Inherited BRCA1 or BRCA2 Gene-Mutated Tumors Often Carry EGFR Mutations Including in Their Stromal Cells: Implications for Therapy with Tyrosine Kinase Inhibitors

Abstract

A new class of anti-cancer drugs that has rarely helped breast-cancer patients may perform poorly because of the mutations in a gene the drugs are designed to target, according to new research here.

The drugs are tyrosine kinase inhibitors (TKIs), which include gefitinib (Iressa) and imatinib (Gleevec), and they target the gene known as EGFR, or epidermal growth factor receptor.

The study, led by Ohio State University cancer researchers, suggests that EGFR mutations occur more often in hereditary breast tumors than they do in nonhereditary tumors, and that the mutations occur in both tumor cells and in neighboring normal cells, which are also known as stromal cells.

Furthermore, it found that the mutations occur more frequently in the stromal cells than in the cancer cells. The findings were published in the April 19 Advance Online edition of the British Journal of Cancer.

"It's been known for some time that breast cancers don't respond well to TKIs," says principal investigator Dr. Charis Eng, director of the clinical cancer genetics program at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

"These findings may help explain why."

For this study, the researchers sequenced a portion of the EGFR gene in cancer cells and non-cancer stromal cells from 48 samples of noninherited (i.e., sporadic) breast cancer and from 24 samples of inherited breast cancer. The inherited cancers had mutations in either the BRCA1 or the BRCA2 gene. Mutations in these genes are a significant cause of hereditary breast cancer.

The investigators used a technique known as laser-capture microdissection to separate cancer cells from surrounding stromal cells in the breast-cancer samples. The technology allows the precise removal of small numbers of selected cells from surrounding cells.

The investigators found EGFR mutations in 46 percent of the inherited tumors and in 15 percent of the sporadic tumors (11 of 24 vs. seven out of 48), a statistically significant difference.

Furthermore, eight of the 11 inherited tumors (73 percent) had the EGFR mutations only in stromal cells, and four of the seven noninherited breast cancers (57 percent) had the mutations only in the stromal cells.

"We were surprised to find a high frequency of acquired mutations in the stromal cells," says Eng, who is also professor of internal medicine; of molecular virology, immunology and medical genetics; of pharmacology; and of molecular genetics.

"From this evidence, we conclude that EGFR mutations do occur in breast-cancer stromal cells, and that they occur much more often in inherited breast cancer than they do in sporadic breast cancer. We predict that tumors with these mutations will be highly resistant to TKI drugs that act on the EFGR gene."

Other OSU researchers involved in this study were Frank Weber, Koich Fukino, Takeshi Sawada, Nita Williams, Kevin Sweet, Romulo M. Brena, Christoph Plass and Miguel A. Villalona.

Funding from the U.S. Department of Defense Breast Cancer Research Program and from the National Cancer Institute supported this research. Eng is holder of the Klotz Chair in Cancer Research and a recipient of the Doris Duke Distinguished Clinical Scientist Award.

Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of the nation's leading centers for research on the prevention, detection, diagnosis and treatment of cancer. The OSU CCC-James encompasses six interdisciplinary research programs and includes more than 200 investigators who generate over $95 million annually in external funding. It is a founding member of the National Comprehensive Cancer Network, and OSU's James Cancer Hospital is consistently ranked by U.S. News & World Report as one of America's best cancer hospitals.