After breast cancer surgery, women diagnosed with early-stage, HER2-positive breast cancer usually receive the targeted therapy medicine Herceptin (chemical name: trastuzumab) and a combination of chemotherapy medicines. Treatments given after surgery are called adjuvant therapies and are used to lower the risk of the cancer coming back (recurrence).
In the United States, Herceptin is approved to be given at two times:
Still, Herceptin usually is given concurrently in the United States. In other countries, Herceptin is approved only to be given sequentially.
The study reviewed here found that women who got Herceptin at the same time as chemotherapy were 25% less likely to have a breast cancer recurrence than women who got Herceptin after chemotherapy. These results were presented at the 2009 San Antonio Breast Cancer Symposium.
In this study, 3,133 women diagnosed with HER2-positive, early-stage breast cancer got the chemotherapy combination of:after surgery.
The women randomly were split into three groups:
The women who got Herceptin received it for a total of 52 weeks.
To see if the timing of Herceptin treatment made a difference, the researchers looked the risk of recurrence 5 years after treatment.
This difference was statistically significant, which means that it was likely due to the timing of Herceptin treatment and not because of chance. While this difference in disease-free survival may seem small, it is a 25% lower risk of recurrence for women who got Herceptin at the same time as chemotherapy instead of after.
Other research has shown that women diagnosed with HER2-positive, early-stage breast cancer treated with Herceptin have a lower risk of recurrence than women not treated with Herceptin. So in this study, women in the chemotherapy-only group (no Herceptin) could start taking Herceptin if they wanted to do so. When a group in a study switches to a different treatment, researchers call it a crossover. Also, when preliminary results form this study suggested that getting Herceptin at the same time as chemotherapy was better than getting Herceptin after chemotherapy, women were allowed to switch to concurrent Herceptin (another crossover).
Crossover can make the analysis of a study more complicated, so researchers sometimes do a separate analysis that excludes all crossover results. When the researchers did a separate analysis with no crossover results for this study, they found an even greater reduction in the risk of recurrence for Herceptin given at the same time as chemotherapy: recurrence was 33% less likely with Herceptin given at the same time as chemotherapy compared to Herceptin given after chemotherapy.
Both Herceptin and Adriamycin can cause heart problems, including decreased heart function and heart failure. In this study, 3.3% of women who got Herceptin and chemotherapy at the same time developed heart problems compared to 2.8% of the women who got Herceptin after chemotherapy. Only 0.3% of the women who received chemotherapy and no Herceptin developed heart problems.
Based on the results, most doctors think that giving Herceptin at the same time as chemotherapy rather than after chemotherapy should be the standard when treating women diagnosed with early-stage, HER2-positive breast cancer.
If you've been diagnosed with HER2-positive, early-stage breast cancer, your doctor will likely recommend Herceptin and chemotherapy after surgery to reduce the risk of the cancer coming back. Your doctor probably will plan on starting Herceptin during chemotherapy. Still, if your doctor recommends starting Herceptin treatment after chemotherapy is completed, you might want to ask why and talk about the results of this study. Armed with the most-up-to-date information, you and your doctor can decide on a treatment plan that makes the most sense for your and your unique situation.
SAN ANTONIO (MedPage Today) -- Delaying trastuzumab (Herceptin) until chemotherapy is finished may impair outcomes for women with breast cancer, researchers found.
Women with HER2-positive cancer had 25% better disease-free survival rates at five years when trastuzumab was started concurrently with chemotherapy, rather than sequentially (80.1% versus 84.2%, P=0.019), Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla., and colleagues reported here at the San Antonio Breast Cancer Symposium.
"Based on a positive risk/benefit ratio, we recommend that adjuvant trastuzumab be incorporated in a concurrent fashion with the taxane portion of chemotherapy," Perez said.
These findings largely confirm current U.S. practice, which is weighted toward concurrent scheduling.
Both methods are sanctioned by the FDA in the United States, Perez said, but that that isn't generally the case elsewhere. In most countries, only the sequential strategy is approved.
For that reason, many oncologists have eagerly awaited these findings, according to Claudine Isaacs, MD, of the Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C., who moderated a press conference at which the results were presented.
The study included 3,133 women with HER2-positive tumors randomized to anthracycline-based chemotherapy alone (doxorubicin [Adriamycin] and cyclophosphamide [Cytoxan] followed by paclitaxel [Taxotere]); to the same chemotherapy with trastuzumab started concurrently with the paclitaxel, or with trastuzumab started after all chemotherapy was done.
Trastuzumab treatment continued for a total of 52 weeks in the two experimental arms.
The trial was complicated by temporary closure of the concurrent trastuzumab arm early in the study for analysis of potential adverse cardiac events.
As previously reported, the cardiac adverse event rate was 3.3% in the concurrent trastuzumab arm compared with 2.8% in the sequential arm and just 0.3% in the chemotherapy-only group.
While much discussion has focused on this difference, most cases were manageable with appropriate medical therapy, Perez said.
Results from another large trial presented here at SABCS suggested that eliminating the anthracycline would reduce cardiac toxicity associated with trastuzumab therapy while preserving outcomes, but Perez cautioned that the risk of cancer recurrence is much more important to patients and oncologists than the potential for cardiac problems.
"At least we can manage it [cardiac toxicity] and the patient can survive," Perez told MedPage Today. "The biggest issue is recurrence."
Both trastuzumab strategies appeared more effective at five years for the primary endpoint of disease-free survival, compared with the chemotherapy-only control group.
Midway through the trial, all control patients were allowed to crossover to receive trastuzumab while those on sequential trastuzumab could crossover to concurrent dosing.
With crossovers censored, sequential therapy yielded a 33% higher disease-free survival rate (80.1% versus 71.9%, P=0.0005). For the concurrent strategy, the difference was significant as well (HR 0.48, P<0.00001).
Although the concurrent trastuzumab strategy appeared significantly better than sequential administration, Perez's group said they could only call it a strong trend.
"This is based on the fact that the results of this long-term follow-up are based on a first interim analysis [for this comparison]," she said.
Projections made during the trial design "were completely off," with twice as many disease-free survival events projected to be required for statistical power, Perez explained.
So at a little over five years into the trial, the first interim analysis was triggered at 312 total events (50% of planned) for comparison between trastuzumab schedule arms, she said. The P-value needed for statistical significant in the comparison would have been at 0.0001, she said.
The effectiveness of concurrent therapy was supported by the overall survival analysis, which showed a significant benefit compared with the chemotherapy-only arm (HR 0.65, P=0.0007). whereas the sequential arm did not differ from either other arm (P=0.281 and P=0.135).
Perez attributed the benefit of concurrent scheduling to synergy between the taxane and trastuzumab.
The study was funded by the National Cancer Institute, Genetech, and the Breast Cancer Research Foundation.
Perez reported serving on the steering committee for sorafenib (Nexavar) and for a Genetech trial and serving on an independent monitoring committe for Novartis, all without direct funding from the companies.
Isaacs reported serving on the speakers bureau for GlaxoSmithKline, Genentech, Novartis, and AstraZeneca.
Primary source: San Antonio Breast Cancer Symposium Source reference: Perez E, et al "Results of chemotherapy alone, with sequential or concurrent addition of 52 weeks of trastruzumab in the NCCTG N9831 HER2-positive adjuvant breast cancer trial" SABCS 2009; Abstract 80.
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