Topoisomerase II-Alpha gene copy number alterations in ERBB2-Positive primary breast carcinomas: A fluorescence in situ hybridization study

A Colomer1, N Erill1, M Górriz1,2, M Verdú2, R Roman1, R Ibáñez1, C Cordon-Cardo1 and X Puig1,2.

1BIOPAT. Biopatologia Molecular, SL, Grup Assistència, Barcelona, Spain and 2 Histopat Laboratoris, Barcelona, Spain.

Background: Topoisomerase II-alpha gene (TOP2A) aberrations have been recently pointed as predictive markers of anthracycline-based adjuvant chemotherapy in breast cancer. While coamplification of ERBB2 and TOP2A seems to define a subgroup of high-risk patients likely to benefit from anthracycline treatment, the significance of a patient having TOP2A deletions in the presence of ERBB2 amplification is still unclear. On the other hand, patients with normal TOP2A copy number have been suggested not to take advantage of treatment. In this retrospective study, we investigated the incidence of TOP2A genomic alterations in a cohort of primary breast invasive carcinomas previously characterized for ERBB2 genomic status by fluorescence in situ hybridization (FISH). Design: Our series included 32 formalin-fixed, paraffin-embedded tumors obtained from an equal number of women surgically treated for primary breast cancer in Barcelona, Catalonia. Concerning histopathology, lesions were classified as 29 ductal carcinomas, 2 lobular carcinomas and 1 medullary carcinoma. Assessment of ERBB2 and TOP2A copy number was independently done by dual-color FISH (Vysis) using a common centromeric probe (CEP17) and loci specific probes (HER2 LSI or TOP2A LSI, respectively). Relative copy numbers were calculated as ratios between mean number of LSI signals and mean number of CEP17 signals. Result: TOP2A genomic aberrations were identified in 25 out of 32 ERBB2-positive tumors (78%). TOP2A was coamplified with ERBB2 (TOP2A LSI/CEP17 ≥ 2.0) in 15 cases (47%), deleted (TOP2A LSI/CEP17 ≤ 0.7) in 10 cases (31%), while no alterations (0.8 ≤ TOP2A LSI/CEP17 ≤ 1.9) were found in 7 cases (22%). The mean ERBB2 LSI/CEP17 ratio was 4.6 (range 2.0-10), which was higher than the mean TOP2A LSI/CEP17 ratio of 2.8 (range 2.0-5.4). Seven out of 15 ERBB2 and TOP2A-coamplified tumors exhibited monosomy, whereas 6 were polysomic, and 2 were eusomic. No tumors exhibited monosomy amongst those with TOP2A deletions, 6 out of 10 were polysomic, and the 4 left were eusomic. Conclusion: These results are in agreement with those previously published reporting high incidences of TOP2A amplification and deletion within the group of ERBB2-amplified breast invasive carcinomas. In our series, FISH allowed identification of 78% ERBB2-positive patients likely to benefit from tailored and dose-escalated adjuvant anthracycline-based regimens.

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Abstract exhibited at the:

96th Annual Meeting of the United States and Canadian Academy of Pathology
San Diego, California, USA
March, 24-30, 2007

Abstract in:

Modern Pathology 2007; 20 (suppl. 2): 27A-28A.