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Study Indicates That Detection of EGFR in Blood May Predict Iressa and Tarceva Response in NSCLC


Researchers from the National Cancer Research Center in Tokyo report in the current issue of Clinical Cancer Research that they have successfully used DxS' Amplified Refractory Mutation System technology to identify drug-sensitizing mutations in the epidermal growth factor receptor gene from DNA floating free in serum, a step that may foreshadow the use of molecular diagnostics to monitor patients' likely drug responses in non-small cell lung cancer, and by extension other cancers.

"Although previous studies of genetic and epigenetic markers in free plasma DNA have shown the potential value of this source of tumor-derived material, the study by [Hideharu] Kimura et al. links plasma DNA-based mutational analysis to a therapeutic choice relating to the administration of [tyrosine-kinase inhibitors] in NSCLC," wrote Daphne Bell, an assistant professor of medicine at Massachusetts General Hospital Cancer Center, and Daniel Haber, a professor of medicine at Harvard Medical School, in an editorial commentary about the research that appears in the same CCR issue.

Bell and Haber suggest that a minimally invasive blood-based test for drug response, if used repeatedly during therapy, could help guide therapies for epithelial cancers like NSCLC, much like molecular diagnostics for Bcr/Abl are already used to monitor Gleevec effectiveness and guide selection of secondary drugs for chronic myelogenous leukemia.

Even fine-needle aspirates are too invasive and potentially dangerous, Bell and Haber wrote, while DNA sequencing, which is commonly used for most EGFR mutation testing, has sensitivity shortcomings. In general, a heterozygous mutation has to be present in at least 60 percent of cells, while surgical specimens containing less than 60 percent tumor cells are usually ineligible for testing, they wrote.

In the National Cancer Research Center study, Kimura and colleagues detected two EGFR-sensitizing mutations — L858R and del E746-A750 — from among 10,000 wild-type alleles. The researchers also showed that patients' EGFR genotype detected in serum predicted their responses to Iressa and Tarceva, with those patients exhibiting sensitizing mutations having longer median progression-free survival and (statistically insignificant) overall survival.

"It's the beginning of a larger process, and we don't know how important blood-based testing is going to be," Stephen Little, DxS' CEO, told Pharmacogenomics Reporter this week. The paper "makes it very clear that it might be practical to use DNA isolated from serum, and the next year or so will tell whether that converts in this first report to something that's really clinically useful," he said.

The origin of free tumor cell DNA is still not known, but Bell and Haber said it probably comes from lysed and necrotic cancer cells.

DxS has developed assays for the 27 most common EGFR mutations predicting drug response or drug resistance, the firm said in a statement this week. "We're certainly broadening the range of mutations that we test for, and we're confident that we'll have assays with very good analytical performance," said Little.

The company plans to launch a research-only test for EGFR mutations that confer resistance to Iressa and Tarceva at the American Association for Clinical Chemistry meeting later this month in Chicago, Little said. Whether DxS will develop a clinical diagnostic for EGFR mutations depends entirely on the clinical utility shown by its research product during testing, but the company would probably first seek a CE Mark from the European Community, he added.

"Whether these turn out to be clinically useful will depend a lot on the biology and the pharmacogenetics of the targets and the drugs," Little said. Next, the firm plans to develop similar assays with "a much broader range of sensitivity," he said.

Asked whether AstraZeneca, the manufacturer of Iressa, is interested in the possibility that DxS' assay might be a useful tool to guide lung-cancer treatment, Little answered obliquely. "I'm sure AstraZeneca are aware of this paper."

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