Comprehensive molecular analysis to predict the efficacy of chemotherapy containing bevacizumab in patients with metastatic colorectal cancer.

Abstract

Although bevacizumab is an important treatment for metastatic colorectal cancer (CRC), not all patients with CRC benefit from it; in unselected patient populations, only modest survival benefits have been reported. We evaluated clinical outcomes in 110 patients using comprehensive molecular characterization to identify biomarkers for a response to bevacizumab-containing treatment. The molecular analysis comprised whole-exome sequencing, ribonucleic acid sequencing, and a methylation array on patient tissues. Genomic and molecular characterization was successfully conducted in 103 patients. Six of 103 CRC samples were hypermutated, and none of the non-hypermutant tumors were microsatellite unstable. Among those 103 patients, 89 had adenocarcinoma (ADC), 15 were diagnosed with mucinous ADC, and six had signet-ring cell carcinoma (SRCC). Consensus molecular subtype (CMS) 2 was unique to ADC. Of the four SRCCs, two were CMS1, one was CMS4, and the other was CMS3. APC mutation status was a significantly enriched factor in responders to bevacizumab treatment. Fibroblast growth factor receptor (FGFR) 1/2 signaling was upregulated in non-responders, whereas cell cycle, transfer ribonucleic acid processing, nucleotide excision repair, and oxidative phosphorylation pathways were enriched in responders. In addition, IGF1 was differentially expressed in non-responders (log2 fold change = -1.43, p = 4.11 × 10-5, false discovery rate = 0.098), and FLT1 was highly methylated in non-responders (p = 7.55 × 10-3). When the molecular pathways were reanalyzed separately according to the backbone chemotherapy (FOLFOX vs. FOLFIRI), the significance of the molecular pathways varied according to the backbone chemotherapy. This study sought a subset of CRC patients with a distinct clinical response to chemotherapy containing bevacizumab. Our results need to be validated in a large group of homogenous patient cohort and examined according to the different chemotherapy backbones to create personalized therapeutic opportunities in CRC.