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Are Anthracyclines Justified for Breast Cancer?

Most patients are not likely to benefit from anthracycline-based adjuvant chemotherapy.

For the past 2 decades, standard adjuvant chemotherapy for early-stage breast cancer has included an anthracycline. This strategy was supported by results of the Oxford Overview meta-analysis, in which patients who received anthracycline-based adjuvant therapy achieved longer recurrence-free survival (RFS) and overall survival (OS) than counterparts who did not receive an anthracycline (Lancet 2005; 365:1687). However, recent findings indicate that benefits from anthracycline-containing regimens are restricted mainly to the minority of patients with HER2-positive breast tumors. One hypothesis to explain the association between HER2 status and anthracycline response is that HER2 amplification is merely a marker for changes in topoisomerase II alpha, an enzyme that influences anthracycline activity and whose gene (TOP2A) abuts HER2 on chromosome 17.

To further examine the association between TOP2A alterations and benefit from anthracycline-based adjuvant therapy, Canadian investigators performed additional analyses of samples from their Mammary 5 (MA.5) trial, in which CMF (cyclophosphamide, methotrexate, 5-FU) and CEF (cyclophosphamide, epirubicin, 5-FU) were compared (N Engl J Med 2006; 354:2103). Tissue microarrays were constructed from 438 tumor blocks, TOP2A alterations and HER2 amplification were measured by fluorescence in situ hybridization, and associations with survival outcomes were evaluated.

Patients whose tumors had amplifications or deletions in TOP2A achieved longer OS in response to CEF than to CMF (hazard ratio, 0.38; P=0.02); these patients had similar RFS in response to each regimen. Patients whose tumors lacked TOP2A alterations had similar OS and RFS in response to each regimen. Regarding the association between TOP2A and HER2 status, other reports indicate that the vast majority of TOP2A-amplified cases are in the HER2-positive group of breast cancers and that TOP2A changes rarely occur in HER2-normal tumors. Collectively, these data suggest that patients most likely to benefit from anthracycline-based therapy have TOP2A-altered, HER2-positive tumors.

Comment: These data support the long-standing argument that most patients gain little or nothing from adjuvant anthracycline-based therapy. In an era when the availability of anti-HER2 therapies (such as trastuzumab [Herceptin] and lapatinib [Tykerb]) result in new treatment strategies and better outcomes for HER2-positive disease, the benefit from anthracyclines is difficult to quantify. We must study more patients to determine which measurement — TOP2A alteration or HER2 status — is more closely associated with responsiveness to anthracyclines.

— William J. Gradishar, MD

Published in Journal Watch Oncology and Hematology June 2, 2009

Citation(s):

O’Malley FP et al. Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 2009 May 6; 101:644.

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• Medline abstract (Free)

Slamon DJ and Press MF. Alterations in the TOP2A and HER2 genes: Association with adjuvant anthracycline sensitivity in human breast cancers. J Natl Cancer Inst 2009 May 6; 101:615.

• Original article (Subscription may be required)
• Medline abstract (Free)