Drug combo effective for advanced breast cancer

A pair of studies at UCLA's Jonsson Cancer Center that takes laboratory science to the patients' bedside found that combining the molecularly targeted therapy Herceptin with a specific chemotherapy combination resulted in significant tumor response rates and longer relapse-free periods in women with an aggressive form of advanced breast cancer.

The results of the studies, the first done on cell lines in the laboratory and the second translated into more than 120 patients in two Phase II clinical trials, appear May 18 in the peer‑reviewed Journal of the National Cancer Institute.

In an accompanying editorial, Dr. George W. Sledge Jr., co-director of the Breast Cancer Program at the Indiana University School of Medicine, called the studies "an impressive example of translational research at its best."

"Designing a sequential series of experiments, both laboratory and clinical, that lead intentionally to proof-of-concept adjuvant (Phase III) trials is all too rare," Sledge states in the editorial. "But, as (UCLA researchers) remind us, it is not impossible."

Jonsson Cancer Center researchers first tested drug combinations in the laboratory with the goal of translating their results into patients with HER2/neu amplification, a genetic alternation found in 20 percent to 25 percent of patients that leads to an aggressive form of breast cancer.

Lead by researchers Dr. Dennis Slamon and Dr. Mark Pegram, the laboratory studies analyzed Herceptin for interaction with nine chemotherapy drugs commonly used to treat breast cancer. Researchers found that the chemotherapy agents Taxotere, Navelbine, Cyclophosphamide and the platinum salts Cisplatin and Carboplatin increased the activity of Herceptin in lab models with HER2/neu amplification. In other words, Herceptin and the chemotherapy agents each made the other more effective, a synergistic effect. The laboratory studies pointed researchers to the optimum chemotherapy combination, which they then tested in the clinic.

In two Phase II clinical trials, Taxotere was given with Herceptin in combination with either Cisplatin or Carboplatin to women who tested positive for the HER2/neu alteration. Each study enrolled 62 women. Responses — shrinkage in tumor size — were observed in 79 percent of patients in one of the studies and in 58 percent of patients in the other. Additionally, the period before the cancer continued to grow again, called time to progression, was unusually long in the study subjects with this aggressive form of breast cancer.

"The median times to progression emerging from the trials are among the longest times reported to date for a patient population with HER2-amplified metastatic breast cancer," said Pegram, director of the Women's Cancer Program Area at UCLA's Jonsson Cancer Center and the lead author of the studies.

"Response rates were extraordinary," Pegram said, "superior to what was expected."

The HER2/neu alteration is associated with aggressive disease that grows quickly, resulting in a poor prognosis. Patients with this alteration relapse more quickly and die more often than those who do not have it. Based on 12 years of laboratory and clinical research by Slamon and other UCLA researchers, Herceptin targets the HER2/neu alteration and blocks its effect. It was among the first targeted therapies for cancer when it was approved by the U.S. Food and Drug Administration in 1998. Since then, other successful targeted therapies have been approved, including Gleevec for leukemia and Avastin for advanced colorectal cancer, both also tested in Jonsson Cancer Center clinical trials.

Targeted therapies attack what is broken in a cell that makes it cancerous, resulting in fewer side effects than traditional therapies. Herceptin blocks a receptor on the surface of the cell that receives excess growth signals, interrupting the out-of-control growth that characterizes cancer.

Slamon, director of Clinical/Translational Research at UCLA's Jonsson Cancer Center, said the two studies are important because, as Sledge said, they provide an example of how translational research is supposed to work.

"This shows you can actually predict what will work in patients," Slamon said. "That's why these articles appear together. The first shows what we did in the lab and the second proves that it is effective in patients with this alteration."

The treatment combination currently is being tested in large, randomized Phase III studies to further confirm the UCLA results and provide proof of principle. If the studies are successful, it will change the way breast cancer patients with this genetic alteration are treated, Pegram said.

UCLA's Jonsson Comprehensive Cancer Center is composed of more than 240 cancer researchers and clinicians engaged in cancer research, prevention, detection, control and education. The center, one of the nation's largest comprehensive cancer centers, is dedicated to promoting cancer research and applying the results to clinical situations. In 2003 the Jonsson Cancer Center was named the best cancer center in the Western United States by U.S. News & World Report, a ranking it has held for four consecutive years.

For more information on the Jonsson Cancer Center, visit www.cancer.mednet.ucla.edu.