Previous studies indicate that activation of the epidermal growth factor receptor (EGFR) can stimulate the growth of cancer cells. Mutations within the tyrosine kinase (TK) portion of this receptor may give cancer cells a growth advantage but at the same time make them more susceptible to drugs, like gefitinib, which inhibit growth. Gefitinib does not appear to be effective in women whose cancer does not have a mutation in the TK portion of EGFR.
"Researchers continue to study how best to incorporate EGFR-inhibiting drugs into therapy for ovarian cancer, but that requires a cost-effective way to screen patients to identify various mutations," said lead researcher Russell Schilder, M.D., a medical oncologist at Fox Chase. "In regard to ovarian cancer, there are 25,000 cases diagnosed annually. Someday, we'll be able to sequence key genes in ovarian tumors to identify the women who would be responsive to gefitinib or other targeted therapies."
The Fox Chase translational research team headed by Schilder and Andrew K. Godwin, Ph.D., director of Fox Chase's Clinical Molecular Genetics Laboratory, where the mutation studies were performed, was spurred by recent studies that indicated the same mutations appear to identify lung cancer patients who respond well to gefitinib therapy. Gefitinib has been used as a single agent to treat patients with recurrent non-small-cell lung cancer (NSCLC). Schilder and Godwin have replicated this finding retrospectively in ovarian cancer samples. "This was the first report that has documented mutations in the EGFR in ovarian cancer," Schilder said.
For the study, the researchers examined archived tumor tissue from a phase II trial designed to assess the activity and tolerability of gefitinib in patients with recurrent or persistent ovarian carcinoma or primary peritoneal cancer. They found that a mutation in the EGFR occurred in the tumor of the one patient whose tumor shrunk during treatment with gefitinib. No mutations of the EGFR were detected in the tumors of the patients who did not respond.
"We went back to these samples and analyzed them to see if we could detect mutations in the tyrosine kinase portion of the receptor," reported Schilder.
The researchers performed a blinded study and found that the one patient who experienced the only objective response to gefitinib during the 23-month trial had a mutation in the tyrosine kinase portion of the EGFR. Conversely, no mutations were observed in 23 of the cases that had no measurable response to gefitinib.
Given the apparent clustering of EGFR mutations found in previous studies of NSCLC, the researchers sequenced genes in an additional 32 ovarian tumor samples not treated with gefitinib. The majority of the tumors were late-stage serous adenocarcinomas. One additional sample was found to have a mutation (3.1%; 1 of 32).
Overall, the researchers detected mutations in the TK domain region in 2 of 56 (3.6%) of ovarian adenocarcinomas and observed that a patient on the clinical trial with a mutation in the catalytic domain of EGFR responded to gefitinib, suggesting a method to pre-select a subset of patients whose tumors may be more responsive to this EGF receptor-targeted therapy.
"This finding could have a dramatic impact on clinical care," indicated Schilder. "While this mutation is a relatively rare event, it could have a profound effect for some ovarian cancer patients," he says.
Along with Schilder and Godwin, scientists contributing to this research include postdoctoral associate Xiaowei Chen, Ph.D., scientific technician Brock A. Armstrong and surgical fellow Cletus A. Arciero, M.D., of Fox Chase Cancer Center and Michael W. Sill, Ph.D., and Kathleen M. Darcy, Ph.D., of the Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, N.Y.
Fox Chase Cancer Center was founded in 1904 in Philadelphia as the nation's first cancer hospital. In 1974, Fox Chase became one of the first institutions designated as a National Cancer Institute Comprehensive Cancer Center. Fox Chase conducts basic, clinical, population and translational research; programs of prevention, detection and treatment of cancer; and community outreach. For more information about Fox Chase activities, visit the Center's web site at www.fccc.edu or call 1-888-FOX CHASE.