Powerful new cancer-fighting property of Herceptin

For many patients with advanced breast cancer, the cancer drug Herceptin (trastuzumab) has offered new hope when traditional cancer drugs failed to work, shrinking tumors and sending some patients into remission.

Now Dihua Yu, M.D., Ph.D., and her colleagues at The University of Texas M. D. Anderson Cancer Center have uncovered a powerful new cancer-fighting property of Herceptin, an antibody-based drug that targets a protein on breast cancer cells called HER-2 (also called ErbB2). The discovery explains why some HER-2 positive patients don’t respond as well to the drug and also offers a potential solution that could allow more HER-2 positive patients to benefit from the treatment.

The study, which appears in the August 2004 issue of the journal Cancer Cell, demonstrates that the presence of a protein called PTEN in HER-2 positive patients’ tumor cells is a powerful predictor of who will respond to Herceptin. In normal cells, the PTEN protein helps control cell division, but in about half of breast tumors PTEN levels are very low or the protein is completely missing. Those PTEN-missing tumors did not respond to Herceptin treatment.

“Our goal is to allow doctors to quickly and accurately tailor cancer treatment to each individual patient,” says Yu, professor of surgical oncology, and the study’s principal investigator. “Tailored treatment means giving each patient the medication most likely to benefit her, while simultaneously minimizing side effects.”

In a recent clinical trial at M. D. Anderson, 65 percent of HER-2 positive patients taking Herceptin in addition to chemotherapy had a complete response rate, compared to 26 percent taking chemotherapy alone. But doctors have had no way to predict who among HER-2-positive patients, which account for about one-third of all breast cancer patients, is most likely to benefit.

“Previously, it was known that Herceptin binds to the HER-2 protein and causes it to degrade,” says Yu. “But this process takes days. What we found is that very quickly, within ten minutes of administration, Herceptin activates PTEN, a powerful tumor suppressor gene. We are adding a very new understanding of how Herceptin works.”

The scientists studied the tumors of 47 metastatic HER-2 positive breast cancer patients who had received Herceptin and chemotherapy as well as 37 patients who received chemotherapy alone. PTEN levels varied widely among both groups, but only 11 percent of patients who had a very low level of PTEN responded to Herceptin, versus 66 percent of those with high levels of PTEN. There was no correlation between PTEN level and response to traditional chemotherapy agents called taxanes.

“Our results show PTEN is a very powerful predictor of who will respond to Herceptin,” says Yu.

Breast cancer patients whose tumors make too much of the HER-2 protein are at much greater risk of metastasis because the HER-2 protein stimulates cells to grow and spread aggressively.

When Herceptin attaches to the HER-2 protein, it interrupts those growth signals, which are sent through a series of signaling proteins inside the cell. PTEN acts as a natural brake on tumor growth by, among other things, blocking the effect of a growth promoting protein called PI3K.

Yu and her colleagues discovered that if they administered a drug that turns off PI3K in breast cancer cells in the laboratory, they became much more sensitive to the effects of Herceptin. The PI3K inhibitor mimicked the action of PTEN and restored the ability of Herceptin to slow or stop the growth of cancer cells.

Yu pointed out that there are several experimental PI3K inhibitors currently in clinical trials for treatment of breast cancer that, if they prove to be safe, could potentially be combined with Herceptin to boost its effectiveness in PTEN-missing breast cancers.

“In the past we looked for patients’ HER-2 expression, and if HER-2 was high we gave them Herceptin,” says Yu. “In the future, when patients come to M. D. Anderson we will look for patients with high levels of HER-2 and PTEN expression and these are the patients that we expect will benefit most from Herceptin. For those with low PTEN, we hope to be able to offer combination therapy with a PI3K inhibitor that might work synergistically to boost the effectiveness of Herceptin.”

Yu says she and her colleagues in the Breast Medical Oncology Department are planning a clinical trial to be conducted at M. D. Anderson in which they would test each patient for HER-2 and PTEN proteins and offer targeted treatment based on the level of each protein.

“There has been a need to develop new markers that can improve the efficacy of Herceptin,” says Francisco Esteva, M.D., Ph.D., an associate professor in the Department of Breast Medical Oncology. “This is one of the first studies that allows us to understand the mechanism of Herceptin resistance and offers a potential way to counteract it.”

“In the past, selecting a particular chemotherapy drug has been a lottery,” says Yu. “Patients had no way of knowing if they would benefit. The new generation of cancer drugs is providing targeted treatment with fewer side effects and giving patients a better chance that a particular treatment will work for them.”

The study was funded by grants from the National Institutes of Health and M. D. Anderson Cancer Center. Yu’s co-authors include Yoichi Nagata, M.D., Ph.D.; Keng-Hsueh Lan, M.D.; Xiaoyan Zhou; Ming Tan, M.D., Ph.D.; Esteva; Aysegul A. Sahin, M.D.; Kristine S. Klos, Ph.D.; Ping Li; Nina T. Nguyen; Gabriel N. Hortobagyi, M.D. and Mien-Chie Hung, Ph.D. of M. D. Anderson; and Brett P. Monia of ISIS Pharmaceuticals.