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Monogram's Herceptin Response Test May Rival IHC, FISH Dxs, Preliminary Data Say

Monogram Biosciences last week said that preliminary data from a study of its HERmark assay suggests that it may be an improvement over immunohistochemistry- and fluorescence in situ hybridization-based tests in determining which patients with metastatic breast cancer will likely benefit from Herceptin therapy.
The company said it would present the findings in more detail on June 2 at the American Society of Clinical Oncology's annual meeting in Chicago.
The two top players in the HER2 breast cancer diagnostics market are currently Dako’s IHC-based HercepTest and the FISH-based PathVysion HER-2 DNA probe kits made by Vysis, which was acquired by Abbott in 2001. Both tests are approved by the US Food and Drug Administration.
According to guidelines released last February by ASCO and the College of American Pathologists, although certain FISH and IHC tests have received FDA approval, analyses of prospective, randomized, adjuvant trialsof Herceptin show that testing algorithms to gauge HER2 expression have not been standardized and were developed “somewhat arbitrarily.”
Additionally, an expert panel formed by ASCO and CAP found “as many as 15 percent to 20 percent of the HER2 assays performed in the field may be incorrect when the same specimen was reevaluated in a high-volume, central laboratory.” [PGx Reporter 02-28-2007].
"Current testing methods for determination of the likelihood of benefit from Herceptin are not adequate," Allan Lipton, professor of medicine and oncology at Hershey Medical Center/Penn State University and a co-author in the HERmark study, said in a statement from Monogram. HERmark “could provide enhanced information on which patient therapy decisions may be based."
Monogram conducted the study — which looked at HERmark's ability to accurately identify the metastatic breast cancer patients most likely to benefit from Herceptin treatment, as well as discern different degrees of response to the drug — in collaboration with Lipton and colleagues at the Experimental Oncology Research Lab at Penn State/Hershey Medical Center. Kim Leitzel, a senior researcher at Lipton's laboratory, will discuss the findings at the ASCO conference.
Monogram Chief Financial Officer Alf Merriweather told Pharmacogenomics Reporter this week that by quantifying HER2 and HER2 homodimer levels, HERmark can provide a better response assessment than existing IHC and FISH tests and improve knowledge of HER2 biology in clinical specimens.

“While current testing methods identified all these patients as being equally likely to respond to Herceptin treatment, Monogram's HERmark assay was able to distinguish separate sub-groups of patients with different clinical outcomes, and those outcomes correlated with the quantitative measurements of HER2 status provided by HERmark.”

“Less than half of metastatic breast cancer patients determined by current technologies to be HER2 positive do not in fact respond to Herceptin,” Merriweather said. “In some of these cases, this may be because there are other signaling pathways that are active and knowledge of HER2 itself is not enough. In many cases, however, the results are so qualitative and highly variable from lab to lab that they do not give a sufficiently accurate measure.”
HERmark is the first diagnostic Monogram has built on its VeraTag (previously known as E-Tag) technology, designed to run on standard formalin-fixed paraffin embedded patient samples. The so-called “proximity-based assay” tags particular analytes, and then releases these tags when they come close after protein dimerization through light-activated "molecular scissors." The released tags are quantified by capillary electrophoresis.
“The result is a very precise and quantitative measure of the presence of the underlying biological marker,” Merriweather said.
The study to be presented at ASCO used the HERmark assay to analyze tissue samples from metastatic breast cancer patients previously selected for Herceptin therapy by IHC or FISH testing.
“While current testing methods identified all these patients as being equally likely to respond to Herceptin treatment, Monogram's HERmark assay was able to distinguish separate sub-groups of patients with different clinical outcomes, and those outcomes correlated with the quantitative measurements of HER2 status provided by HERmark,” the company said in a statement.
In the clinical trial, patients with higher levels of HER2 and HER2 homodimers had a higher probability of objective response to Herceptin. Patients with higher HER2 expression levels had a median time-to-progression of 11.6 months while those in the lower half of the distribution had a median time-to-progression of 5.4 months.
Similarly, patients with higher levels of HER2 homodimers had a median time-to-progression of 11.6 months while those with lower HER2 levels had a median time-to-progression of 5.8 months. Further analysis revealed a trend in favor of higher HER2 expression and longer overall survival (median survival 37.4 months vs. 28.7 months), but this finding was not statistically significant (p=0.2).
“Cox multivariate analyses identified HER2 expression and HER2 homodimer levels as independent correlates of both time-to-progression and overall survival,” Monogram said in a statement.
While this preliminary study suggests that quantifying HER2 homodimer levels yields similar results to quantification of HER2 expression, Monogram hopes to elucidate the added benefits of gauging HER2 homodimer levels in later studies.
“HERmark provides a quantitative measure of the level of HER2 and for the first time a [quantitative] measure of the level of HER2 homodimers,” Merriweather said. “There may be unique insights available from the two measurements being available. Other studies and analyses are ongoing and will provide further information in this regard.”
Additionally, since clinical trial participants were previously identified by IHC and FISH-based tests, the preliminary study showed that HERmark is no worse than existing methods. Monogram has studied over 2,000 patient tumor samples with HERmark and plans to present data comparing HERmark to IHC and FISH-based assays “at a later time,” Merriweather said. Additional studies of HERmark for breast cancer in both the metastatic and adjuvant settings are in progress.
Currently, although HERmark is approved for routine testing in Monogram's CLIA-certified clinical reference laboratory, the test is not available to doctors. “Monogram is evaluating the timing and details of a commercial introduction of HERmark,” Merriweather said. No price has yet been set for HERmark.
Dako and Abbott Molecular did not respond to requests for comment on Monogram's clinical trial or the effectiveness of their technologies compared to HERmark.

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