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Biobase, Strategic Medicine Find Adjunct Biomarker to Improve Her2 Testing Protocols

A partnership that Biobase forged last year with the commercial arm of the Windber Research Institute has discovered a molecule that may serve as an “adjunct” biomarker to help resolve the “strong discrepancy” in outcomes of immunohistochemistry- and fluorescence in situ hybridization-based Her2 testing in women with breast cancer.
Speaking at Cambridge Healthtech Institute’s Molecular Medicine Tri-Conference meeting last month in San Francisco, Frank Schacherer, executive vice president of Biobase, said that while the use of Her2 overexpression to help guide physicians in prescribing Herceptin for breast cancer patients is a “Cinderella story” for personalized medicine, only 40 percent of patients who test positive for the Her2 marker actually respond to the drug.
Furthermore, he noted, the results of IHC, which measures protein over-expression, and FISH, which measures gene amplification, often don’t agree. Schacherer said that around 25 percent of the time, patients test negative for Her2 with FISH, but positive with IHC, leaving doctors in the dark about whether to prescribe the drug.
Hoping to resolve these discrepancies, the partners said they have identified a molecule that they believe explains the difference between the FISH and the IHC response. They are now further refining that computationally and beginning to do some experimental validation.
Last year, Biobase began working with Strategic Medicine — a company formed to commercialize research from Windber — to analyze clinical breast cancer samples using its ExPlain bioinformatics platform [BioInform 03-02-07].
Schacherer told BioInform following the conference that the partners reasoned that if they could identify a biomarker for use alongside the current Her2 tests, clinicians could make more informed dosing decisions because they’d be based on two data points instead of one.
Michael Liebman, president and managing director of Strategic Medicine, said that the goal of the project was to determine “why the gene copy number and protein level … don’t agree mechanistically, and then whether that might tie into giving you a better indicator for response.”
Following Schacherer’s talk at the conference, several attendees questioned the partners’ approach, noting that it might be more effective to search for entirely new markers for response to Herceptin rather than markers to better inform Her2 testing.

“An adjunct to the existing test is just a 510(k) application, so it gets into practice much more rapidly. But it isn’t necessarily the best mechanistic marker, it’s just improving the existing markers.”

Schacherer and Liebman both agreed that an alternative marker for Her2 would be preferable, but described the current work as a step toward that goal.
Liebman, who is also executive director of the Windber Research Institute, told BioInform that the adjunct biomarker approach is a “tactical” project designed to improve Her2 testing in the short term, but noted that the ultimate goal of this work would be a “strategic” project that would “ignore those markers altogether and just look at patients who have or haven’t responded [to Herceptin] to find out what the best biomarkers are.”
However, he said, the tactical approach “can be implemented much more rapidly” because it would not be subject to rigorous FDA approval. “An adjunct to the existing test is just a 510(k) application, so it gets into practice much more rapidly. But it isn’t necessarily the best mechanistic marker; it’s just improving the existing markers,” he said.
Liebman said “we’re continuing the data collection and analysis to enable us to do the long-term project. So we’re not just stopping along the way but using it as something tactical to try and improve patient care immediately, recognizing that it’s still not the ultimate solution.”
ExPlaining Her2 Outcomes
In the study, the partners performed IHC and FISH tests on 71 breast cancer patients from the Clinical Breast Care project, a collaboration between Windber and the Walter Reed Medical Center. Of the 71 patients, 14, or nearly 20 percent, tested negative for Her2 with FISH but positive with IHC.
They then conducted microarray gene-expression analysis on blood serum samples from the patients and identified differentially expressed genes. From there, Biobase used its ExPlain platform and suite of manually curated databases to help map those differentiated genes to biological pathways.
Liebman said that a key aspect of the collaboration was Biobase’s ability to perform “upstream” analysis of these genes to help identify common regulation in signaling and transcription processes.
Schacherer said that the company uses its Transfac database of transcription factors and transcription factor binding sites to identify those factors that are “specific for differential regulation.” Often, he said, combinations of transcription factors act together to activate a gene, so the company uses a tool in ExPlain called Composite Module Analyst that allows it to build “promoter models” that indicate which factors or combinations of factors are regulating those genes.
Next, Schacherer said, the company uses its TransPath pathway database to identify “which other pathway are regulating the transcription factors, and then which proteins are regulating those proteins, and which proteins are regulating those proteins, and so on,” until the analysis results in a “key regulator” that serves as a potential biomarker.
Liebman described these key regulators as “linkers that aren’t differentially expressed, but can play a key role in producing the response.”
He noted that even though the partners have identified a potential adjunct biomarker, they have yet to determine whether it will work as a clinical test. “What we’re tying to look at is not only mechanistically what is the important marker, but how would we best ‘operationalize’ it, meaning how do we convert it into something that’s measurable that gives you consistency,” he said.
“It may be that the best mechanistic marker isn’t the best operational marker,” he added. “We want to make sure it can be applied at the highest degree of resolution across multiple laboratories, so that’s why we also look at this operational concept, because if you have the best marker, but you can’t apply it, you’re not helping anyone.”
Liebman said that the team hopes to have a biomarker validated within the next six months. He said that Strategic Medicine is currently in discussions with several undisclosed diagnostic firms that are “interested” in marketing the test once it is approved.
As for Biobase, this work is its first foray into the clinical arena, but Schacherer said that it likely won’t be its last. The bioinformatics pipeline that the company developed for this study is “a very general approach” for biomarker discovery, he said.
“One of our main partners is Strategic Medicine, but we are working on establishing collaborations with several other partners exactly for the purpose of doing marker discovery,” he said. He did not elaborate.

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