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Molecular Marker Predicts Patients Most Likely to Benefit Longest From EGFR Inhibitors

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Key Points

  • Researchers found very high levels of protein production from the Mig6 gene in laboratory-derived lung and head and neck cancer cell lines that were resistant to EGFR inhibitors.
  • In the xenografts of tumors without EGFR mutations, as Mig6 levels increased, so did the resistance to EGFR inhibitors. Investigators confirmed the correlation in tissue samples from lung cancer patients treated with EGFR inhibitors.
  • Of 18 patients with low Mig6 levels, 5 of them survived more than 1 year without disease progression and 4 survived more than 2 years progression-free. Among 16 patients with higher Mig6 levels, 2 survived more than 1 year and none experienced progression-free survival beyond 2 years.

Scientists at Johns Hopkins have identified a molecular marker called Mig6 that appears to accurately predict longer survival—up to 2 years—among patients being treated with the EGFR inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Results from the preliminary study were published in PLoS ONE.

Gefitinib and erlotinib are prescribed for patients with lung and pancreatic cancer, but only those who have mutations in the EGFR gene usually benefit with a prolonged reduction of tumor size. 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 survival 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, Professor of Otolaryngology, Oncology, Pathology, Urology, and Genetics at Johns Hopkins. Looking at the precise level of protein production from the EGFR gene alone in specific patients was not proven to be a good indicator of patients’ response to EGFR-blocking drugs, but the presence or absence of Mig6 might be, he added.

Study Details

In a preliminary study, researchers found the genetic marker in a series of experiments that began with laboratory-derived lung and head and neck cancer cell lines resistant to EGFR-inhibitor drugs. In the cell lines, the team found very high levels of protein production from the Mig6 gene—up to three times the level in sensitive cell lines. Mig6 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 Mig6 occur often in cells that don’t respond to EGFR inhibitors,” said Dr. Sidransky. “Most tumors are known to have high Mig6 levels and are not expected to respond to EGFR inhibitors.”

Next, the research team studied Mig6 levels in a variety of tumors that were directly xenografted into mice and treated with an EGFR inhibitor. These new models contain a more complete sampling of the tumor that includes stromal cells, “These tumors are implanted along with their own microenvironment, into the mice, and we believe this model may be more predictive of what happens in human patients,” said Dr. Sidransky.

Correlation Between Mig6 and Response to EGFR Inhibitors

In the xenografts of tumors without EGFR mutations, as Mig6 levels increased, so did the resistance to EGFR inhibitors, suggesting a correlation between high Mig6 and lack of response to the drugs. To confirm the correlation, the scientists tested tissue samples of 65 lung cancer patients treated with EGFR inhibitors to compare their Mig6 levels with outcomes.

Of 18 patients with low Mig6 levels, 5 of them survived more than a year without progression of their cancer and 4 survived more than 2 years progression-free. Among 16 patients with higher Mig6 levels, 2 survived more than 1 year and none experienced progression-free survival beyond 2 years.

“The beauty of this finding is that it’s simple. We’re looking for tumors with low levels of Mig6 to predict clinical benefit, and there aren’t many of them,” said Dr. Sidransky.

Dr. Sidransky’s team expects to license the Mig6 marker to a biotechnology or pharmaceutical company and conduct further tests in larger groups of patients.

The research was funded by the National Institutes of Health (National Cancer Institute, P50 DE019032, U01 CA084986, and R37DE012588) and FAMRI (The Flight Attendant Medical Research Institute).

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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