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

Abstract

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.

ABCG2 Protein Levels and Association to Response to First-Line Irinotecan-Based Therapy for Patients with Metastatic Colorectal Cancer

“…This is in accordance with results published by others [9][10][11]. Using mRNA expression data from patients enrolled in the PETACC-3 study [12], it appeared that in the adjuvant setting of stage III colon cancer increased ABCG2 mRNA expression together with low Topoisomerase 1 (TOP 1) gene expression were associated with decreased benefit from the addition of irinotecan to 5-FU [13]. However, conflicting results are published for the association between efflux transporters, including ABCG2, and clinical outcome in various solids tumors [9,[14][15][16][17].…”

“…This calls for additional independent validation studies. However, our results from the adjuvant PETACC-3 study [ 13 , 29 ], strongly suggest a predictive value of ABCG2 mRNA expression in relation to adjuvant irinotecan treatment in chemo-naïve patients.…”

“…It is important to note that in the latter study, which investigated both the membrane (apical) and the cytoplasmic expression of ABCG2 protein in 225 primary CRC tissues, the authors only reported survival analysis for 69 patients. More recently, we have published on the association between ABCG2 mRNA expression and irinotecan effects in the PETACC-3 prospective randomized clinical trial [13], where patients with stage III colon cancer were randomized to adjuvant 5FU/LV or 5FU/LV and irinotecan [8]. In that study a trend for a predictive effect of ABCG2 mRNA expression as divided by the median ABCG2 mRNA expression, was observed in relation to benefit of irinotecan containing therapy.…”

“…In that study a trend for a predictive effect of ABCG2 mRNA expression as divided by the median ABCG2 mRNA expression, was observed in relation to benefit of irinotecan containing therapy. However, when combined with another putative irinotecan predictive biomarker, TOP-1 mRNA (TOP-1 is the target for irinotecan) expression [26], a significant association with recurrence-free survival and OS were observed [13].…”

Poziotinib Inhibits the Efflux Activity of the ABCB1 and ABCG2 Transporters and the Expression of the ABCG2 Transporter Protein in Multidrug Resistant Colon Cancer Cells

“…It has been reported that in CRC biopsy samples, there was a 10-fold increase in the ABCG2 transporter expression level after irinotecan treatment [14]. There are also data suggesting that the ABCG2 transporter is a potential biomarker for CRC [15,16]. Similarly, high ABCB1 expression levels were correlated with the developments of intrinsic drug resistance in colon cancer cell lines to daunorubicin and doxorubicin [17,18].…”