Not only is it important that women with HER2-positive breast cancer receive adjuvant therapy with the anti-human epidermal growth factor receptor (HER2) monoclonal antibody trastuzumab, but it also makes a difference when the drug is administered, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium.
In findings that have been eagerly awaited by breast cancer specialists and their patients, Edith A. Perez, MD, and colleagues found that trastuzumab therapy should be given at the same time as adjuvant chemotherapy, not after chemotherapy is concluded.
“Giving the drugs concurrently instead of sequentially results in an additional 8,000 women with HER2-positive cancer in the US being alive and without disease each year,” said Dr. Perez, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/Oncology at the Mayo Clinic in Jacksonville, FL.
Concurrent trastuzumab with adjuvant chemotherapy should be the standard of care, she said.
Compared with chemotherapy alone, giving trastuzumab after chemotherapy has ended reduces the risk of recurrence within five years by about one-third, said Dr. Perez, Chair of the North Central Cancer Treatment Group Breast Committee, which ran the study (N9831).
Giving trastuzumab and chemotherapy together reduces the risk of recurrence by another 25%—“It's a huge gain,” she said.
Three Treatment Groups
EDITH A. PEREZ, MD G...Image Tools
The study involved 3,133 women with HER2-positive tumors. All were treated with doxorubicin at 60 mg/m2 once every three weeks for four treatments cycles along with cyclophosphamide at 600 mg/m2.
After that therapy, the 1,087 women in the control arm–those who received chemotherapy alone—received paclitaxel 80 mg/m2 once a week for 12 weeks. A group of 1,097 women then received trastuzumab in a 4 mg/kg loading dose followed by 2 mg/mg once a week for 52 weeks.
A second group of 949 women were given the same dose of trastuzumab concurrently with the paclitaxel; after 12 weeks of concurrent treatment, trastuzumab was continued for an additional 40 weeks.
The two patient groups who received trastuzumab, received it for a total of one year, Dr. Perez noted.
The researchers performed two different comparisons among the patients enrolled in the studies.
The first involved 2,448 women, randomly assigned to chemotherapy alone or chemotherapy followed by trastuzumab. After 5.5 years, there were 386 events.
After adjustment for confounding variables such as tumor size, number of positive nodes, and estrogen-receptor status, the disease-free survival rate was 80.1% for sequential chemotherapy and trastuzumab vs 71.9% for chemotherapy alone, a statistically significant difference.
The second comparison included 1,903 women who received trastuzumab after chemotherapy or trastuzumab concurrently with paclitaxel.
At a median follow-up of 5.3 years, the adjusted disease-free survival rate was 84.2% for concurrent therapy vs 79.8% for the sequential therapy.
That difference is not statistically significant, but the 25% reduction in the risk for recurrence or death with concurrent, compared with sequential, therapy, does show a “strong trend,” Dr. Perez said, explaining, though, that the result was not statistically significant because there were not as many patient events as had been initially projected.
CLAUDINE ISAACS, MD,...Image Tools
“When we began planning this study we did not expect this therapy to be as effective. We expected there would be about 640 events and we ended up with about half of that.”
About 75% of the women in the study have been followed for at least five years, Dr. Perez added.
She speculated that the difference in the two trastuzumab arms is due to the positive interaction between anthracycline therapy and trastuzumab therapy—“Our clinical trial confirms what we suspected,” she said.
Cardiac Problems Manageable
The three-year cumulative incidence of Grade 3–4 congestive heart failure or sudden cardiac death was 3.3% for concurrent therapy and 2.8% for sequential therapy, as previously reported, she said.
“Most of these [cardiac problems] are transient in nature and manageable with medical therapy. Cancer recurrence is the big problem you want to avoid,” Dr. Perez said.
“Often the research community conducts studies that conclude with ‘that was interesting, but let's do more research.’ This is an important finding on how we can help prevent breast cancer recurrence and improve survival.
“Based on a positive risk benefit ratio we recommend that trastuzumab be incorporated in a concurrent fashion in a taxane therapy. This will not only have implications here in the United States but certainly around the world.”
Both Approaches Approved in US
Both the concurrent and sequential methods of giving the drugs are approved by the FDA, and most US physicians already give the drugs together, said Claudine J.D. Isaacs, MD, Director of the Breast Cancer Program at the Lombardi Comprehensive Cancer Care Center and Associate Professor of Medicine in the Division of Hematology/ Oncology at Georgetown University Medical Center, who was not involved with the research.
But in Europe and elsewhere, physicians tend to give trastuzumab after chemotherapy has ended, she said. “This is a very important finding that we have been waiting for,” Dr. Isaacs said.
“The trial gives us evidence that there appears to be a greater effect if there is concurrent treatment with trastuzumab. These findings will have an impact on clinical practice,” she said.
During the question-and-answer period, a physician from Japan agreed, “These are long-awaited data [that will help] our practice.”
Dr. Perez estimated the findings will inform treatment decisions for about 50,000 women in the United States and 200,000 women around the world every year.
The National Cancer Institute, the Breast Cancer Research Foundation, and Genentech funded the study.
© 2010 Lippincott Williams & Wilkins, Inc.