Association of MAPK signaling subtypes with prognostic benefit for bevacizumab in left-sided metastatic colorectal cancer (mCRC) patients treated with FOLFIRI + cetuximab / bevacizumab (FIRE-3 trial).

Abstract

3584 Background: We investigated the role of the MAPK pathway by mRNA expression profiles in microarrays of the FIRE-3 trial as it was formerly associated with prognosis. Methods: 451 patients provided eligible mRNA material for subsequent analyses of the MAPK pathway (295 genes). Non-negative matrix factorized (NMF) clustering for normalized mRNA microarray data (Almac Inc, Xcel Array) was performed for 2 to 6 ranks against randomized controls. Linear models with adjustment for multiple testing showed differential gene expression between groups. Single sample gene set enrichment analysis (ssGSEA) was used to compare differentially enriched hallmarks of cancer gene sets. Kaplan Meier method, log rank test and Cox regression analyses were performed to estimate overall (OS) and progression free survival (PFS) between MAPK subtypes. Results: NMF clustering built two groups of MAPK mRNA expression (coph: 0.91, silh: 1.00) without cohort-based bias in principal component analysis. Group MAPK1 (n = 238) was significantly associated with CMS2 (66.4 %), group MAPK2 (n = 213) with CMS4 (67.6 %, p < 0.0001). 5.551 of 23.561 genes were significantly differentially expressed between MAPK subtypes. 49 cancer hallmark gene sets were significantly differentially enriched in ssGSEA ( MAPK1: myc targets, DNA repair, cell cycle, PI3K- AKT- mTOR pathway upregulation; MAPK2: EMT-related signatures, TGFß pathway, angiogenesis upregulation among others). In overall analysis, MAPK1 showed slightly better outcome than MAPK2 (OS: HR: 0.80, 95% CI: 0.65 – 0.99, p = 0.049; PFS: HR: 0.81, 95% CI: 0.66 – 1.00, p = 0.05). However, MAPK1 was significantly more favourable for bevacizumab treatment in OS ( MAPK1: 30.8 m, MAPK2: 19.4 m, HR: 0.56, 95% CI: 0.39 – 0.81, p = 0.002) and PFS ( MAPK1: 11.7 m, MAPK2: 9.8 m, HR: 0.68, 95% CI: 0.48 – 0.98, p = 0.038) in left sided tumors, while no difference was seen for cetuximab treatment, RAS and BRAF status. Conclusions: mCRC subtypes by MAPK mRNA expression might contain prognostic information for the treatment with bevacizumab beyond mutational status in patients with left sided tumors of the FIRE-3 trial.