Anthracyclines May Not Be Necessary in Adjuvant Therapy of Breast Cancer

Zosia Chustecka

December 18, 2006

December 18, 2006 (San Antonio) — Anthracyclines have formed the backbone of adjuvant treatment for breast cancer, but new data presented at the 29th Annual San Antonio Breast Cancer (SABC) Symposium have raised the provocative question of whether they are necessary. A large study has shown that a regimen of taxane plus trastuzumab ( Herceptin, Roche/Genentech) is similar in terms of prolonging survival to a regimen containing an anthracycline plus trastuzumab but has much less toxicity.

The data offer a new option for women with early-stage HER2+
breast cancer and will influence daily clinical practice, predicted cochair of the study, Dennis Slamon, MD, PhD, from the University of California, Los Angeles Jonsson Comprehensive Cancer Center.

However, other experts were less enthusiastic. At a separate session, Gabriel Hortobagyi, MD, from the University of Texas MD Anderson Cancer Center, in Houston, said he wasn’t convinced enough yet to stop using anthracyclines.

In an interview with Medscape, David Cameron, MD, from the Western General Infirmary, in Edinburgh, Scotland, said he thought that anthracyclines will continue to play a major role in the treatment of breast cancer, but he agreed that their role is being challenged in the treatment of HER2+ breast cancer (a subgroup representing some 20% to 25% of all breast cancers) by these new data.

Study in Early-Stage HER2+ Breast Cancer

The new findings come from the Breast Cancer International Research Group (BCIRG) 006 study, which involved 3233 women with early-stage HER2+
breast cancer, with or without axillary lymph node involvement. Supported by Sanofi Aventis with funding from Genentech, the study had 3 groups, comparing standard therapy with 2 experimental ones, as follows:

  • Group A, the control group — 4 cycles of doxorubicin (Adriamycin) and cyclophosphamide followed by 4 cycles of docetaxel (Taxotere, Sanofi-Aventis).

  • Group B — Trastuzumab added to the group A regimen.

  • Group C, the group without an anthracycline — 6 cycles of the taxane docetaxel with carboplatin and trastuzumab.

At the meeting, Dr. Slamon presented results from a second interim analysis of this trial, with a median follow-up of 3 years. The results confirm the findings of the first interim analysis, announced in April 2005. Dr. Slamon noted that since that time, only 17 patients from 1073 randomized to group A (1.6%) have crossed over to receive trastuzumab, which leaves 98.4% of the control group intact.

Both experimental groups had significantly better outcomes than the control group in reducing the risk for death and improving disease-free survival. The differences between the 2 experimental groups were not statistically significant, Dr. Slamon noted.

Second Interim Analysis of BCIRG 006, Median 3-Year Follow-Up

Group A
Group B
Group C
Patients, n
Deaths, n
49 ( P = .004)*
56 ( P = .017)*
Relapses, n
128 ( P < .0001)*
142 ( P = .0003)*
* P for comparison of experimental group with control group (A).

Significant Differences in Toxicity

However, the 2 experimental groups, while similar in efficacy, showed significant differences in toxicity. This was particularly apparent with cardiotoxicity, which was 5 times lower in with the nonanthracycline regimen (group C) compared with group B, which had the double whammy of cardiac damage from the anthracycline and from trastuzumab. Congestive heart failure (grade 3/4) developed in 20 patients in group B, compared with 4 patients in group C group and 5 patients in group A. An asymptomatic decline in cardiac function was seen in 8.6% of patients in group C, compared with 10% in group A and 18% in group B.

Group C also showed significantly lower toxicity than both anthracycline-containing groups with regard to several other side effects, including arthralgia and myalgia, hand-foot syndrome (none seen in group C), stomatitis, vomiting, nail changes, and neuropathy.

Hematological toxicity showed different patterns between the groups, with group C showing significantly less neutropenia and leukopenia but more anemia and thrombocytopenia. Dr. Slamon noted secondary leukemia developed in both of the anthracycline-containing groups — in 3 patients in the group A and in 1 patient in group B, but no cases have been seen in group C.

In summary, Dr. Slamon said the updated results show a difference in the number of disease-free survival events and breast cancer deaths in favor of the group B regimen, but neither is statistically significant, and they are now exceeded by the number of critical adverse events, including CHF, loss of cardiac function, and anthracycline-related leukemia, all of which are highly statistically significant. Thus, the trial demonstrates an optimal therapeutic index for these patients with the use of the group C regimen, he concluded.

Dr. Slamon noted that, quite separately, a recently published trial has shown significantly superior efficacy in breast cancer for an anthracycline-free regimen of docetaxel plus cyclophosphamide compared with doxorubicin plus cyclophosphamide (Jones SE et al. J Clin Oncol. 2006;24:5381). In view of this reported superior efficacy and now the equivalent efficacy but milder toxicity reported from his own study, he threw out the provocative question of whether anthracyclines were necessary for adjuvant therapy.

29th Annual SABC Symposium: Abstract 52. Presented December 14, 2006.


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