Advances in molecular biology have markedly increased our understanding of the heterogeneous molecular landscape of colorectal cancer (CRC). Up to 15% of CRCs harbor the BRAF p.V600E somatic mutation (BRAFmt), a well-established negative prognostic marker in patients with metastatic CRC (mCRC). The BEACON CRC trial set a new standard of care in patients with progressive BRAFmt cancers, consisting of the combination of encorafenib and cetuximab. On these bases, BRAF mutational testing is now recommended in patients with mCRC. However, efforts are needed to further stratify patients carrying this mutation. Here, we discuss the heterogeneous pathologic and molecular landscape of BRAFmt CRCs, focusing on the promises and pitfalls of molecular diagnostics, on novel biomarkers to improve patients' stratification and on the current diagnostic scenario for CRC. We believe that a better stratification based on histopathological features and novel molecular biomarkers should be performed to optimize patient management and therapeutic decision-making.
