NGS-based oncogenic mutations analysis in advanced colorectal cancer patients improves targeted therapy prediction

Abstract

Background: Characterization of genetic alterations has been revealed to be important to predict the outcomes of targeted therapy in cancer. We here aimed to assess the mutation profiling of 526 colorectal cancer (CRC) patients by next-generation sequencing (NGS) to enable a more personalized anti-EGFR treatment.

Methods: Tumors were analyzed using NGS to determine hotspot mutations in 22 cancer-related genes.

Results: Mutations were observed in 13 genes in 436 of 526 (82.9%) tumors, and the most common mutations occurred in TP53 and KRAS. PIK3CA mutations usually coexisted with KRAS, NRAS or BRAF mutations. A higher frequency of concomitant PIK3CA mutations was observed in tumors with KRAS outside codon 13 mutations, with NRAS codon 61 mutations and with BRAF kinase-activated mutations. Moreover, KRAS, PIK3CA, AKT1 and FBXW7 mutations were statistically associated with some clinicopathological features, including location, age or metastasis of CRC patients. For RAS wild-type patients treated with cetuximab, longer progression-free survival (PFS) was observed in patients identified as wild type in all 22 genes compared with patients with mutations in one or more genes.

Conclusions: A wild-type result in all 22 cancer-related genes detected by NGS is associated with a better outcome of cetuximab treatment. Determining mutation patterns by NGS may aid to understand the molecular mechanisms of CRC and improve targeted therapy prediction.

Keywords: Colorectal cancer; Concomitant mutation; Next-generation sequencing; Oncogenic mutations; Targeted therapy.