HER2 status may predict response to adjuvant anthracycline therapy

Issue: March 10, 2008

The supplementary benefits of administering adjuvant chemotherapy with anthracyclines were reported to be limited to patients with amplified or overexpressed HER2 breast tumors, according to recent findings of a literature review published in the Journal of the National Cancer Institute.

“The administration of anthracyclines is a big issue because many people still believe that current anthracycline still represents the mainstay of the adjuvant treatment of all breast cancer patients,” Alessandra Gennari, MD, PhD, National Cancer Research Institute, told HemOnc Today.

Gennari and colleagues from the National Cancer Research Institute analyzed eight randomized trials (n=6,564 patients) that compared nonanthracycline-based adjuvant therapies with anthracycline-based therapies in treating patients with early-stage breast cancer.

They observed that in 1,536 patients with HER2-positive disease administration of anthracycline therapies was superior to nonanthracycline-based therapies regarding overall survival (HR=0.73; 95% CI, 0.62-0.85) and disease-free survival (HR=0.71; 95% CI, 0.61-0.85).

In the 3,818 patients with HER2-negative disease, anthracyclines were not reported to increase overall survival (HR=1.03; 95% CI, 0.92-1.16) or disease-free survival (HR=1.00; 95% CI, 0.90-1.11).

“The statistically significant interaction for both disease-free and overall survival revealed by our meta-analysis provides convincing statistical evidence of a quantitative interaction between HER2 status and responsiveness to adjuvant anthracyclines,” the researchers wrote.

The results of this study could help a physician when examining a HER2-negative patient and may help them to better determine if anthracycline is the optimal treatment choice, Gennari said.

There is enough statistical evidence to indicate that HER2-negative patients might be spared from the detrimental effects of adjuvant anthracyclines, Gennari said.

Risk for secondary leukemia and cardiotoxicity, although small, were clinically significant concerns of widespread administration of anthracyclines as an adjuvant treatment for early-stage breast cancer. The data showed that although patients benefited from anthracyclines, their effect was moderate and were not constant through the different trials examined. – by Paul Burress

J Natl Cancer Inst. 2008;100:14-20.

Anthracycline-based chemotherapy significantly reduces annual breast cancer mortality by 38% in women aged younger than 50 and 20% in those aged 50 to 69 irrespective of adjuvant hormonal treatment. This effect is mediated by topoisomerase 2 alpha. The researchers evaluated the interaction between treatment effect and HER2 status in women treated with anthracycline vs. nonanthracycline therapy. None received taxane or aromatase inhibitor therapy. Strict inclusion criteria and robust statistical evaluation to exclude study heterogeneity as a confounding factor enabled pooled analysis. About 50% of the patients included in this analysis were premenopausal. Overall, there was a 10% reduction in relapse (P=.01) but not mortality risk. HER2-positive breast tumors were associated with a 29% decrease in risk for relapse (range, 16%-48%) and a mortality reduction of 27% (range, 15%-39%). This meta-analysis corroborates the findings of prior studies (see list of studies below) and has identified a subgroup of node-positive patients with HER2 overexpression/amplification who derive significant benefit from anthracycline therapy. This has significant implications for treatment decisions in women who may not need taxane therapy.

– Thelma C. Hurd, MD

Associate Professor, Director, Breast Surgery Program, Division of Surgical Oncology,
Department of Surgery, University of Texas Health Science Center, San Antonio

For more information:
Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;365:1687-1717.
Pritchard KI, Shephard LE, O’Malley FP, et al. HER2 responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006;354:2177-2179.
Paik S, Bryant J, Park C, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst. 1998;90:1361-1370.
Knoop AS, Knudsen H, Balslev E, et al. Retrospective analysis of topoisomerase II alpha amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate and fluorouracil or cyclophosphamide, epirubicin and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol. 2005;20:7483-7490.
Paik S, Bryant J, Tan-Chiu E, et al. HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst. 2000;92:1991-1998.
Di Leo A, Gancberg D, Larsimont D, et al. HER2 and topoisomerase II alpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate and 5-fluorouracil. Clin Cancer Res. 2002;8:1107-1116.