Herceptin® Combined With Chemotherapy Improves Disease-Free Survival for Patients With Early-Stage Breast Cancer
Results from two large randomized clinical trials for patients with HER-2
positive invasive breast cancer show that those patients with early-stage
breast cancer who received Herceptin® (trastuzumab) in combination with
chemotherapy had a significant decrease in risk for breast cancer recurrence
compared with patients who received the same chemotherapy without trastuzumab.
Patients are considered "HER-2 positive" if their cancer cells "overexpress,"
or make too much of, a protein called HER-2, which is found on the surface of
cancer cells. Trastuzumab slows or stops the growth of these cells, and it is
only used to treat cancers that overexpress the HER-2 protein. Approximately 20
percent of breast cancers overexpress HER-2. These tumors tend to grow faster
and are generally more likely to recur than tumors that do not overproduce
HER-2.
The clinical trials were sponsored by the National Cancer Institute (NCI), part
of the National Institutes of Health, and conducted by a network of researchers
led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the
North Central Cancer Treatment Group (NCCTG), in collaboration with the Cancer
and Leukemia Group B, the Eastern Cooperative Oncology Group, and the Southwest
Oncology Group. Genentech, Inc., South San Francisco, Calif., which
manufactures trastuzumab, provided the drug for the trials under the
Cooperative Research and Development Agreement (CRADA) with NCI for the
clinical development of trastuzumab.
The Data Monitoring Committees overseeing the combined analysis of these trials
(known as NSABP-B-31 and NCCTG-N9831)* recommended in April 2005 that the
results of a recent combined interim analysis be made public because the
studies had met their primary endpoints of increasing disease-free survival
(the amount of time patients live without return of the cancer) in patients
receiving trastuzumab in combination with chemotherapy. The improvement in
overall survival also was statistically significant for women receiving a
combination of chemotherapy and trastuzumab. Study results, with complete
details, were published in the October 20, 2005 New England Journal of
Medicine**.
Patients in the clinical trials who received trastuzumab in combination with
standard combination chemotherapy had a 52 percent decrease in disease
recurrence compared to patients treated with chemotherapy alone. This
difference is highly statistically significant. "This is a major advance for
many thousands of women with breast cancer," said NCI Director Andrew C. von
Eschenbach, M.D. "These results are one more example that we are at a major
turning point in the use of targeted therapies to eliminate suffering and death
from cancer," he added.
The leaders of the studies underscored the significance of these results and
cited the collaborative efforts involved. "These findings confirm that we now
have a very potent weapon against the recurrence of cancer cells that
overexpress HER-2," said Edith A. Perez, M.D., who chaired the NCCTG trial and
is a medical oncologist at the Mayo Clinic in Jacksonville, Fla. "We gratefully
acknowledge the contribution of our co-investigators and, most importantly, our
courageous patients in helping to achieve these unprecedented results."
Edward Romond, M.D., study chair for the NSABP and professor of oncology at the
University of Kentucky, in Lexington, Ky., noted, "For women with this type of
aggressive breast cancer, the addition of trastuzumab to chemotherapy appears
to virtually reverse prognosis from unfavorable to good."
"These are truly life-saving results in a major disease, however, additional
follow-up is ongoing and will help determine the long-term safety and
effectiveness of this agent," said Jo Anne Zujewski, M.D., who oversees breast cancer trials for NCI's Cancer
Therapy Evaluation Program.
Among the specific findings from the study were:
-
At a median follow-up of two years, there were 261 events (such as return of
the cancer, second primary cancer, or death before recurrence) in the control
group and 133 events in the trastuzumab group.
-
The percentage of patients alive and disease-free at three years was 87.1
percent in the trastuzumab group and 75.4 percent in the control group. After
four years, the respective percentages were 85.3 percent for trastuzumab vs.
67.1 percent for those on standard chemotherapy.
-
Women taking trastuzumab with a particular chemotherapy regimen had a 33
percent reduction in risk of death.
Information from over 3,300 patients enrolled in these studies was used for
analysis. Patients with operable breast cancer whose tumors over-expressed
HER-2 were enrolled in these studies between February 2000 and April 2005.
Patients were assigned by chance to receive chemotherapy with doxorubicin and
cyclophosphamide followed by paclitaxel, or doxorubicin and cyclophosphamide
followed by paclitaxel and trastuzumab. Most patients had positive axillary
(under arm) lymph nodes involved with breast cancer with only a minority having
no disease in the nodes. The limited information in those without lymph node
involvement did not allow for a separate analysis of this group.
Chemotherapy of the type given in these studies has a risk of congestive heart
failure (weakening of the heart muscle) of less than 1 percent. In these
studies, the likelihood of congestive heart failure in women receiving the
combination of chemotherapy and trastuzumab was increased by 3 percent to 4
percent. Cardiac toxicity in the B-31 trial was 4.1 percent for those taking
trastuzumab vs. 0.8 percent for those on standard chemotherapy. Cardiac toxicity
in the N9831 trial was 2.9 percent for those taking trastuzumab vs. 0.0 percent
for those on standard chemotherapy. Patients in these studies will continue to
be followed for any additional side effects.
Trastuzumab is an example of a "targeted" therapy -- an agent that is directed
against a specific change in the cancer cell. Trastuzumab was approved for the
treatment of advanced breast cancer in 1998.
An estimated 211,240 women will be diagnosed with breast cancer in the United
States in 2005. Of these, about 30 percent have lymph node-positive breast
cancer, and about 20 percent of these tumors overexpress the HER-2 protein, the
target for trastuzumab. Breast cancer is the most commonly diagnosed cancer in
women and the second leading cause of cancer-related death in women in this
country. An estimated 40,110 deaths from female breast cancer will occur in
2005 in the United States, accounting for about 15 percent of all
cancer-related deaths in women in the nation.
# # #
For more information about cancer, please visit the NCI Web site at
http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4
CANCER (1-800-422-6237).
* NSABP-B-31: Phase III Randomized Study of Doxorubicin and
Cyclophosphamide Followed By Paclitaxel With or Without Trastuzumab (Herceptin)
in Women with Node-Positive Breast Cancer That Overexpresses HER2
NCCTG-N9831: Phase III Randomized Study of Doxorubicin Plus
Cyclophosphamide Followed By Paclitaxel With or Without Trastuzumab
(Herceptin®) in Women with HER-2-Overexpressing Node-Positive or High-Risk
Node-Negative Breast Cancer
** Romond EH, Perez EA, et al. Trastuzumab Plus
Chemotherapy for Operable HER2-Positive Breast Cancer. NEJM, Vol. 353. No. 16, pp.
1673-1684.
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