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Open AccessArticle

An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial

1
Section of Molecular Disease Biology, Institute of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
2
Scandion Oncology, Symbion, 2100 Copenhagen, Denmark
3
RECETOX, Faculty of Science, Masarykova Univerzita, 625 00 Brno, Czech Republic
4
Digestive Oncology Department, University Hospitals Leuven and KU Leuven, 3001 Leuven, Belgium
5
University Institute of Pathology, University of Lausanne, 1011 Lausanne, Switzerland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to the study.
Cancers 2020, 12(4), 977; https://doi.org/10.3390/cancers12040977
Received: 24 March 2020 / Revised: 8 April 2020 / Accepted: 8 April 2020 / Published: 15 April 2020
(This article belongs to the Special Issue Novel Biomarkers and Molecular Targets in Cancer)
Biomarker-guided treatment for patients with colon cancer is needed. We tested ABCG2 and topoisomerase 1 (TOP1) mRNA expression as predictive biomarkers for irinotecan benefit in the PETACC-3 patient cohort. The present study included 580 patients with mRNA expression data from Stage III colon cancer samples from the PETACC-3 study, which randomized the patients to Fluorouracil/leucovorin (5FUL) +/− irinotecan. The primary end-points were recurrence free survival (RFS) and overall survival (OS). Patients were divided into one group with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (“resistant”) (n = 216) and another group including all other combinations of these two genes (“sensitive”) (n = 364). The rationale for the cut-offs were based on the distribution of expression levels in the PETACC-3 Stage II set of patients, where ABCG2 was unimodal and TOP1 was bimodal with a high expression level mode in the top quarter of the patients. Cox proportional hazards regression was used to estimate the hazard ratios and the association between variables and end-points and log-rank tests to assess the statistical significance of differences in survival between groups. Kaplan-Meier estimates of the survival functions were used for visualization and estimation of survival rates at specific time points. Significant differences were found for both RFS (Hazard ratio (HR): 0.63 (0.44–0.92); p = 0.016) and OS (HR: 0.60 (0.39–0.93); p = 0.02) between the two biomarker groups when the patients received FOLFIRI (5FUL+irinotecan). Considering only the Microsatellite Stable (MSS) and Microsatellite Instability-Low (MSI-L) patients (n = 470), the differences were even more pronounced. In contrast, no significant differences were observed between the groups when patients received 5FUL alone. This study shows that the combination of ABCG2 and TOP1 gene expression significantly divided the Stage III colon cancer patients into two groups regarding benefit from adjuvant treatment with FOLFIRI but not 5FUL. View Full-Text
Keywords: biomarkers; ABCG2; TOP-1; adjuvant irinotecan; colon cancer biomarkers; ABCG2; TOP-1; adjuvant irinotecan; colon cancer
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MDPI and ACS Style

Stenvang, J.; Budinská, E.; van Cutsem, E.; Bosman, F.; Popovici, V.; Brünner, N. An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial. Cancers 2020, 12, 977. https://doi.org/10.3390/cancers12040977

AMA Style

Stenvang J, Budinská E, van Cutsem E, Bosman F, Popovici V, Brünner N. An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial. Cancers. 2020; 12(4):977. https://doi.org/10.3390/cancers12040977

Chicago/Turabian Style

Stenvang, Jan; Budinská, Eva; van Cutsem, Eric; Bosman, Fred; Popovici, Vlad; Brünner, Nils. 2020. "An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial" Cancers 12, no. 4: 977. https://doi.org/10.3390/cancers12040977

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