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.
Highlights
Based on the results from the MOSAIC prospective randomized clinical trial (PRCT) [1], treatment of high risk Stage II and of Stage III colon cancer (CC) patients currently consists of5-Fluorouracil or Xeloda plus leucovorin (5FUL) plus oxaliplatin (FOLFOX or XELOX).Presently, irinotecan is not used in adjuvant treatment of primary CC but only in the metastatic setting [2]
PRCTs have not shown any added benefit from adjuvant irinotecan of CC cancer when co-administered with 5FUL, it is conceivable that specific subgroups of patients may benefit from the addition of irinotecan treatment but that these patients are concealed within the total patient population
With gender composition as exception, the present study population was representative of the global PETACC-3 study population
Summary
Irinotecan is not used in adjuvant treatment of primary CC but only in the metastatic setting [2] The reason for this is that none of two high-powered and independent PRCTs CALGB 89803 [4]), including high risk Stage II and Stage III colon cancer and randomizing patients to 5FUL ± irinotecan, could demonstrate a significant difference between the treatment groups with respect to recurrence free survival (RFS) or overall survival (OS). With a five-year recurrence rate of approximately 30% following adjuvant FOLFOX/XELOX treatment of Stage III CC patients [1], there is obviously a need for other adjuvant treatment modalities using drugs with different mechanisms of action than FOLFOX/XELOX. PRCTs have not shown any added benefit from adjuvant irinotecan of CC cancer when co-administered with 5FUL, it is conceivable that specific subgroups of patients may benefit from the addition of irinotecan treatment but that these patients are concealed within the total patient population
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