PHILADELPHIA—The anti-HER-2/neu monoclonal antibody is now in the final stages of phase III testing, in combination with an anthracycline, in patients with advanced breast cancer tumors that overexpress the gene product, Dennis Slamon, MD, of the UCLA School of Medicine, said at a breast cancer symposium at Fox Chase Cancer Center.
The researchers are seeing complete responses in some patients, he said, adding that he hopes to have complete data available by the next American Society of Clinical Oncology meeting in May 1998.
Now is the time to move into new approaches, particularly biologic approaches, to cancer therapy, Dr. Slamon said. “We’ve probably taken the paradigm of traditional chemotherapies as far as it can go. We need to target the molecular alterations of cancer, instead of making nonspecific bombs.” he commented.
Other promising targets besides HER-2/neu include growth factor receptors, transcription factors, signal transduction, and angiogenesis. In fact, he said, the latest generation of angiogenesis inhibitors is more powerful than those discovered earlier and currently in clinical trials.
Dr. Slamon played a pioneering role in the research leading to the phase III trial of the anti-HER-2/neu antibody. HER-2/neu is a proto-oncogene that encodes a 185 kDa transmembrane receptor, tyrosine kinase. It is amplified or overexpressed in 25% to 30% of human breast and ovarian cancers.
Tumor cells may have many extra copies of the HER-2-neu gene, he said. When these extra copies also overexpress the protein, instead of 50,000 HER-2/neu receptors on the cell surface, there will be as many as 1 million per cell.
Overexpression of HER-2/neu translates into a poor prognosis for women with breast cancer. Studies show that women whose tumor cells have a single copy of HER-2/neu survive an average of 1,879 days, compared with 959 days for those with two to four copies and 243 days for those with five or more.
As part of the initial research, Dr. Slamon wanted to find out whether HER-2/neu was responsible for this effect or whether it was simply a marker of poor prognosis. To do so, he increased the number of copies of HER-2/neu in breast cancer cell lines that previously had normal expression of this receptor to levels seen in human breast cancer samples.
‘The Effects Are Real’
This produced a significant alteration in biologic behavior of the cells, he said. The DNA synthesis rate jumped by 50% to 75%, and when injected into nude mice bearing breast tumors, the metastatic potential of the tumors increased by 200%. In short order, large tumors formed, which is not usually seen in this model. “The effects are real, they’re biologic, and they have an impact on how cells behave,” he said.
Next, the mice were administered a MoAB developed specifically to block HER-2/neu receptors. The antibody therapy almost completely suppressed tumor growth. The effect is cytostatic, not cytotoxic. Once antibody dosing is ended, tumor growth resumes. Further studies showed that HER-2/neu overexpression simply makes breast cancer cells grow faster; it does not induce intrinsic drug resistance or sensitivity, he said.
In studies of women with breast cancer who had failed traditional therapies, administration of the HER-2/neu antibody produced a 12% response rate. Another study using cisplatin(Drug information on cisplatin) (Platinol) in combination with the HER-2/neu antibody yielded a 25% response rate. Normally, one would expect a 7% response rate in this group, Dr. Slamon said. The median response duration is about 5 months, but he said that one patient who had lung lesions is still alive at 5 years.
