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MetaStat Ramps Up Validation Trials for 2016 Launch of Breast Cancer Prognostic Tests

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NEW YORK (GenomeWeb) –Boston-based diagnostic firm MetaStat plans to launch two tests next year – one that assesses the risk of metastasis for estrogen receptor-positive, HER2-negative breast cancer patients and another that gauges disease prognoses across all breast cancer types.

The two diagnostics, called MetaSite Breast and MenaCalc Breast, use immunohistochemistry and quantitative immunofluorescence to interrogate the role of the Mena protein and its isoforms in driving metastatic disease. Mena is a protein involved in the development of the nervous system in embryos. However, Mena expression is suppressed after birth, and isn't particularly active in healthy adults.

"All epithelial cancers turn back on the gene that codes for Mena," MetaStat CEO Oscar Bronsther told GenomeWeb. "Furthermore, the environment in which the tumor finds itself, which is sort of an epigenetic phenomena, determines what isoform of Mena the gene codes."

The science underlying MetaSite and MenaCalc is drawn from the work of John Condeelis at Albert Einstein College of Medicine, who elucidated the tumor microenvironment characteristics fostering metastasis, and Frank Gertler at the Massachusetts Institute of Technology, who cloned Mena and described its role in metastatic disease progression.

Using intravital microscopy – an imaging tool that allows researchers to observe biological processes in live animal models – Condeelis and his team identified the portal or window that cancer cells use to escape into the blood stream. This escape hatch, it turns out, comprises a three-cell cluster involving Mena-expressing cancer cells, endothelial cells lining the blood vessel, and white blood cells around the blood vessels, called macrophages.

"This is the portal of entry that individual cancer cells use to enter the blood vessels," Bronsther said. "Once they've used this portal to enter the blood vessels surrounding these cancers, the potential for metastatic disease arises." After Condeelis identified these tumor microenvironment features in rodents, Joan Jones, a pathologist now at Albert Einstein and Condeelis' wife, figured out a way to identify these portals in humans using unique stains for the three cell types while she was at Weill Cornell Medical College.

Jones, Condeelis, and Gertler are all on MetaStat's scientific board. In a paper published last year in the Journal of the National Cancer Institute, the three researchers and others described using a tumor microenvironment of metastasis, or TMEM score, to predict the risk of distant metastasis in ER-positive, HER2-negative breast cancer patients. This is the score that underlies the MetaSite Breast cancer test. 

The researchers conducted a case control study within a cohort of more than 3,700 patientswithin the Kaiser Permanente Northwest system who were diagnosed with invasive ductal breast carcinoma between 1980 and 2000 and followed through 2010. Using the TMEM score, researchers analyzed samples from more than 250 patients who had metastatic disease and matched controls. Using a composite of the TMEM score and clinical factors, researchers reported that patients deemed to be at low risk of metastasis had a 5.9 percent absolute risk of distant metastasis, medium-risk patients had a 14.1 percent risk of metastasis, and the high-risk group's risk was 30.3 percent.

The score was able to predict metastatic risk for the 60 percent of breast cancer patients who had ER-positive, HER2-negative breast cancer patients, the same subset of patients served by Genomic Health's Oncotype DX breast cancer recurrence test. The JNCI study suggested the score performed better than the IHC4 recurrence test, but did not find that the TMEM score was associated with metastatic risk of breast cancer for triple negative or HER2-positive patients.

MetaStat is hoping that its test will be an improvement over currently available prognostic breast cancer tests. Bronsther noted that other multi-gene expression prognostic tests, such as Oncotype DX, analyze genes associated with driving cell proliferation and local growth of the tumor and employ an algorithm to gauge the risk for distant recurrence. This diagnostic strategy has been powerful, he said, but has limitations since it doesn't specifically look at the mechanism that drives metastatic disease.

"Gertler and Condeelis … were looking for the mechanism that drives metastatic disease rather than just creating a gene signature and letting a computer work out a formula," he said. "Over a decade and [with] tens of millions of NIH funding, these men discovered the pathway by which most if not all epithelial cancers develop a metastatic potential."

An editorial accompanying the JNCI publication last year emphasized the importance of looking at the tumor microenvironment in elucidating the highly complex, poorly understood metastatic process. "This overwhelming complexity of the metastatic process highlights the importance of mechanism-based, tumor-type specific studies in clinically relevant murine models," Dan Duda from Massachusetts General Hospital and others wrote in the editorial, adding that the study by Jones and colleagues needs further validation. "This approach may greatly facilitate the development of efficacious anti-metastatic strategies."

While MetaSite Breast cancer will address the ER-positive, HER2-negative subpopulation of patients, MetaStat's second test planned for launch next year is MenaCalc Breast. The company is hoping that the test will be a prognostic tool that can address all breast cancer types. MenaCalc assesses the ratio of Mena isoforms, MenaINV and Mena11A.

Disease aggressiveness and likelihood of metastasis increases with greater expression of MenaINV. The isoform drives metastatic cancer by allowing individual cancer cells to free themselves from the primary tumor, by changing the shape of the cancer cells from round to narrow and elongated, and by upregulating the sensitivity of the epidermal growth factor receptor [EGFR] on macrophages lining the tumor blood vessels, which draws cancer cells toward them. However, if tumors express greater amounts of Mena11A, the protective Mena isoform, patients have a reduced likelihood of metastasis.

MetaStat has validated MenaCalc Breast in two studies so far, one involving nearly 800 patients and another involving 400 patients. However, the company believes MenaCalc has broader utility in all epithelial cancers, and has submitted an abstract for presentation at a medical conference at the end of April, which shows the test is prognostic in non-small cell lung cancer.

MetaStat is planning to initially launch MetaSite Breast and MenaCalc Breast as lab-developed tests (LDTs) performed at a CLIA-certified lab. However, the firm will prepare for a submission with the US Food and Drug Administration if the agency's evolving LDT regulations require premarket review for these tests. "As an LDT, we're not obligated to do any further trials," Bronsther said. "However, we are going to do many additional trials this year, so we have the strongest data possible and we're well positioned to impact the medical community."

MetaStat is planning to conduct at least three more trials this year involving 400-plus new patients, before launching the tests next year. In January, MetaStat announced that it had inked a transfer agreement for materials and data with Kaiser Foundation Hospitals. Under the deal, MetaStat will receive de-identified tissue samples, clinical information, and the medical histories of up to 500 patients with and without metastatic breast cancer for testing with MetaSite Breast and MenaCalc Breast. The company is planning to use the samples to further verify and validate the findings published in the JNCI paper.

According to Bronsther, the company has already gotten a CPT code for its tests (code 88361 describing quantitative or semi-quantitative IHC using computer-assisted technology). The tests will be priced at a discount to the existing multi-gene algorithm-based prognostic tests, according to MetaStat. "From our perspective that's okay because IHC and immunoflourescence are well-established diagnostic tools," he said. "We still have very substantial margins."

 


An earlier version of this article incorrectly stated in the headline that MetaStat is aiming for a 2015 launch of its breast cancer test.

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