Activated signaling pathway may predict lung cancer patients' response to gefitinib


There are multiple signaling pathways in a cell that control its behavior, such as the ability to survive and divide rapidly. A new study in the August 4 issue of the Journal of the National Cancer Institute has found that, among patients with non–small-cell lung cancer (NSCLC) whose tumor cells contain a specific activated signaling pathway, the cancer drug gefitinib (Iressa) was associated with a better response rate, disease control rate, and time to progression compared with patients in whom the pathway was not activated.

NSCLC is the most common type of lung cancer. Less than 15% of patients with NSCLC are cured despite aggressive surgical and chemotherapeutic intervention. Gefitinib, a cancer drug that interferes with the epidermal growth factor receptor (EGFR) pathway, is active in approximately 10% of NSCLC patients in whom standard therapy has failed. Although earlier studies have found that the expression of EGFR alone does not predict whether a patient will respond to gefitinib, there are many signaling pathways that are dependent on EGFR expression.

To determine whether two such pathways--called Akt and MAPK--may be involved in a patient's response to gefitinib, Federico Cappuzzo, M.D., of Bellaria Hospital in Bologna, Italy, and colleagues, looked at the association between phosphorylation status (a measure of activation) of Akt and MAPK in tumors from 103 patients with NSCLC before they received treatment and any subsequent response to gefitinib.

The authors found that 51 patients had tumors that were positive for Akt phosphorylation (P-Akt). P-Akt positivity was associated with being female and having a history of never smoking. Patients with P-Akt–positive tumors had a better response rate, disease control rate (which includes complete and partial responses and stable disease), and time to progression than patients with P-Akt negative tumors. There was no difference in outcome according to MAPK phosyphorylation (P-MAPK) status. P-Akt positivity, but not P-MAPK positivity, was associated with a reduced risk of disease progression.

"[O]ur findings suggest that gefitinib therapy is more active in patients with tumors that are positive for P-Akt than in those with tumors that are negative for P-Akt. Further prospective studies are needed to evaluate the role of other associated markers … and to assess the impact of previous therapies on Akt signaling pathway," the authors write.

In an editorial, Mark G. Kris, M.D., of Memorial Sloan-Kettering Cancer Center in New York, and colleagues consider recent data on the strong association between EGFR mutations and gefitinib sensitivity in patients with NSCLC and also whether phosphorylated Akt has a role in predicting gefitinib sensitivity. Although this new report is interesting, they write, "the findings do not supercede better predictors of response to gefitinib. When patients with NSCLC enter the clinic today, treatment decisions must be guided by both clinical characteristics and EGFR mutation status."

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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