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Monogram Hopes to Challenge Existing EGFR Dxs with Its Dimerization Assay

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In a play to enhance the standing of its eTag assay in the identification of patients who will respond to AstraZeneca's lung cancer drug Iressa, Monogram Biosciences last week at the American Association of Cancer Research meeting in Philadelphia presented a study of Japanese patients in which the company used its fledgling technology to correlate receptor protein dimerization and expression with drug response.

In Monogram's new study, its scientists made predictions of Iressa response based on examinations of formalin-fixed paraffin-embedded tissue with eTag, and compared the actual response rate. The dimerization of EGF-family receptors is considered a key step in the beginning of the signal cascade that supports the proliferation and growth of several cancer types. Unlike the situation with the Her2 receptor, which is a member of the EGFR family and is very easily activated, a raw accounting of the levels of other EGFR proteins does not provide a reliable estimate of their activity, Mike Bates, Monogram vice president of clinical research, told Pharmacogenomics Reporter.

The study involved samples from 55 patients, one set of 35 and one set of 20, who had been treated with standard chemotherapy and later treated with Iressa monotherapy, said Bates. Using the recursive partitioning statistical technique to identify which molecular feature was best able to discriminate between Iressa responders and non-responders, the relative levels of Her1-Her2 dimers and Her 2-Her3 dimers proved more useful than EGFR-family protein levels, Bates said. In the 35-patient set, there were 21 Iressa responders and 14 non-responders, and the ratios of Her1-Her1 and Her1-Her2 dimers minus the level of Her2-Her3 dimers "essentially correctly classified all these guys, except for three," said Bates.

"Looking at the overall dataset [of 55 patient samples], you're looking at sensitivity of 86 percent and a positive predictive value of 80 percent," Bates said. However, some samples do not fit into the company's classification system, likely because there exist other molecular factors that were not measured in the study, he added.

The patients were treated by Yasushi Yatabe, director of the Department of Pathology and Clinical Laboratories at the Aichi Cancer Center Hospital in Nagoya, Japan.

The company presented its new results, along with four other presentations featuring the eTag assay, in a venue at which they risked being overshadowed — the same conference last week featured several studies of Iressa Survival Evaluation in Lung, or ISEL, trial data that pointed to epidermal growth-factor gene copy number as the best known indicator of drug response.

Among the variables the company measured, "we looked at Her1 total [protein levels in each sample], Her2 total, Her3 total, [and] Pten [protein] levels — and then we looked at … the formation of Her1-Her1 dimers Her1-Her2 dimers, Her1-Her3 dimers, and Her2-Her3 dimers," to see how these correlated to Iressa response, he said.

Based on data gathered at Monogram, it seems that "some dimer pairs that indicate that signaling is going on through the pathway are dimer pairs that you might expect Iressa to antagonize," said Bates. "The presence of those dimer pairings, in a patient treated with Iressa, would suggest that this is a patient [who] could benefit from [the drug]," he added.

Contrariwise, if EGFR-family dimers that are not expected to be involved in Iressa response are present in large amounts in a patient tumor sample, that patient would not be expected to respond to the drug, said Bates. The presence of Her2-Her3 dimers correlated to a lack of Iressa response, for example, "which would make sense, [because] 2/3 dimers would not be targeted by Iressa, and therefore signaling through 2/3 could conceivably be a [drug]-resistance pathway," he said.

Monogram has tested "six or seven" other sample sets, especially from other ethnicities, to perform similar evaluations and to compare those results with those of the data from Japanese patients, said Bates. The company is also focusing on studies involving breast cancer and colorectal cancer, he said.

The company hopes to launch an EGFR-related test in 2006.

— Chris Womack ([email protected])

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