Trees, Forests, and Other Implications of a BRAF Mutant Gene Signature in Patients With BRAF Wild-Type Disease

Abstract

To identify patients with metastatic colorectal cancer (CRC) for whom the few available targeted therapies are appropriate,KRASand BRAFmutation status is increasingly used in routine clinical practice. However, clinicians and biologists alike are underwhelmed by this classification, given that the presence or absence of KRAS and BRAF mutations frequently fails to capture both the underlying biology for an individual tumor as well as the implications for prognosis and therapy.Indeed,apartfromtheconsistentlackofbenefitofepidermal growth factor receptor (EGFR) ‐directed therapy in patients with KRAS codon 12 mutations, the implications of KRAS mutations are unclear with respect to prognostic and predictive value. The most common mutation in BRAF involves the substitution of a glutamic acidforvalineatposition600(V600E)ofexon15;thisoccursinupto 15% of patients with colon cancer. 1 The predictive value of a BRAF mutationforbenefitfromEGFRinhibitorsisunclear;some 2-4 butnot all 5 reports demonstrate decreased response to EGFR inhibitors. In contrast to the conflicting prognostic data for KRAS mutations, multiple studies link the presence of BRAF mutations to poor prognosis relative to their BRAF wild-type counterparts in stage II and III disease, 6,7 as well as stage IV disease. 4,5,8,9 The interaction of BRAF mutations with known positive prognostic indicators such as microsatelliteinstability(MSI)islessclear,butsuggestsanattenuatingeffect. For example, despite the data that report improved prognosis in patients with microsatellite unstable tumors (MSI-H), BRAF may act as a sort of trump card, with worsened prognosis in a subset of patients withMSI-H,BRAFmutantcoloncancer. 9,10 Inaretrospectiveanalysis of the Cancer and Leukemia Group B (CALGB) trial 89803, an adjuvant chemotherapy trial for stage III colon cancer, patients with MSI-H and concomitant BRAF mutation had an intermediate prognosisflanked on one side by the poor survival that has been exhibited