Perché parlare ancora di RAS nel colon retto.

RAS family proteins, including KRAS and NRAS, are important downstream effectors within the mitogen-activated protein kinase (MAPK) pathway that couples the epidermal growth factor receptor (EGFR) with intracellular signalling cascades. In colorectal cancer (CRC) somatic mutations in RAS genes lead to constitutive activation of the MAPK pathway and consequently the dysregulation of cell proliferation, migration, differentiation and survival. The introduction of monoclonal antibody drugs targeting EGFR, such as cetuximab and panitumumab, in combination to chemotherapy regimens has widened treatment options in metastatic CRC (mCRC). However, not all patients can benefit from these agents; in fact, patients whose tumours carry an activating mutations in exon 2 of the gene KRAS are much less likely to respond to antibodies that block EGFR signalling. Moreover, prospective-retrospective studies underlined that additional mutations in RAS family genes, namely in exons 3 and 4 of KRAS and in exons 2, 3 and 4 of NRAS, predicted a lack of response to anti-EGFR therapy. Based on these data, regulatory authorities in North America and Europe updated their guidelines and in particular the European Medicines Agency currently requires extended RAS analysis for prescription of cetuximab and panitumumab, restricting their use to patients with RAS wild-type mCRC. However this negative predictor role of RAS genes still leaves some questions open, making a current topic the discussion on EGFR signalling. In fact not all patients selected by RAS testing benefit from anti-EGFR therapies, suggesting a role for other genetic determinants of primary resistance. Among these latter the main candidate is the BRAF gene that plays a key regulatory role in the MAPK cascade, while other potential genes are those that act in the PTEN/PI3K/AKT pathway as well as in STAT pathway. Although there has been evaluation of these potential predictive biomarkers in patients with mCRC, RAS mutations represent the only clinically validated biomarkers. Moreover it is clear that a BRAF mutation is prognostic of a poor outcome irrespective of treatment. The American Society for Clinical Pathology, College of American Pathologists and Association for Molecular Pathology are currently developing revised guidelines regarding molecular markers for CRC. In particular, for patients who are being considered for targeted anti-EGFR therapy, the guideline still recommends mutational analysis of exons 2, 3, and 4 of both KRAS and NRAS. In addition, BRAF mutation status can be helpful to guide patient management, but information about tumour’s mismatch repair and microsatellite instability status are also necessary in order to interpret the potential clinical implications of a BRAF mutation. In the future, the comprehensive integrated analysis of whole EGFR signalling pathways will enable us to identify most of the mCRC patients who are unlikely to respond to anti-EGFR therapies. Prospectically the use of emerging technologies, such as next-generation sequencing allowing to screen simultaneously multiple somatic mutations in multiple genes in a single test run, might represent an optimal solution for rapid selection of mCRC patient to address to current and future target therapies.