Topoisomerase II alpha gene copy loss has adverse prognostic significance in ERBB2-amplified breast cancer: a retrospective study of paraffin-embedded tumor specimens and medical charts

<p>Abstract</p> <p>Background</p> <p>Amplification of the <it>ERBB2 </it>(<it>Her-2/neu</it>) 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 <it>topoisomerase II alpha </it>(<it>TOP2A</it>), a target for anthracyclines. We sought to understand the significance of these associated genomic changes for breast cancer prognosis and predicting response to therapy.</p> <p>Methods and patients</p> <p>Archival tissue samples from 63 breast cancer patients with <it>ERBB2 </it>amplification, stages 0–IV, were previously analyzed with FISH probes for genes located near <it>ERBB2</it>. 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.</p> <p>Results</p> <p>Four amplicon patterns (Classes) were identified. These were significantly associated with the clinical outcome, specifically, recurrence of breast cancer. The Amplicon class IV with deleted <it>TOP2A </it>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. <it>TOP2A </it>deletion was also significantly associated with time to recurrence (p-value = 0.0002). After adjusting for age in Cox regression analysis, the association between <it>TOP2A </it>deletion and time to recurrence remains strongly significant (p-value = 0.002) whereas the association with survival is marginally significant (p-value = 0.06).</p> <p>Conclusion</p> <p><it>TOP2A </it>deletion is associated with poor prognosis in <it>ERBB2</it>-amplified breast carcinomas. Clarification of the mechanism of this association will require additional study.</p