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Abstract
Objective. We propose a repurposing strategy where anthracyclines are reintroduced to a subgroup of patients with metastatic colorectal cancer with the highest likelihood of response. In breast cancer, DNA topoisomerase II alpha gene (TOP2A) alterations predict incremental benefit of anthracyclines, but this association has not been investigated in colorectal cancer. Frequency analysis of TOP2A gene alterations in colorectal cancer and the association with prognosis are evaluated and the challenges of using a TOP2A/CEN-17 FISH probe combination are addressed. Material and methods. Formalin-fixed, paraffin-embedded material from 154 stage III colorectal cancer patients included in the RANX05 clinical trial was retrospectively assessed for TOP2A gene alterations using FISH. The TOP2A/CEN-17 ratio as well as the TOP2A gene copy number alone was used to define gene alterations and associations between gene status and outcomes were analyzed. Results. TOP2A gene gain was a frequent finding with 9.8 % having a total of ≥4 TOP2A copies per cell. According to the TOP2A/CEN-17 ratio, 10.5 % had TOP2A gene gain. Polysomy or gain of the centromere region of chromosome-17 was not as frequent as reported in breast cancer. No prognostic characteristic of TOP2A was identified. Conclusion. TOP2A gene gain is present in numbers relevant to identify a subgroup of patients who may benefit from anthracycline therapy. Based on the present findings, we will initiate a prospective clinical trial designed to evaluate this hypothesis in patients with metastatic colorectal cancer who have failed 5-fluorouracil and oxaliplatin chemotherapy.
Acknowledgments
Grant support from the Danish Cancer Society, the Danish Council for Strategic Research, the Danish Medical Research Council, the Simon Fougner Hartmanns Family Foundation, the IMK Almene Foundation, the Kathrine og Vigo Skovgaards Foundation, the Johannes Fog Foundation, the Einar Willumsens Memorial Trust, the Hede Nielsen Foundation, the Ib Henriksens Foundation, the Jeppe Juhl and wife Ovita Juhl Foundation, the Kornerup Foundation, the Aase and Ejnar Danielsen Foundation, and the Aage and Johanne Louis-Hansen Foundation.
Author Contributions
SBN participated in the conception and design of the study, acquisition of data, analysis of data and interpretation, and drafting of the manuscript. IJC performed the statistical analysis. DHS and NFJ participated in the data analysis and interpretation. SLN participated in the acquisition of data. HJN provided the tumor material and clinical database and assisted in the interpretation of data. BV participated in the interpretation of data and assisted in drafting of the manuscript. NB participated in the conception and design of the study, in the interpretation of data and assisted in drafting of the manuscript. All authors read and approved the final manuscript.
Declaration of interest: DHS is employed at Dako A/S, Glostrup, Denmark. The authors SBN, IJC, SLN, NFJ, HJN, BV, NB are report no conflicts of interest.