FIRE-3 compared first-line therapy with FOLFIRI plus either cet or bev in KRAS exon 2 wildtype (wt) patients with mCRC. Identification of RAS mutations as a predictor for the efficacy of EGFR-antibody therapy raised the question of whether miR-21 as a potential regulator of the EGFR dependent pathway influences therapy outcome.
A reverse-transcription quantitative polymerase chain reaction (RT-qPCR) assay was used to identify quantitative miR-21 expression in formalin-fixed paraffin-embedded (FFPE) tumor samples of FIRE-3 patients. The median of miR-21 expression within the FIRE-3 population was determined and subsequently used to segment the population into low and high miR-21 expression groups. Overall response rate (ORR) between treatment groups was compared using Fisheŕs exact test. Median progression free (PFS) and overall survival (OS) were calculated using Kaplan-Meier estimation and compared through log-rank test.
RAS wt population with low miR-21 expression (n = 146) showed a significantly higher ORR when cet instead of bev was added to FOLFIRI chemotherapy (80.0% vs. 57.9%; p = 0.005). High miR-21 expression in RAS wt population (n = 149) showed no significant difference in ORR between treatment groups (74.6% vs. 64.0%; p = 0.21). ORR of RAS mutated patients with high miR-21 expression (n = 48) showed no significant difference between cet or bev when added to FOLFIRI (38.1% vs. 59.3%; p = 0.24). ORR (50.0% vs. 48.3%; p > 0.99) also showed no significant difference in RAS mutated patients with low miR-21 expression (n = 59). The following table presents statistical results of PFS and OS by comparing FOLFIRI plus cet versus FOLFIRI plus bev depending on RAS and miR-21 status.Table: 124P
|RAS wt||RAS mut|
|low miR-21 (n = 166)||high miR-21 (n = 167)||low miR-21 (n = 67)||high miR-21 (n = 62)|
|PFS (months)||10.6 vs. 10.3 p = 0.3||10.1 vs. 9.9 p = 0.5||8.5 vs. 12.2 p = 0.3||7.7 vs. 8.9 p = 0.044|
|OS (months)||35.8 vs. 25.9 p = 0.005||24.5 vs. 23.8 p = 0.4||20.2 vs. 26.0 p = 0.4||16.4 vs. 20.2 p = 0.2|
Along with RAS status, miR-21 expression level may be a promising predictive biomarker for anti-EGFR-therapy.
Clinical trial identification
NCT00433927; Study Start Date: January 2007; First Posted: February 12, 2007.
Legal entity responsible for the study
University Hospital, LMU Munich.
C. Vazart, K. Fontaine: Employee: Integragen. D.P. Modest: Honoraria and advisory boards: Amgen, Bayer, Merck, MSD, Roche, Servier, Taiho, BMS, Sirtex; Travel support/research funding: Amgen, Bayer, Merck, Roche, Servier. V. Heinemann: Advisory boards: Merck KgaA, Roche AG, Amgen, Sanofi, Lilly, Sirtex, Boehringer Ingelheim, Taiho, Servier; Honoraria for talks: Merck KgaA, Roche AG, Amgen, Sanofi, Sirtex, Servier, MSD; Travel expenses to meetings: Merck KgaA, Roche AG, Amgen, Sirtex, Servier, MSD, BMS; Funding of research activity: Merck KgaA, Pfizer, Amgen, Roche, Servier, Sirtex. S. Stintzing: Honoraria for talks and travel support: Amgen, Bayer, Roche, Merck KgaA, SANOFI, Lilly, Takeda. All other authors have declared no conflicts of interest.