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Getting Herceptin to Work for More Patients

Researchers in Texas may have come up with a way to make the powerhouse drug Herceptin work for more breast cancer patients, which could prevent more recurrences and help patients live longer.

Herceptin (trastuzumab) is a biologic therapy that selectively attacks breast cancer cells while leaving healthy cells alone. The drug, which has been used by more than 220,000 patients with breast cancer, targets tumor cells that make too much HER-2, a protein associated with aggressive disease. About 25 percent to 30 percent of breast cancers are characterized as HER-2 positive, and could potentially benefit from Herceptin.

However, an estimated 50 percent of women with HER-2 disease don't respond to Herceptin alone. Their disease is said to be Herceptin resistant.

Reporting at the annual meeting of the American Association for Cancer Research in April, Dihua Yu, M.D., a breast cancer researcher at the University of Texas M.D. Anderson Cancer Center in Houston, announced that she and her colleagues had identified a way to help patients with resistant disease by combining Herceptin with drugs that interfere with the function of a protein identified as PI3 kinase (PI3K) that stimulates the growth of cancer cells.

Although the findings came from test-tube and mouse studies, they were so promising that in May one of Yu's M.D. Anderson colleagues, breast cancer specialist Francisco Esteva, M.D., launched a phase I and II clinical trial for women whose disease hasn't responded to Herceptin.

Yu's findings, which have been submitted for publication, build on previous research in which she found that tumors of Herceptin-resistant patients have low levels of a tumor-suppressing protein called PTEN. Conversely, tumors of patients in whom Herceptin works have higher levels of this protein.

PTEN interferes with the function of the PI3K protein. But because PTEN is a huge protein that is difficult to work with, Yu looked around for smaller molecules that mimic PTEN's activity. She experimented with seven PI3K pathway inhibitors, and got the strongest results when she combined Herceptin with everolimus, also called RAD0001, and when she combined it with triciribine, or TCN-P.

Women in Esteva's trial will get Herceptin and RAD0001.

Yu suspects that other PI3K inhibitors still in development might prove to be even more effective in making Herceptin work for more women. "I'm encouraged," she said. "I want to see an even better effect."