Assessment of the topoisomerase I gene copy number as a predictive biomarker of objective response to irinotecan in metastatic colorectal cancer

Abstract

Objective. DNA topoisomerase I is a putative biomarker of irinotecan efficacy with clinical associations previously demonstrated at the protein level. The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene (TOP1) copy number and objective response following irinotecan treatment in patients with metastatic colorectal cancer. Materials and methods. Formalin-fixed, paraffin-embedded tumor samples from 78 patients, who received irinotecan monotherapy in second line, were included. TOP1 was assessed by fluorescence in situ hybridization using a technically validated dual-probe combination that hybridizes to TOP1, located at 20q12-q13.1, and to the centromere region of chromosome 20 (CEN-20). In univariate logistic regression models, the TOP1 signal count per cell and the TOP1/CEN-20 ratio were associated with objective response, which was evaluated according to RECIST v.1.1. Results. Gain of TOP1 was identified in 52.6% and 37.2% using the following cutoff values: TOP1 signal count per cell ≥3.6 and TOP1/CEN-20 ≥1.5, respectively. A borderline significant association (Odds ratio (OR): 1.62; p = 0.07) between a stepwise increase in the TOP1 signal count and objective response was demonstrated. In relation to the applied cutoff values, nonsignificant associations with objective response were identified for the TOP1 signal count (OR: 2.41; p = 0.23) and for the TOP1/CEN-20 ratio (OR: 2.05; p = 0.30). Conclusions. Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in larger tumor material, preferably in a randomized setting, is highly warranted.

Key Words::

• biomarker
• colorectal cancer
• DNA topoisomerase I
• irinotecan

Acknowledgments

The authors are due to Jan Lindebjerg, MD, Department of Pathology, Vejle Sygehus, 25 Kabbeltoft, DK-7100 Vejle, Denmark, for collecting the tumor samples and for reviewing the original diagnoses of carcinoma, and Birgit Roed Sørensen, Department of Pathology, Vejle Sygehus, 25 Kabbeltoft, DK-7100 Vejle, Denmark, for technical assistance.

Financial support: The Strategic Research Counsel, Danish Cancer Society, Kathrine og Vigo Skovgaards Foundation, Simon Fougner Hartmanns Family Foundation, IMK Almene Foundation, Fabrikant Einar Willumsens Memorial Trust, Director Ib Henriksens Foundation and Sawmill owner Jeppe Juhl and Wife Ovita Juhl Foundation.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.