When combined with chemotherapy and used before surgery in early stage breast cancer the drug proved so beneficial - eliminating 42 percent more tumors than chemotherapy alone - that the clinical trial testing of this new treatment plan was halted early, the researchers report in the Journal of Clinical Oncology.
"This is a far better result than we had anticipated and seems to suggest that simultaneous use of chemotherapy and Herceptin offers a much more potent treatment than use of these drugs sequentially, or alone," says lead investigator Aman Buzdar, M.D., professor in the Department of Breast Medical Oncology at M. D. Anderson.
"This is the best treatment result we have seen in this patient population," Buzdar says. "It shows that we can potentially change the natural history of a disease that is associated with a high risk of recurrence and death."
He cautions, however, that although this combination of therapies seems to show better efficacy, as well as less risk of heart damage than has been seen before with Herceptin treatment, "the jury is still out on the long-term safety and outcome. As in all such studies, we will need to wait years to follow the progress of our patient participants," Buzdar says.
Details of the trial result, slated for the June issue of the journal, were posted online Feb. 28 because of interest in the study. Preliminary results of the trial were presented in June, 2004 at the annual meeting of the American Society of Clinical Oncology.
After only 34 of a planned 164 patients had completed therapy, the trial's Data Monitoring Committee stopped the clinical trial because of the obvious benefit seen in patients who received Herceptin and chemotherapy before surgery, compared to patients treated with chemotherapy alone. In that group, rates of pathological complete remission (pcr), defined as the complete disappearance of cancer in breast tissue removed during surgery, was 66.7 percent in Herceptin-treated patients, compared to 25 percent in patients who received only chemotherapy.
Of all 42 patients who had enrolled in the study, including the eight who continued to receive treatment after the study had been halted, 26 percent in the chemotherapy arm achieved pathologic complete remission, compared with 65.2 percent in patients treated with both Herceptin and chemotherapy, according to the JCO study.
If the trial had enrolled all 164 patients, statisticians calculated a 95 percent probability that the combination of Herceptin and chemotherapy would prove superior, Buzdar says.
Giving a new combination of drugs together and for a longer time
Between 25 percent and 30 percent of breast cancers are known to over-express the human epidermal growth factor receptor 2 (HER-2), a protein that fuels the growth, and thus the aggressiveness, of the cancer. Herceptin is a monoclonal antibody drug designed to block the action of these receptors, but use of the agent by itself has shown only modest benefits.
The Food and Drug Administration approved use of Herceptin in 1998 for treatment of metastatic breast cancer in combination with chemotherapy. The long term outcome of such treatment, however, has not yet been established, according to Buzdar, and several large and lengthy clinical trials are now under way to test for cancer recurrence and survival after use of Herceptin with chemotherapy.
But researchers at M. D. Anderson wanted to test use of the drug combination in patients with earlier stage breast cancer, defined as stage II to IIIa. In order to immediately see if it had an effect on cancer, they sought to use it before surgery, so that when breast tissue was later removed, they could look for evidence of an effect.
The trial they designed was the first to compare preoperative use of Herceptin and chemotherapy against use of chemotherapy alone in patients with operable breast cancer, Buzdar says.
Patients enrolled in the study were randomized to four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin and cyclophosphamide alone or the same regimen with 24 weekly, simultaneous Herceptin treatments. To reduce the substantial incidence of heart failure and cardiac dysfunction seen with traditional use of Herceptin and anthracycline-based chemotherapy, the researchers used epirubicin instead of doxorubicin, which has been shown to be less toxic to the heart.
The researchers offered the combination of therapies for a longer period of time than is usual, and the drugs also were given at the same time - another departure from traditional practice.
The goal of the study has been to see whether tailoring the chemotherapy regimen and adding Herceptin would double rates of pathologicalcompleteremission. "Instead of the 20 percent improvement we had hoped for, we saw almost twice that," Buzdar says. "We were totally surprised with these striking findings, and pleased that we may have a better treatment for women with HER-2 breast cancer."
They also found that it did not matter whether the patients' tumors were estrogen-receptor positive or negative - a distinction that usually demarcates which patients will respond to hormonal therapy. And, to date, no cases of congestive heart failure or other such serious heart problems have yet been observed in the patients, Buzdar says.
Within several months, the research team will launch additional studies, enrolling larger groups of patients, to test the effects of this approach before surgery. "The data from this trial is so convincing that we decided that in these new studies, all patients must receive Herceptin," Buzdar says.
The study was funded by research grants from manufacturers of drugs used in the trial, including Genentech, Pfizer and Bristol-Myers Squibb. Investigators from M. D. Anderson Cancer Center involved in the study also include Nuhad Ibrahim, M.D., Deborah Francis, R.N., Daniel Booser, M.D., Eva Thomas, M.D., Richard Theriault, D.O., Lajos Pusztai, M.D., Ph.D., Marjorie Green, M.D., Banu Arun, M.D., Sharon Giordano, M.D., Massimo Cristofanilli, M.D., Debra Frye, R.N., Terry Smith, Kelly Hunt, M.D., Eva Singletary, M.D., Aysegul Sahin, M.D., Michael Ewer, M.D., Thomas Buchholz, M.D., Donald Berry, Ph.D., and Gabriel Hortobagyi, M.D.