Journal of the National Cancer Institute Advance Access published online on December 25, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm252
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© The Author 2007. Published by Oxford University Press.
ARTICLES |
HER2 Status and Efficacy of Adjuvant Anthracyclines in Early Breast Cancer: A Pooled Analysis of Randomized Trials
Affiliations of authors: National Cancer Research Institute, Genoa, Italy (AG, PP, UP, PB); Department of Health Sciences, University of Genoa, Genoa, Italy (AG, MPS, MP); Galliera Hospital, Genoa, Italy (MP); Perugia Hospital, Perugia, Italy (MC)
Correspondence to: Alessandra Gennari, MD, PhD, National Cancer Research Institute, Largo Rosanna Benzi, 10 16132 Genoa, Italy (e-mail: alessandra.gennari{at}istge.it).
Background: Adjuvant chemotherapy with anthracyclines improves disease-free and overall survival compared with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer. The role of HER2 status as a marker of anthracycline responsiveness has been explored by subset analyses within randomized clinical trials, with inconsistent results. We performed a pooled analysis of the interaction between HER2 status and the efficacy of adjuvant anthracyclines based on the published subset data.
Methods: We searched literature databases to identify randomized trials that compared anthracycline-based with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer and reported efficacy data according to HER2 status. Log hazard ratios (HRs) for disease-free and overall survival were pooled across the studies according to HER2 status by inverse variance weighting. A pooled test for treatment by HER2 status interaction was performed by weighted linear meta-regression. All statistical tests were two-sided.
Results: Eight studies (with 6564 randomly assigned patients, of whom 5354 had HER2 status information available) were eligible for this analysis. In HER2-positive disease (n = 1536 patients), anthracyclines were superior to non–anthracycline-based regimens in terms of disease-free (pooled HR of relapse = 0.71; 95% confidence interval [CI] = 0.61 to 0.83; P < .001) and overall (pooled HR of death from any cause = 0.73; 95% CI = 0.62 to 0.85; P < .001) survival. In HER2-negative disease (n = 3818 patients), anthracyclines did not improve disease-free (HR = 1.00; 95% CI = 0.90 to 1.11; P = .75) or overall (HR = 1.03; 95% CI = 0.92 to 1.16; P = .60) survival. The test for treatment by HER2 status interaction yielded statistically significant results: for disease-free survival, the chi-square statistic for interaction was 13.7 (P < .001), and for overall survival, it was 12.6 (P < .001).
Conclusions: The added benefits of adjuvant chemotherapy with anthracyclines appear to be confined to women who have HER2 overexpressed or amplified breast tumors.
| CONTEXT AND CAVEATS Prior knowledge In the treatment of early breast cancer, anthracycline-based adjuvant chemotherapy improves disease-free and overall survival compared with non–anthracycline-based adjuvant chemotherapy. However, it is unclear whether the HER2 status of breast tumors is a marker of anthracycline responsiveness. Study design A pooled analysis of data from eight randomized controlled trials that compared anthracycline-based with non–anthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer. Contribution The added benefits of adjuvant chemotherapy with anthracyclines appear to be limited to women whose breast tumors have overexpressed or amplified HER2. Implications Patients with HER2-negative breast tumors derive no added benefits from adjuvant chemotherapy with anthracyclines. Limitations Only eight randomized clinical trials published data on the effects of adjuvant anthracyclines according to HER2 status. Summary results rather than individual patient data were analyzed, and there was no centralized reassessment of HER2 status. The methods used to determine HER2 status differed among the trials.
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Manuscript received April 4, 2007; revised October 23, 2007; accepted November 9, 2007.
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