Abstract:
http://jco.ascopubs.org/cgi/content/...2008.20.1566v1
Commentary:
Supplementary editorial provided by OncologySTAT
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HER2 and TOP2A amplification were not predictive of survival in patients with breast cancer who responded to anthracycline-based chemotherapy.
EXPERT COMMENTARY
Lee Schwartzberg, MD, PhD, Editor-in-Chief
A current debate in the adjuvant treatment of breast cancer centers around the use of anthracyclines. Prior studies have suggested that HER2 gene amplifications and alterations in the nearby TOP2A gene may be predictive of enhanced sensitivity to anthracyclines. In this report of patients treated with AC, surprisingly no correlation was detected for DFS or OS with either HER2 or TOP2A. The big question not addressed in the current study or prior analyses is whether there is subgroup of breast cancer patients who benefit preferentially from a taxane vs an anthracycline, or a subgroup who need both classes of drugs to receive maximal benefit. Hopefully, similar analyses will be performed on data from clinically relevant trials (such as the AC vs TC study) that can answer these important questions.
STUDY IN CONTEXT
Anthracycline-based adjuvant chemotherapy improves outcomes in patients with breast cancer, but it is associated with life-threatening toxicities. Identification of patients most likely to benefit from treatment with anthracyclines would be useful in limiting patient risks. Previous studies have suggested that tumors exhibiting amplification or overexpression of the ERBB2 (HER2) gene are more responsive to anthracyclines than are tumors with normal HER2. More recently, the topoisomerase IIα gene TOP2A, which is linked to the HER2 gene on chromosome 17, has been reported to predict response to anthracyclines. TOP2A is coamplified with HER2 in 35% to 40% of patients with breast carcinoma. Simultaneous amplification of both HER2 and TOP2A has thus been proposed as a molecular predictor of anthracycline response. To test this theory, Tubbs et al conducted a post-hoc analysis of 1729 patients with high-risk node-negative or low-risk node-positive breast cancer who were participating in a study conducted by the Southwest Oncology Group. The objective was to evaluate the effects of HER2 and TOP2A amplification on response to chemotherapy with the anthracycline doxorubicin (Adriamycin) plus cyclophosphamide (AC).
Overall, HER2 amplification by classic criteria or HER2 deletion was not associated with survival, although disease-free survival and overall survival were shorter in patients whose tumors had HER2 amplification of 4.0 or greater. TOP2A and HER2 were coamplified in nearly all patients. TOP2A amplification or deletion also was not associated with survival. However, a high copy number for chromosome 17 was associated with increases in both disease-free survival (P =.016) and overall survival (P =.028). After adjustment for receptor status, tumor size, menopausal status, and number of positive nodes, however, the association was no longer significant.
This study paradoxically did not find any relationship between HER2 or TOP2A copy number and survival in patients with breast cancer treated with anthracycline-based chemotherapy. A combination of factors may have contributed to this outcome, including the decreased survival expected with HER2 or TOP2A amplification, and the increased response to anthracyclines characteristic of tumors with HER2 or TOP2A amplification.
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