|The use of a monoclonal antibody has slowed the progression of cancer and increased tumor shrinkage in women with metastatic breast cancer, according to Rush researchers who presented their finding at the annual meeting of the American Society of Clinical Oncology in Los Angeles on May 17.
The monoclonal antibody, Herceptin, targets the HER2 gene, a growth factor receptor protein that is produced in excess, "overexpressed," in many women with metastatic breast cancer, according to Dr. Melody A. Cobleigh, an investigator of the study, which was conducted at Rush and a number of academic medical centers across the country over the past three years. Herceptin is produced by Genentech, Inc., in South San Francisco, CA.
"The results of these studies are impressive and encouraging since we will now have another treatment option, a new, nontoxic biologic approach, for women with this aggressive form of breast cancer," said Cobleigh.
If Herceptin is approved by the Food and Drug Administration, it will be the first treatment that specifically targets this aggressive form of breast cancer that is associated with more rapid cancer progression and shortened survival. It is the first therapy that was developed to target a specific protein defect that contributes to the malignant progression of cancer. HER2 overexpression occurs in 25 to 30 percent of patients with breast cancer.
The Herceptin monoclonal antibody works by binding to the HER2 growth factor receptors present in excessive amounts on the surface of the cancer cells, slowing the growth of HER2 human breast cancer cells.
Two companion Phase III studies were done. In one, patients were treated with Herceptin alone. In the other, they were treated with Herceptin in combination with chemotherapy.
Herceptin Alone Trial
This part of the study (Rush was the only midwest participant) evaluated the overall response rate and safety when using Herceptin as a single agent without chemotherapy. The study included 222 women with metastatic breast cancer and excessive HER2 who had a recurrence of the disease following treatment. The cancer in these women failed to respond to two kinds of prior chemotherapy, and more than a quarter had received bone marrow transplants.
Overall, 16 percent of the patients experienced slowed progression of the disease and tumor shrinkage. Eight patients experienced a complete remission of the disease (4 percent), and 26 (12 percent) experienced a partial remission. The median duration of response, measured from the time the cancer responds to treatment to the time when the cancer begins to enlarge or spread again, was nine months.
"A 16 percent response rate and nine-month duration of response is particularly impressive given the seriousness and aggressive nature of metastatic breast cancer. Patients will have another option that is active as a single agent. Because toxicity is low, the women's quality of life while on therapy can be maintained," said Cobleigh.
Herceptin Plus Chemotherapy Trial
For this part of the study, patients were treated with Herceptin in combination with chemotherapy - either paclitaxel or doxorubicin plus cyclophosphamide (DC). This trial included 469 women who had tumors that overexpressed HER2 who had not been previously treated with chemotherapy for their metastatic disease.
In more than 25 percent of women treated with Herceptin plus chemotherapy, progression of the cancer had stopped at one year compared to 10 percent of the women treated with chemotherapy alone. The median time to disease progression was increased by 65 percent (from 4.6 to 7.6 months). Overall, Herceptin significantly increased the likelihood that the cancer would not advance in the women.
Adding Herceptin to chemotherapy also increased the number of women who had a partial response or tumor shrinkage (of 50 percent or greater) from 32 percent to 48 percent, a 50 percent increase. Patients who received Herceptin in combination with both drug treatments benefited, but the results were greater for those taking paclitaxel. In the Herceptin plus DC, 52 percent of women had a positive response, compared to 43 percent in patients receiving DC alone. In the Herceptin plus paclitaxel group, 42 percent of women had a positive response, compared to 16 percent in patients receiving paclitaxel alone. The medium duration of response was over nine months in the Herceptin group compared to less than six months in the chemotherapy group alone.
Adverse Reactions, Side Effects
Herceptin was generally well tolerated among patients in both trials. Overall, the most common adverse reactions related to Herceptin were chills and fever in 40 percent of patients, primarily with the first infusion. Side effects that occur often in women receiving chemotherapy, including hair loss, mouth sores, and low blood cell count levels, were not seen commonly among women taking Herceptin alone.
An increased risk of heart dysfunction occurred in women receiving Herceptin and the two drug combination compared to women receiving two drugs alone. In most cases, this side effect can be managed with medication. Most of these patients (87 percent) improved with initial treatment for their heart dysfunction and many continued with their weekly infusion of Herceptin without further cardiac events.
The HER2 growth factor receptor was identified in 1985, and researchers began to understand the role that excess production of HER2 plays in the progression of breast cancer. About a quarter of women with breast cancer have tumors that overexpress HER2. Women with breast cancer have not been routinely screened for HER2 overexpression because there had not previously been a treatment that targets this condition directly.
Dr. Melody A. Cobleigh is associate professor of medicine and director of the Comprehensive Breast Center of the Rush Cancer Institute at Rush-Presbyterian-St. Luke's Medical Center, Chicago.