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UC Davis Cancer Center, DxS Closer to Developing Test for Anti-EGFR Response

DxS’ EGFR mutation kit can accurately detect disease recurrence or clinical response in patients with advanced lung cancer treated with small molecule tyrosine kinase inhibitors, a study conducted by the University of California, Davis, Cancer Center has shown.
The study analyzed 57 specimens from NSCLC patients slated for treatment with erlotinib (Genentech/OSI’s Tarceva). “Of these, 14 patients had detectable EGFR mutations. The DxS kit was able to detect mutations not observable by direct sequencing in plasma and tissue,” Manchester, UK-based DxS said in a statement this week.
UC Davis presented the data at the American Society for Clinical Oncology’s annual meeting this year. “The results showed that there was a statistically significant relationship between clinical response and the occurrence of mutations, as measured in plasma. The UC Davis team concluded that the DxS EGFR kit may be suitable for monitoring response or detecting recurrence in advance NSCLC patients,” DxS said in a statement.
In the study, the DxS EGFR Mutation Kit detected EGFR mutations in circulating tumor DNA found in blood.
“It has been known for over a decade that tumors shed DNA into the blood stream,” the company said in a statement, referring to so-called circulating nucleic acids, or CNAs. “What the UC Davis study has now shown is that CNAs can be used to identify EGFR mutations predictive of response to EGFR inhibitors such as erlotinib.”
DxS’s EGFR mutation kit combines the company’s two proprietary technologies: the Amplification Refractory Mutation System for the detection of SNPs and other genetic variations, and its real-time PCR technology Scorpions. The test, currently offered for research use only, detects 29 of the most common somatic EGFR mutations.
The test has been registered and CE-marked in Europe. “We plan to submit an application for FDA clearance in due course,” Andrew Webb, DxS sales and marketing director, told Pharmacogenomics Reporter this week.
Webb noted that the test’s advantage lies in its ability to detect EGFR mutations in blood samples rather than in tumor samples, which requires a biopsy.
According to a study published in Clinical Cancer Research in 2006 (Kimura et al.), EGFR mutations “observed in serum DNA [can] serve as a noninvasive source of information on the genotype of the original tumor cells that could influence treatment and the ability to predict patient response to gefitinib [AstraZeneca’s tyrosine kinase inhibitor Iressa].”

In the study, researchers used DxS’ Scorpion amplified refractory mutation system to analyze serum DNA from 11 lung cancer patients and found that in pairs of tumor and serum samples the EGFR mutation status in the tumors matched the status of those patients analyzed based on serum 72.7 percent of the time.
“In this application the levels of soluble DNA are extremely low and we are not currently aware of any other tests whose performance matches that of the DxS EGFR mutation test kit,” Webb said.

“The results showed that there was a statistically significant relationship between clinical response and the occurrence of mutations, as measured in plasma. The UC Davis team concluded that the DxS EGFR kit may be suitable for monitoring response or detecting recurrence in advanced NSCLC patients.”

According to Webb, the test can accurately detect mutations down to five copies of genomic DNA. “The DxS tests will confirm the presence of the mutation where less than 1 percent of the sample carries the mutant sequence,” Webb said. “This clearly outperforms DNA sequencing, whose limits are probably 25 percent to 50 percent at best in experienced hands.”
The DxS EGFR Mutation Test Kit also identifies patients who will clinically benefit from tyrosine kinase inhibitors by identifying sensitizing mutations. In scientific literature, these so-called sensitizing mutations are related to increased efficacy of small molecule tyrosine kinase inhibitors in NSCLC. The kit includes a test for EGFR T790M polymorphism, which is linked to approximately half of the tyrosine kinase-resistant tumors.  
According to Webb, since the frequency of EGFR mutations is approximately three-fold higher in Asian populations, current areas of marketing focus include Japan, China, South Korea, and Taiwan, in addition to territories in North America and Europe.
Last month, DxS launched its K-RAS Mutation Detection Kit, which uses the same enabling technologies as the EGFR mutation test kit to identify patients most likely to benefit from tyrosine kinase inhibitors based on their K-RAS mutation status.

The real-time PCR-based kit detects seven key mutations in the K-RAS gene. The assays can detect less than 1 percent of mutations in wild type genomic DNA and have a limit of detection of 10 copies or below.

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