A combined oncogenic pathway signature ofBRAF,KRASandPI3KCAmutation improves colorectal cancer classification and cetuximab treatment prediction

Abstract

ObjectiveTo develop gene expression profiles that characterise KRAS-, BRAF- or PIK3CA-activated- tumours, and to explore whether these profiles might be helpful in predicting the response to the epidermal growth factor receptor (EGFR) pathway inhibitors better than mutation status alone.DesignFresh frozen tumour samples from 381 colorectal cancer (CRC) patients were collected and mutations in KRAS, BRAF and PIK3CA were assessed. Using microarray data, three individual oncogenic and a combined model were developed and validated in an independent set of 80 CRC patients, and in a dataset from metastatic CRC patients treated with cetuximab.Results175 tumours (45.9%) harboured oncogenic mutations in KRAS (30.2%), BRAF (11.0%) and PIK3CA (11.5%). Activating mutation signatures for KRAS (75 genes), for BRAF (58 genes,) and for PIK3CA (49 genes) were developed. The development of a combined oncogenic pathway signature-classified tumours as ‘activated oncogenic’, or as ‘wildtype-like’ with a sensitivity of 90.3% and a specificity of 61.7%. The identified signature revealed other mechanisms that can activate ERK/MAPK pathway in KRAS, BRAF and PIK3CA wildtype patients. The combined signature is associated with response to cetuximab treatment in patients with metastatic CRC (HR 2.51, p<0.0009).ConclusionA combined oncogenic pathway signature allows the identification of patients with an active EGFR-signalling pathway that could benefit from downstream pathway inhibition.

Colorectal Cancer Heterogeneity and Targeted Therapy: A Case for Molecular Disease Subtypes

“…For example, mutations in the genes encoding the downstream KRAS effectors BRAF and PIK3CA are associated with a lack of cetuximab response (2). Moreover, gene expression signatures that correspond to KRAS, BRAF, and PIK3CA-activating mutations predict efficacy of anti-EGFR therapy, suggesting that it is a shared downstream component of these pathways that mediates the resistance (20). Recently, several other modes of resistance against anti-EGFR therapy have been detected that involve direct mutations within EGFR that impair binding of cetuximab, thereby preventing its effect (21).…”

DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?

“…As a final example, BRAF-mutant colon cancers have a distinctive gene expression pattern and have a poor prognosis upon relapse. However, some 10% of colon cancers do not have a BRAF mutation but share the gene expression pattern of BRAF-mutant tumors and also have a poor prognosis after relapse (23).…”

High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival

“…Sensitive biomarkers are crucial for early diagnosis and predicting prognosis [4,5]. Although several independent clinical prognostic factors for CRC have been identified, increasing evidence suggests that it is insufficient for predicting the clinical outcome of these patients [6][7][8]. To improve clinical outcome of colorectal cancer patients, novel molecular prognostic markers are needed as well as improved understanding of the mechanism of tumorigenesis.…”