Molecular marker predicts which patients benefit longest from EGFR inhibitors

A molecular marker, Mig 6, appears to accurately predict longer survival of up to two years among patients prescribed two of the most widely used drugs in the class of anticancer agents known as EGFR inhibitors.

The drugs gefitinib and erlotinib are prescribed for patients with lung and pancreatic cancer, but a prolonged reduction of tumor size only occurs in the few who have mutations in the EGFR gene. The two drugs block the gene's ramped-up protein production, but patients' response to the drug varies widely– from no survival benefit to several years. The average is several months.

"Clinicians have had no reliable method for distinguishing patients who are not likely to respond to EGFR inhibitors and those who will respond very well," said David Sidransky, MD, of Johns Hopkins Medicine in Baltimore, Maryland. He added that while responses to EGFR-blocking drugs were not well predicted by examining the level of protein production from the EGFR gene alone, responses might be predicted by the presence or absence of Mig 6.

The preliminary study was described in the online journal PLoS ONE (2013; doi: 10.1371/journal.pone.0068966). The genetic marker was found with a series of experiments that began with laboratory cancer cell lines resistant to EGFR-inhibitor drugs. These cell lines had very high levels of protein production from the Mig 6 gene--up to three times the level in sensitive cell lines. Mig 6 is one of the molecules that controls the activity of the EGFR protein.

"In the first set of experiments, we found that higher levels of Mig 6 occur often in cells that don't respond to EGFR inhibitors," said Sidransky. "Most tumors are known to have high Mig 6 levels and are not expected to respond to EGFR inhibitors."

Next, the research team studied Mig 6 levels in a variety of tumors that were directly engrafted into mice, a research model known as a xenograft, and treated with an EGFR inhibitor. These new models contain a more complete sampling of the tumor that includes stromal cells, which surround and interact with the cancer cells.

In the xenografts of tumors without EGFR mutations, as Mig 6 levels increased, so did the resistance to EGFR inhibitors, suggesting a correlation between high Mig 6 and lack of response to the drugs. To confirm the correlation, the scientists tested tissue samples of 65 patients with lung cancer who were treated with EGFR inhibitors to compare their Mig 6 levels with outcomes.

Of 18 patients with low Mig 6 levels, five of them survived more than a year without progression of their cancer; four survived more than two years progression-free. Among 16 patients with higher Mig 6 levels, two survived more than one year and none survived progression-free beyond two years.

"The beauty of this finding is that it's simple. We're looking for tumors with low levels of Mig 6 to predict clinical benefit, and there aren't many of them," said Sidransky.

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