After breast cancer surgery, many women diagnosed with early-stage, HER2-positive breast cancer are treated with the targeted therapy Herceptin (chemical name: trastuzumab) and a combination of chemotherapy medicines. Because these treatments are given after surgery, they're called adjuvant therapies. These adjuvant therapies are used to reduce the risk of the cancer coming back (recurrence).
An anthracycline chemotherapy medicine is typically part of the combination used to treat HER2-positive breast cancer. Adriamycin (chemical name: doxorubicin) and Ellence (chemical name: epirubicin) are anthracyclines. Like all chemotherapy medicines, anthracyclines may cause serious side effects including heart damage, which can lead to heart failure. Doctors also are concerned about a higher risk of leukemia in women who have been treated with Adriamycin. Because of these potential risks, chemotherapy without an anthracycline could makes sense for some women, as long as there's no increase in recurrence risk.
The study reviewed here compared three adjuvant treatment plans for women diagnosed with HER2-positive, early-stage breast cancer and found that Herceptin plus chemotherapy that didn't include an anthracycline was as effective as Herceptin plus chemotherapy that did include an anthracycline. Women who didn't get an anthracycline had the same risk of recurrence as women who got an anthracycline. Women who didn't get an anthracycline also had a lower risk of certain side effects, including heart failure. These results were reported at the 2009 San Antonio Breast Cancer Symposium.
After surgery, 3,222 women diagnosed with HER2-positive, early-stage breast cancer got one of three adjuvant therapy plans:
The women were followed for more than 5 years.
The women who got Herceptin and chemotherapy without the anthracycline Adriamycin (CTH) did just as well as women who got Herceptin and chemotherapy with Adriamycin (ACTH):
This very small difference wasn't statistically significant, which means it could have been due to chance and not because of the different treatments.
Women who got chemotherapy but no Herceptin (ACT) didn't do as well as women who got Herceptin:
The difference in survival and recurrence rates between women who did and didn't get Herceptin was statistically significant, which means the difference was likely due to the Herceptin and not just because of chance.
This study also showed that even women with an extremely high risk of recurrence got no additional benefits from Adriamycin as long as they got Herceptin.
No matter which treatment they got, the overall rate of side effects was similar for all the women. About 2% of women who got Adriamycin developed heart failure, which was 5 times higher than in women who didn't get Adriamycin.
Based on these results, some doctors think not using Adriamycin in the adjuvant chemotherapy combination for women diagnosed with HER2-positive, early-stage breast cancer makes sense as long as Herceptin is included. Other doctors think that more research is needed before they confidently can avoid using Adriamycin.
Most doctors would agree that Herceptin makes a difference and should be used to treat almost all women diagnosed with HER2-positive breast cancer. Still, some doctors say that the difference Herceptin makes is small and that the expense of Herceptin ($10,000 per month) makes adjuvant chemotherapy without Herceptin a reasonable alternative for some women.
If you've been diagnosed with HER2-positive, early-stage breast cancer, your doctor will likely recommend Herceptin and a chemotherapy combination after surgery to lower the risk of the cancer coming back. Your doctor may recommend a chemotherapy plan that includes an anthracycline such as Adriamycin. If so, you might want to talk to your doctor about the results of this study. Ask about your doctor's reasons for recommending Adriamycin and the benefits, risks, and side effects of all the medicines being considered. 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) -- Eliminating the anthracycline from chemotherapy when using trastuzumab (Herceptin) may be just as effective long term, with less risk of heart failure and leukemia, according to highly anticipated but controversial data from the BCIRG-006 trial.
A nonanthracycline based regimen with trastuzumab was not associated with significantly more breast cancer recurrences or deaths at 5.5 years, Dennis Slamon, MD, PhD, of the University of California Los Angeles, and colleagues found.
Nor was there any group of HER2-positive patients, high risk or otherwise, that benefited more from the anthracycline-based regimen, Slamon reported here at the San Antonio Breast Cancer Symposium.
Moreover, using an anthracycline-based regimen with trastuzumab was associated with five times more heart failure (grade 3/4 1.96% versus 0.38%, P<0.001) and a small risk of treatment-related leukemias (0.1% versus 0.00% excluding one case that received anthracycline for B-cell lymphoma or 0.1% with the case) in the trial.
"We should no longer think that the high-risk patient needs anthracycline-based chemotherapy. The data doesn't support that," Slamon said at a press briefing.
The trial, which included 3,222 HER2-positive breast cancer patients, compared standard anthracycline-based chemotherapy -- doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), docetaxel (Taxotere) -- with the same combination with trastuzumab, and to a third arm of just docetaxel, carboplatin (Paraplatin), and trastuzumab.
The 36-month results reported at this meeting in 2006 left the nonanthracycline regimen looking a little less effective, but without the statistical power to show whether it was truly equivalent as hoped.
However, opinions have been polarized on the results and their implications.
"Most oncologists have kind of gravitated into a couple of camps -- those who use anthracyclines and those who don't," commented Gary Lyman, MD, MPH, of Duke University.
Like others here, he questioned the conclusion that the arms produced similar outcomes. If anything, the disease-free survival curves looked further apart at the new analysis than at the prior one, despite the lack of statistical significance, Lyman said.
At the new 65-month analysis, disease-free survival was 84% with the anthracycline-based arm with trastuzumab compared with 81% with the nonanthracycline arm, both significant compared with the nontrastuzumab group's 75% (HR 0.64, P<0.001, and HR 0.75, P=0.04, respectively) but not compared with each other (P=0.21).
At the 36-month analysis, the separation from nontrastuzumab therapy was 6% and 5%, respectively, also not a significant difference.
"I don't think it's likely to change practice," Lyman told MedPage Today. "I don't see my patients by and large deciding to go with TCH [docetaxel, carboplatin, and trastuzumab]. The apparent impact on controlling cancer with ACTH [the anthracycline regimen] is going to weigh more heavily in their decision."
Overall survival rates at the latest analysis showed a similar pattern with rates of 92% with anthracycline-based therapy, 91% with nonanthracycline-based therapy, and 87% with nontrastuzumab therapy (P<0.001 and P=0.038 versus nontrastuzumab and P=0.14 between trastuzumab arms).
Anthracycline-based therapy was expected to benefit high-risk patients most, Slamon noted.
But even in the patients with at least four positive lymph nodes, the two trastuzumab regimens produced identical disease-free survival outcomes (both HR 0.66, P=0.002 versus nontrastuzumab therapy).
Likewise, the results were similarly superior for both anthracycline-based and nonanthracycline-based regimens in lymph node negative patients compared with the nontrastuzumab group.
The safety results were largely unchanged from the last analysis, Slamon said.
"The acute and chronic toxicity profiles of TCH are better than those seen with the ACTH regimen in almost all parameters measured," he told the SABCS.
Thus, "at this point when we see a HER2 positive patient we've elected to treat those patients with nonanthracycline-containing regimen to get close to equivalent efficacy but considerably better safety, in particular not for the acute toxicity but more important for the life-changing toxicities," Slamon concluded.
However, Edith Perez, MD, of the Mayo Clinic in Jacksonville, Fla., commented that these so-called life-changing cardiac effects are less of a concern. "At least we can manage it and the patient can survive," she said. "The bottom line, the biggest issue is recurrence."
Another controversial issue has been the analysis by Topo IIa amplification, which Slamon described as a genetic neighbor of the HER2 gene.
The researchers found that disease-free survival results were as expected from the main analyses for those who didn't have amplified levels of Topo IIa. But for those with Topo IIa amplification along with HER2 positivity, all three arms were statistically similar.
Slamon suggested that these patients, too, should get the nonanthracycline trastuzumab regimen because of its easier side effect profile, but audience members at the presentation questioned whether the nontrastuzumab regimen wouldn't be preferred as a much less expensive option.
Trastuzumab alone costs approximately $10,000 per month.
The study was sponsored by sanofi-aventis with additional support from Genetech, the National Cancer Institute, and the Cancer International Research Group. Slamon reported conflicts of interest with sanofi-aventis, Genetech, Amgen, and Pfizer.
Lyman reported no conflicts of interest.
Perez reported having served on steering committees for sorafenib (Nexavar) and Genetech trials as well as on an independent monitoring committee for Novartis, all without receiving direct funding from the pharmaceutical companies.
Primary source: San Antonio Breast Cancer Symposium Source reference: Slamon D, et al "Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2neu positive early breast cancer patients: BCIRG 006 study" SABCS 2009; Abstract 62.
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