M-S and Mandl KD. National expenditure for false-positive mammograms and breast cancer overdiagnoses estimated at $4 billion a year. Health Aff. 2015 Apr;34(4):576-583.
[vi] Elmore JG, Longton GM, Carney PA, et al. Diagnostic concordance among pathologists interpreting breast biopsy specimens. JAMA. 2015;313(11)1122-1132.
[vii] Rohan TE, Xue X, Lin HM, et al. Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer. J Natl Cancer Inst. 2014 Jun 3;106(8). pii: dju136.
[viii] Agarwal S, Gertler FB, Balsamo M, et al. Quantitative assessment of invasive mena isoforms (Menacalc) as an independent prognostic marker in breast cancer. Breast Cancer Res. 2012 Sep 12;14(5):R124.
[ix] Gustavson M, Davis W, Bronsther O, Gertler F. Menacalc as an independent prognostic factor and predictor of metastasis in non-small cell lung cancer. Presentation abstract. AACR Annual Meeting 2015. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3682&sKey=01bb2ef5-a627-4194-8c2b-e97f9f028817&cKey=67c034a9-db42-4b50-9951-3bffbecf6b52&mKey=19573a54-ae8f-4e00-9c23-bd6d62268424
[x] National Cancer Institute. Cancer prevalence and cost of care projections. Available at: http://costprojections.cancer.gov/.
