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Dennis Slamon: Anthracycline Not Needed with Trastuzumab; Nonanthracycline-based Regimen Just as Effective but Has Lower Risk of Side Effects

Laino, Charlene

doi: 10.1097/01.COT.0000368886.76017.74

Patients receiving trastuzumab typically do need adjuvant anthracycline-based chemotherapy, according to new results from the Breast Cancer International Research Group-006 trial.

A nonanthracycline-based regimen is just as effective, but carries a lower risk of heart failure and leukemia, said Dennis J. Slamon, MD, PhD, Chief of the Division of Hematology/Oncology at UCLA and Director of Clinical/Translational Research and Director of the Revlon/UCLA Women's Cancer Research Program.

“We should no longer think that the high-risk patient needs anthracycline-based chemotherapy. The data doesn't support that,” Dr. Slamon said at the CTRC-AACR San Antonio Breast Cancer Symposium.

The trial included 3,222 women with HER2-positive early breast cancer, randomized to one of three groups: (1) standard anthracycline-based chemotherapy with doxorubicin, cyclophosphamide, and docetaxel; (2) the same chemotherapy regimen plus trastuzumab; or (3) a nonanthracycline regimen of docetaxel, carboplatin, and trastuzumab.

About 50% of the women in all three groups had hormone-receptor-positive tumors and were given hormonal therapy for five years after chemotherapy. About 60% of all patients in all arms had a mastectomy, and 68% of women in all groups received radiotherapy.

The new findings are from a planned third analysis, which was conducted after 650 events, Dr. Slamon said.

The disease-free survival rate, the trial's primary endpoint, was 84% in the anthracycline-based arm that included trastuzumab and 81% in the nonanthracycline arm, both of which were significantly superior to the 75% rate in the non-trastuzumab group, but not significantly different from one another.

The same pattern held true for the secondary endpoint of overall survival rates, which were 92% in the anthracycline-based treatment arm, 91% in the nonanthracycline-based therapy arm, and 87% in the arm that did not include trastuzumab.

While anthracycline-based therapy was expected to particularly benefit high-risk patients, the two trastuzumab (Herceptin) regimens were associated with similar disease-free survival rates even in the patients with four or more positive lymph nodes, Dr. Slamon said.

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Safety Analysis

Altogether, there were 29 fewer events among the 1,074 women in the anthracycline-based group than among the 1,074 women in the taxane-based group, he said.

This came, however, he added, at a cost of 21 cases of congestive heart failure and eight cases of acute leukemia.

The anthracycline-based regimen was also associated with higher rates of Grade 3–4 arthralgia, myalgia, hand-foot syndrome, stomatitis, and vomiting, and of Grade 3–4 neutropenia and leucopenia.

The bottom line, he said, is that the efficacy differences associated with an anthracycline are outweighed by the toxicity differences.

The only patients who appear to benefit from anthracycline-based therapy are the subgroup of HER2-positive women with tumors containing alterations in the topoisomerase II alpha (TOP2A) gene, Dr. Slamon said. But even these women should get a nonanthracycline trastuzumab-based regimen because of a gentler side effect profile, he said.

“The only place it makes sense to use anthracyclines is in women who are TOP2A-amplified and can't get Herceptin.



“When we see a HER2-positive patient we should treat those patients with nonanthracycline-containing regimens to get close to equivalent efficacy but considerably better safety, in term of both acute and long-term toxicities,” Dr. Slamon concluded.

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Anthracycline—Or Not?

Edith A. Perez, MD, Director of the Breast Cancer Program and Professor of Medicine in the Division of Hematology/ Oncology at the Mayo Clinic in Jacksonville, FL, said that she believes cardiac safety is less of an issue than efficacy: “At least we can manage it and the patient can survive. The big issue is recurrence,” she said,

But Dr. Slamon said the cardiac damage may not be reversible and in fact continues to worsen over time.

Echoing the sentiments of many, Gary H. Lyman, MD, MPH, Professor of Medicine at Duke University Medical Center, also said he was not ready to give up on anthracyclines.

In fact, the anthracycline-based regimen looked better in this analysis than the last one, he said. ‘”If you look at the disease-free survival and overall survival curves, they have widened since the last analysis, favoring the anthracycline regimen,” Dr. Lyman said.

One group of women for whom anthracyclines may not be indicated are those with HER2-positive breast cancer and significant cardiac risk, he said.

The study was sponsored by Sanofi-Aventis with support from Genentech.

© 2010 Lippincott Williams & Wilkins, Inc.
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