Influence of mRNA expression of fibroblast growth factor 2 (FGF2) in colorectal cancer (CRC) cell lines and in patients with metastatic colorectal cancer (mCRC) treated with FUFIRI or mIrOx (FIRE1).

3570 Background: Our aim was to evaluate fibroblast growth factor 2 (FGF2) expression in CRC cell lines exposed to 5-Fluorouracil (5-FU) and validate results with clinical data from mCRC patients receiving first-line treatment. Methods: 5-FU IC50 was determined in the CRC cell lines DLD1, LoVo, and HCT-15 applying MTT assays. mRNA expression of FGF2 was measured by RT-qPCR using HPRT as reference gene. Threshold values were determined by minimum p-value method. FGF2 expression was knocked down using sh (short hairpin) RNA in vitro with eGFP as control. In vitroresults were validated by data of the randomized FIRE1 trial (5-FU/LV/irinotecan [FUFIRI] vs. irinotecan/oxaliplatin [mIrOx] using Nanostring. 187 patients were included in this analysis. Results: Decreasing sensitivity of DLD1 [IC50 : 8.8 µM, 95% CI: 6.0 – 13.1 µM], LoVo [IC50 : 10.0 µM, 95% CI: 8.6 – 11.5 µM] and HCT-15 [IC50 : 15.4 µM, 95% CI: 13.3 – 17.9 µM] for 5-FU was associated with relative FGF2 expression levels [DLD1: 1.0; LoVo: 154.0; HCT-15: 92.4]. Knocking down FGF2 expression [rel. expression DLD1: sheGFP : 1.00, shFGF2 : 0.02, p = 0.009; LoVo: sheGFP : 1.00, shFGF2 : 0.19, p = 0.032] correlated with a significant decrease of IC50 for DLD1 [100 to 32% (95% CI: 29.9 – 34.8 %), p < 0.001] and LoVo [100 to 64% (95% CI: 55.2% - 74.1%), p = 0.001]. In FIRE1, high (n = 89) vs. low (n = 98) FGF2 expression was not correlated significantly with PFS [8.0 vs. 8.2 months, HR: 0.87, 95% CI: 0.65 – 1.17, p = 0.370], but with OS [17.9 vs. 23.5 months, HR: 0.70, 95% CI: 0.51 – 0.96, p = 0.025]. Higher FGF2 expression was significantly associated with worse objective response rate [PR and CR (n = 84) vs. SD and PD (n = 21); 24.85 vs. 31.89, p = 0.049]. Effects in FIRE1 were noticed in patients treated with FUFIRI as well as mIrOx. Conclusions: FGF2 expression might reflect chemosensitivity in CRC cell lines as a knockdown of FGF2 led to a decrease of IC50 for 5-FU in vitro. In FIRE1, high FGF2 expression was associated with lower response rate and overall survival significantly. Interfering the FGF2 system might be a modulator for acquired chemoresistance.