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20/20 GeneSystems Developing mTOR Pathway Test to Predict Herceptin Response in HER2-Positive Patients

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Diagnostics company 20/20 GeneSystems presented data last week showing high sensitivity and specificity for its protein biomarker test to predict response to Herceptin (trastuzumab) in HER2-positive breast cancer patients.

With the support of a $3 million Small Business Innovative Research grant from the National Cancer Institute, the company is developing several theranostic and companion diagnostic tests focusing on the mTOR and VEGF pathways using its proprietary layered immunochemistry platform.

20/20 presented data for one of these diagnostic projects — the Herceptin response test, which the firm calls PredicTOR Breast — in a poster at the American Society of Clinical Oncology Breast Cancer Symposium last week.

The company hopes the test will be used to help identify the close-to-half of HER2-positive patients who are unlikely to respond to Herceptin, and to suggest they could benefit from additional treatment with an mTOR inhibitor.

Jonathan Cohen, 20/20 GeneSystems' CEO, told PGx Reporter that though the company is hoping to evaluate at least an additional hundred samples to fully validate PredicTOR Breast, 20/20 considers the sensitivity and specificity its researchers demonstrated in the ASCO poster — 87 percent and 78 percent, respectively — to be "promising."

In the presentation, the company reported using its layered IHC technology to measure a set of 14 proteins in the mTOR and HER2 pathways in a blinded sample cohort of 24 Herceptin responders and nine non-responders.

The group found that four of the mTOR markers — p-mTOR, p-4EBP1, pERK, and HIF1a — could discriminate responders from non-responders with 82 percent accuracy, correctly identifying 21 of the 24 responders and seven of the nine non-responders.

"Obviously we need larger numbers, certainly at least more than 100, before we can really guarantee that we will be able to offer this [test]," Cohen said. "But it certainly looks encouraging with the numbers we have."

In July, the US Food and Drug Administration approved Novartis's mTOR inhibitor Afinitor (everolimus) in combination with Aromasin (exemestane) as a treatment for postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer. However, there is data suggesting that mTOR inhibitors can be a treatment option for a subset of HER2-positive breast cancer patients, as well.

According to Cohen, while some of the company's other diagnostic projects deal with drugs that directly target mTOR or VEGF, the breast cancer test is slightly different. "We have found that over-activation of mTOR correlates very nicely with non-response to Herceptin," he said. "The idea is that it acts as a short circuit or a bypass.

"This conceptual idea is not new to us; there is a good deal of discussion in the literature about mTOR bypass," he said.

About half of all HER2-positive patients do not respond to Herceptin therapy, according to Cohen. He explained that 20/20 intends the PredicTOR test to be a tool for identifying at least some of those 50 percent, and indicating that they might benefit from additional therapy with an mTOR inhibitor.

"The practical use would be that a woman with advanced breast cancer would have two tests" — HER2 and PredicTOR, he said. "If you are positive on the HER2 and negative on the PredicTOR, you would be treated according to normal guidelines. If you are double positive, you would be getting both Herceptin and an mTOR inhibitor."

He noted that current guidelines do not recommend mTOR inhibitor therapy in HER2-positive patients with over-activation of mTOR, but said that the firm expects that may change.

As the company moves forward with the Herceptin response test, Cohen said 20/20 is also working on a number of other pharmacogenomic tests, including one to predict whether patients with advanced kidney cancer are likely to respond to anti-angiogenic drugs such as sunitinib (Pfizer's Sutent), and another to predict response to mTOR inhibitors in metastatic kidney cancer, and potentially other cancers as well.

Cohen said the company's stacked IHC technology allows clinicians to examine up to ten different biomarkers using a single formalin-fixed, paraffin-embedded tissue sample, a routinely collected clinical sample that does not require extra handling or preparation.

The method also preserves morphology, allowing pathologists to assign a biomarker signal to a specific region of interest, such as cancer cells versus surrounding tissue.

Interestingly, Cohen said, looking at proteins rather than genes or gene expression seems to have allowed the company to identify predictive markers other techniques could miss.

For example, 20/20's Director of Medical Affairs, John Gillespie, told PGx Reporter that three of the four markers in the breast cancer test and four of six in the kidney cancer test are phosphorylated, which genomic or RNA profiling would not have picked up.

"This is evidence of the utility of looking at proteins," Cohen said. "You simply can't do this at the DNA or RNA level."

Cohen said the company is planning to increase its validation effort for the breast cancer test in the next few months, and hopes at least one of its mTOR tests will be ready for commercialization as a laboratory-developed test in the company's CLIA lab by the end of next year.

He said that 20/20 is also open to making its layered IHC technology available to outside companies or clinical investigators on a case-by-case basis through technology-access partnerships.

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