TAMPA, Fla. –In what may be a significant advance for the treatment of breast cancer, researchers at H. Lee Moffitt Cancer Center & Research Institute and Montefiore Medical Center in New York, have discovered they can more effectively wipe out tumor cells from the breast when a drug targeting a molecular switch in cancer cells is combined with standard chemotherapy.
In a multicenter clinical trial reported in current issue of the Journal of Clinical Oncology, women with locally advanced breast cancer were given an oral medication that targets cancer causing pathways in the cancer cell, in addition to routine intravenous chemotherapy, before undergoing surgery. Analysis of the breast tissue taken at surgery showed no signs of cancer in a third of the women, compared with five to 10 percent expected for chemotherapy alone.
The study included 21 women with locally advanced breast cancer who were considered suboptimal candidates for surgery because of the advanced stage of their disease. They received standard chemotherapy, doxorubicin and cyclophosphamide given intravenously once every two weeks for four treatments. After each chemotherapy treatment, they also received 200 mg of the farnesyltransferase inhibitor tipifarnib taken orally twice a day for six days. All patients then underwent a mastectomy or a lumpectomy. Pathological analyses of breast tissue retrieved from the surgeries showed no cancerous tissue in seven patients, or 33 percent of the women who received the treatment, compared with the five to 10 percent rate expected with chemotherapy alone.
The researchers also demonstrated that tipifarnib, a drug that works by inhibiting
an enzyme called farnesyltransferase, inhibited the enzyme in tumor tissue by an average of 90 percent. Farnesyltransferase is essential for activating proteins such as Ras that contribute to oncogenesis.
“This important study suggests that breast tumors from one third of the patients treated depend on farnesylated proteins for cell division and/or survival" says Said Sebti, Ph.D., Director of Moffitt’s Drug Discovery Program and senior author of the study.
"The findings are extremely encouraging," says Dr. Joseph Sparano, lead author of the study and director of the Breast Evaluation Center at the Montefiore-Einstein Cancer Center in New York. "Eradication of cancer cells in breast tissue is a short term endpoint that translates into a greater chance of being cured in the long term. This strategy of giving treatment preoperatively and determining how often cancer cells are completely eradicated allows us to identify potentially promising treatments with a small number of patients, and then move ahead and study more patients if the treatment looks promising. This combination definitely looks promising, and we are moving ahead with larger confirmatory trials.”
“We next plan on using gene expression profiling and proteomic technologies to identify farnesylated proteins and the pathways they regulate that predict clinical responses," says Sebti.
"We believe that by switching the farnesylation dependent pathways to the off position, that we made the chemotherapy much more effective" says Dr. Sparano. "Our next step will be to combine tipifarnib with other types of standard chemotherapy in order to push the response rate even higher, and perform randomized trials that provide more definitive proof of the benefits of this treatment."
The trial was performed at Moffitt Cancer Center and the New York Cancer Consortium, a multicenter clinical trials group that is funded by the National Cancer Institute to evaluate the newest and most promising cancer treatments. The work was also partially funded by an NCI R01 grant to the Moffitt Cancer Center (PI: Sebti).
In 2001, H. Lee Moffitt Cancer Center & Research Institute earned NCI Comprehensive Cancer Center status in recognition of its excellence in research and contributions to clinical trials, prevention and cancer control. Additionally, Moffitt is a member of the National Comprehensive Cancer Network, a prestigious alliance of the country’s leading cancer centers, and is listed in U.S. News & World Report as one of America’s Best Hospitals for cancer. Moffitt’s sole mission is to contribute to the prevention and cure of cancer.