Abstract
BackgroundAmplification of the ERBB2 (Her-2/neu) oncogene, which occurs in approximately 25% of breast carcinomas, is a known negative prognostic factor. Available data indicate that a variable number of nearby genes on chromosome 17q may be co-amplified or deleted, forming a continuous amplicon of variable size. In approximately 25% of these patients, the amplicon extends to the gene for topoisomerase II alpha (TOP2A), a target for anthracyclines. We sought to understand the significance of these associated genomic changes for breast cancer prognosis and predicting response to therapy.Methods and patientsArchival tissue samples from 63 breast cancer patients with ERBB2 amplification, stages 0–IV, were previously analyzed with FISH probes for genes located near ERBB2. In the present study, the clinical outcome data were determined for all patients presenting at stages I–III for whom adequate clinical follow up was available.ResultsFour amplicon patterns (Classes) were identified. These were significantly associated with the clinical outcome, specifically, recurrence of breast cancer. The Amplicon class IV with deleted TOP2A had 67% (6/9) cases with recurrence, whereas the other three classes combined had only 12% (3/25) cases (p-value = 0.004) at the time of last follow-up. TOP2A deletion was also significantly associated with time to recurrence (p-value = 0.0002). After adjusting for age in Cox regression analysis, the association between TOP2A deletion and time to recurrence remains strongly significant (p-value = 0.002) whereas the association with survival is marginally significant (p-value = 0.06).ConclusionTOP2A deletion is associated with poor prognosis in ERBB2-amplified breast carcinomas. Clarification of the mechanism of this association will require additional study.
Highlights
Amplification of the ERBB2 (Her-2/neu) oncogene, which occurs in approximately 25% of breast carcinomas, is a known negative prognostic factor
TOP2A deletion is associated with poor prognosis in ERBB2-amplified breast carcinomas
The first targeted anti-neoplastic agent, Trastuzumab (Herceptin©), a monoclonal antibody to ERBB2, produces a response in approximately 15% of heavily pretreated patients with metastatic breast carcinomas (BC) as a single agent [5] and in combination with chemotherapy improved the overall survival of patients with metastatic BC by 5 months [6]
Summary
Amplification of the ERBB2 (Her-2/neu) oncogene, which occurs in approximately 25% of breast carcinomas, is a known negative prognostic factor. In approximately 25% of these patients, the amplicon extends to the gene for topoisomerase II alpha (TOP2A), a target for anthracyclines. ERBB2 amplification confers an unfavorable prognosis, its significance is less than that of the traditional prognostic factors – stage and grade. It seems that the prognosis and response to therapy varies considerably within the spectrum of ERBB2-amplified breast carcinomas (BC), indicating that they are biologically heterogeneous. Only a fraction of patients with ERBB2-amplified breast carcinomas respond to Trastuzumab, further evidence for heterogeneity among these tumors
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