Abstract
Colorectal carcinoma (CRC) is an heterogeneous disease in which different genetic alterations play a role in its pathogenesis and progression and offer potential for therapeutic intervention. The research on predictive biomarkers in metastatic CRC (mCRC) mainly focused on the identification of biomarkers of response or resistance to anti-epidermal growth factor receptor monoclonal antibodies. In this respect, international guidelines suggest testing mCRC patients only for KRAS, NRAS and BRAF mutations and for microsatellite instability. However, the use of novel testing methods is raising relevant issue related to these biomarkers, such as the presence of sub-clonal RAS mutations or the clinical interpretation of rare no-V600 BRAF variants. In addition, a number of novel biomarkers is emerging from recent studies including amplification of ERBB2, mutations in ERBB2, MAP2K1 and NF1 and rearrangements of ALK, ROS1, NTRK and RET. Mutations in POLE and the levels of tumor mutation burden also appear as possible biomarkers of response to immunotherapy in CRC. Finally, the consensus molecular subtypes classification of CRC based on gene expression profiling has prognostic and predictive implications. Integration of all these information will be likely necessary in the next future in order to improve precision/personalized medicine in mCRC patients.
Highlights
Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women [1]
Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit
The addition of cetuximab to FOLFOX-4 significantly improved progression free survival (PFS) and response in patients with KRAS wild-type tumors. This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced CRC
Summary
Colorectal cancer (CRC) is the third most common cancer in men and the second most common in women [1]. A series of retrospective analyses has shown that KRAS exon 2 mutations (codons 12 and 13) are associated with resistance to antiEGFR therapy in patients with mCRC, in the context of randomized studies in which the anti-EGFR cetuximab or panitumumab monoclonal antibodies were used alone or in combination with chemotherapy [10,11,12,13,14,15,16,17] (Table 2). Different drugs targeting the KRASG12C mutation are in clinical development in patients with solid tumors, including CRC.
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