Identification of a Poor Prognosis BRAF-Mutant–Like Population of Patients with Colon Cancer: a step forward towards personalised therapy

Erika Martinelli

The development of colorectal cancer is a multistep process that occurs because of the accumulation of several genetic alterations, including chromosomal abnormalities, gene mutations, and epigenetic modifications involving several genes that regulate proliferation, differentiation, apoptosis, and angiogenesis. Of the various genetic alterations, an important molecular target for metastatic colorectal cancer (CRC) treatment is the epidermal growth factor receptor (EGFR), and the activation of its downstream pathway KRAS/BRAF/MEK/ERK cascade is believed to occur frequently in colorectal cancer on the basis of the observed 40% incidence of KRAS mutations and 10% to 15% incidence of BRAF mutations. KRAS and BRAF mutations are mutually exclusive, which has long been interpreted as a sign of functional redundancy.

Several reports suggested that tumours harbouring BRAF mutations have different clinical and histopathological features when compared with tumours harboring KRAS mutations. BRAF mutations are significant negative prognostic biomarkers in patients with recurrent colorectal cancer across all disease stages. Importantly, BRAF mutant metastatic colorectal cancer does not respond to any current chemotherapy, and the outcome of patients with BRAF mutant CRC is similar to that of untreated patients.

Little is  known about the biology of BRAF mutant (BRAFm) colorectal cancer detected  by gene expression classifier: the  manuscript proposed by Popovici V et al. describes a BRAF gene signature which allows accurate identification of BRAF mutant samples, and which, when applied to BRAF wild-type tumours, identified additional colon cancer samples manifesting a similar gene expression pattern.

A set of 668 stage II and III colorectal cancer samples from the PETACC-3 trial (Pan-European Trials in Alimentary Tract Cancers) were studied and a 64 gene-based classifier was developed with 96% sensitivity and 86% specificity for detecting BRAF mutant colorectal cancer. When the BRAF classifier was applied to the whole population, it identified a BRAF wild-type subpopulation, with similar gene expression and prognostic characteristics. Approximately 62% of these BRAFm-like tumours were KRAS mutant (30%), with the rest being KAS/BRAF wild-type (13%). The BRAFm-like tumours displayed a gene expression pattern and had poor overall survival and survival after relapse, similar to those observed in BRAF-mutant patients. In Popovici’s data, the BRAFm- like population represented 18% of CRCs.

This intriguing finding suggests a common biology between these tumours, not predicted by the mutation status, and manifesting a coherent clinical behaviour which suggests that a new definition of CRC subgroups is needed.

Therefore the authors conclude that current classifications of tumours as KRAS- or BRAF-mutant or mitogen-activated protein kinase–active versus non-active are inadequate to describe the whole underlying biology and clinical behaviour which should be differently targeted.

Although the analysis proposed by Popovici is retrospective, it provides an important tool for new trial designs within which patients are assigned to combinations of cytotoxic or targeted therapies on the basis of gene signature rather than on KRAS and BRAF mutational status.

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