New study of first successful targeted therapy for breast cancer launched; Thousands of volunteers sought

UCLA physicians are seeking more than 3,000 women with early-stage breast cancer for a new study of the breakthrough drug Herceptin, the first successful targeted therapy for breast cancer. The study, headquartered at UCLA's Jonsson Cancer Center, will be the largest international clinical trial to investigate Herceptin in women with early-stage breast cancer.

Up to 600 institutions on five continents may participate in the clinical trial through the Breast Cancer International Research Group (BCIRG), a global network that spans 35 countries, 850 medical centers and involves 1,500 clinical investigators who test new therapies for breast cancer.

The most recent and comprehensive research on Herceptin, published in the March 15 issue of the New England Journal of Medicine, proved the drug's effectiveness in women with a particular kind of breast cancer that has metastasized, or spread, beyond the breast and local lymph nodes. The data show that combining Herceptin with chemotherapy as a first-line treatment offers the best chance at increasing survival for those with a fast-growing form of late-stage breast cancer.

By investigating Herceptin in women with aggressive breast cancer that has been diagnosed early - before it has spread from the breast to other parts of the body - researchers hope to demonstrate significant improvements in patient survival and cure rates, said Dr. Dennis Slamon, director of the Revlon/UCLA Women's Cancer Research Program at the Jonsson Cancer Center and leader of the UCLA team whose scientific and clinical research in the 1980s laid the foundation for Herceptin's development.

"The Herceptin-chemotherapy combinations have been shown to decrease breast cancer deaths by 27 percent in women whose metastatic breast cancer is characterized by an alteration in the HER-2/neu gene. This is significant because the life expectancy of patients who have the genetic alteration can be as low as half the life expectancy of patients who don't have it," said Slamon, who also is director of Clinical/Translational Research at the Jonsson Cancer Center and chief of the Division of Hematology/Oncology at the UCLA School of Medicine.

"By giving Herceptin and chemotherapy at an earlier stage, we hope to help patients who have the genetic alteration live longer and ultimately have the best chance of being cured. Our lab studies demonstrate that this stage of the disease is likely to be where we can have our greatest impact on cure rates. However, this has to be proven first in a clinical trial," Slamon said.

Approved by the U.S. Food and Drug Administration in September 1998, Herceptin is the first breast cancer treatment to successfully attack a specific genetic mutation that causes an aggressive form of the disease. The drug can be effective for breast cancer patients who have a mutation in a gene called HER-2/neu in their tumor cells, an abnormality that causes their cancer to grow and spread quickly. About 25 to 30 percent of women with breast cancer - or about 125,000 to 150,000 cases a year worldwide - fall into that category.

The new study will test standard chemotherapy combinations for early-stage breast cancer with and without Herceptin.

Slamon emphasized that no study participant will receive less than the best available standard therapies for early-stage breast cancer.

"This study is critical because it will compare various combinations of the four most effective therapies for breast cancer," Slamon said. "By identifying which combinations are the most efficacious in attacking the cancer and the least likely to subject patients to serious side effects, this study may indicate a completely new standard of treatment for a specific group of patients. We hope that the high efficacy seen in testing these therapeutic combinations against late-stage breast cancer will translate to better results in treating aggressive early-stage disease."

Researchers are seeking women who recently have been diagnosed with early-stage breast cancer for the new clinical trial. Through a randomized selection process, study participants will be assigned to one of three treatment groups, all of which include combinations of standard chemotherapy drugs for breast cancer. Participants will receive Herceptin in conjunction with Taxotere and Platinum; Adriamycin and Cytoxan followed by a combination of Herceptin and Taxotere; or Adriamycin and Cytoxan followed by Taxotere. The Adriamycin-Cytoxan-Taxotere regimen is believed to be among the most effective standard chemotherapy combinations to date for the treatment of early-stage breast cancer.

"The only way to determine Herceptin's safety and effectiveness in women with early-stage disease is to study the drug in a scientific and rigorous way," Slamon said. "We believe that Herceptin holds significant promise to help women who are newly diagnosed with aggressive breast cancer. But without large-scale clinical trials, we can't know for sure, and the drug could never be approved by the FDA for widespread use."

To be eligible for the study, patients' tumor cells must have an overabundance of the HER-2/neu protein, which stimulates cell growth. Women diagnosed with breast tumors that are two centimeters or larger and have no lymph node involvement or women who have smaller tumors with at least one positive lymph node involved will be considered for the study. To test for the genetic alteration that gives rise to overproduction of the HER-2/neu protein, researchers will use the newest and most accurate diagnostic testing method, called florescent in-situ hybridization (FISH). This method was initially tested and validated at the Jonsson Cancer Center and now is coming into widespread use. Using FISH will ensure that only women who actually have this specific genetic alteration will qualify for the study.

Herceptin, manufactured by Genentech Inc., does not cause the serious side effects associated with traditional chemotherapy, such as hair loss, nausea, fatigue and low blood counts. Herceptin alone is generally well-tolerated by patients, but physicians will closely monitor patients who receive Herceptin after exposure to Adriamycin. Although Adriamycin is currently considered among the best standard agents for treating early-stage breast cancer, approximately 28 percent of patients who receive Herceptin with Adriamycin may experience cardiac abnormalities. In most cases, medication can alleviate those symptoms.

Slamon anticipates that it will take 18 to 30 months to screen an estimated 15,000 women, from whom 3,150 eligible patients will be identified and enrolled in the trial.

Dr. Linnea Chap, an oncologist who specializes in breast and ovarian cancers, will be the principal investigator for the UCLA arm of the study.

For women whose breast cancers do not test positive for alterations in the HER-2/neu gene, other studies are being offered through the Jonsson Cancer Center and the BCIRG.

The BCIRG, a division of the not-for-profit Cancer International Research Group (CIRG), is the first academic global cooperative group of cancer researchers dedicated solely to developing promising new therapies for breast cancer. Dr. Jean-Marc Nabholtz, founder and chairman of the BCIRG and director of the Cancer Therapy Development Program at the Jonsson Cancer Center, was a leader in the development of Taxotere and Taxol, now widely used to treat breast cancer. He established the BCIRG in 1997 to improve speed and efficiency in testing new breast cancer treatments. Nabholtz was recruited to UCLA's Jonsson Cancer Center in July 2000 to help broaden the spectrum of clinical trials available to cancer patients at UCLA, and to help hasten the translation of scientific discoveries into viable treatments for patients.

For more information on the new Herceptin study, or to learn about studies for patients with other forms of breast cancer, please call the Jonsson Cancer Center clinical trials toll-free hotline at 888-798-0719.

For information on UCLA's Jonsson Cancer Center, its research and its resources, please visit our Web site at http://www.cancer.mednet.ucla.edu/.