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. 2013 Mar 28:13:163.
doi: 10.1186/1471-2407-13-163.

Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials

George Fountzilas  1 , Urania Dafni, Mattheos Bobos, Vassiliki Kotoula, Anna Batistatou, Ioannis Xanthakis, Christos Papadimitriou, Ioannis Kostopoulos, Triantafillia Koletsa, Eleftheria Tsolaki, Despina Televantou, Eleni Timotheadou, Angelos Koutras, George Klouvas, Epaminontas Samantas, Nikolaos Pisanidis, Charisios Karanikiotis, Ioanna Sfakianaki, Nicholas Pavlidis, Helen Gogas, Helena Linardou, Konstantine T Kalogeras, Dimitrios Pectasides, Meletios A Dimopoulos
Affiliations

Evaluation of the prognostic role of centromere 17 gain and HER2/topoisomerase II alpha gene status and protein expression in patients with breast cancer treated with anthracycline-containing adjuvant chemotherapy: pooled analysis of two Hellenic Cooperative Oncology Group (HeCOG) phase III trials

George Fountzilas et al. BMC Cancer. .

Abstract

Background: The HER2 gene has been established as a valid biological marker for the treatment of breast cancer patients with trastuzumab and probably other agents, such as paclitaxel and anthracyclines. The TOP2A gene has been associated with response to anthracyclines. Limited information exists on the relationship of HER2/TOP2A gene status in the presence of centromere 17 (CEP17) gain with outcome of patients treated with anthracycline-containing adjuvant chemotherapy.

Methods: Formalin-fixed paraffin-embedded tumor tissue samples from 1031 patients with high-risk operable breast cancer, enrolled in two consecutive phase III trials, were assessed in a central laboratory by fluorescence in situ hybridization for HER2/TOP2A gene amplification and CEP17 gain (CEP17 probe). Amplification of HER2 and TOP2A were defined as a gene/CEP17 ratio of >2.2 and ≥2.0, respectively, or gene copy number higher than 6. Additionally, HER2, TopoIIa, ER/PgR and Ki67 protein expression was assessed by immunohistochemistry (IHC) and patients were classified according to their IHC phenotype. Treatment consisted of epirubicin-based adjuvant chemotherapy followed by hormonal therapy and radiation, as indicated.

Results: HER2 amplification was found in 23.7% of the patients and TOP2A amplification in 10.1%. In total, 41.8% of HER2-amplified tumors demonstrated TOP2A co-amplification. The median (range) of HER2, TOP2A and CEP17 gain was 2.55 (0.70-45.15), 2.20 (0.70-26.15) and 2.00 (0.70-26.55), respectively. Forty percent of the tumors had CEP17 gain (51% of those with HER2 amplification). Adjusting for treatment groups in the Cox model, HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with time to relapse or time to death.

Conclusion: HER2 amplification, TOP2A amplification, CEP17 gain and HER2/TOP2A co-amplification were not associated with outcome in high-risk breast cancer patients treated with anthracycline-based adjuvant chemotherapy.

Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12611000506998 and ACTRN12609001036202.

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Figures

Figure 1
Figure 1
REMARK diagram.
Figure 2
Figure 2
Representative FISH images in invasive breast carcinoma (IBC) cases, using the HER2/ TOP2A /CEP17 triple-color probes. In the first four panels (A-D) an IBC case is shown with normal status of the HER2 gene (A), TOP2A gene (B) and CEP17 (C). An IBC case (E-H) showing simultaneous amplification of the HER2 and TOP2A genes (E-F), as well as CEP17 gain (G). The third IBC case presented in panels (I-L) showed amplification of the HER2 gene (I), normal status of the TOP2A gene (J) and CEP17 gain (K). In the last case, co-amplification of the HER2 (M) and TOP2A genes (N) was found in tumor cells, accompanied by high-level CEP17 gain (O). The last panel for each case (panels D, H, L and P) depicts a merged image of the three-colored probes. Magnification x1000. CEP17, centromere 17 enumeration probe.
Figure 3
Figure 3
Distribution of HER2, TOP2A and CEP17 copies (A, B and C). Red line represents 6 gene copies (for A and B) and 3 copies for C.
Figure 4
Figure 4
Kaplan-Meier curves for DFS and OS according to HER2 gene status (log-rank test p-values).
Figure 5
Figure 5
Kaplan-Meier curves for DFS and OS according to TOP2A gene status (log-rank test p-values).
Figure 6
Figure 6
Kaplan-Meier curves for DFS and OS according to CEP17 gain (log-rank test p-values).
Figure 7
Figure 7
Kaplan-Meier curves for DFS and OS according to HER2/TOP2A co-amplification (log-rank test p-values).
Figure 8
Figure 8
Multivariate analyses presented by forest plots in terms of DFS (A) and OS (B).
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