Abstract
In the evolving molecular landscape of metastatic colorectal cancer, optimizing available tools to select patients to receive anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies is a modern challenge of colorectal oncologists. Several molecular biomarkers have been investigated in recent years as potential predictors of resistance to anti-EGFR agents in preclinical and clinical retrospective series. Nevertheless, none of them have been implemented in clinical practice due to the lack of a formal prospective demonstration. Here, we propose a literature review of molecular alterations associated with resistance to anti-EGFRs, underlining the reasons why their roadmap from laboratories to clinics was prematurely halted.
Highlights
Epidermal Growth Factor Receptor (EGFR) is the first discovered member of the family of ErbB tyrosine kinase receptors
Data from two meta-analyses, including results from key clinical trials testing the addition of an anti-EGFR to standard chemotherapy regimens or best supportive care (BSC) in BRAF wild-type and BRAF V600E-mutated metastatic colorectal cancer (mCRC), showed that the addition of an anti-EGFR in RAS and BRAF wild-type tumors provides a clear benefit, whereas the impact in BRAF V600E-mutant disease is limited or null [21,22], the interaction effect between anti-EGFR treatment and BRAF mutational status was not statistically significant, especially in terms of overall survival [22]
196 RAS and BRAF wild-type mCRC patients treated with anti-EGFR therapy
Summary
Epidermal Growth Factor Receptor (EGFR) is the first discovered member of the family of ErbB tyrosine kinase receptors. Targeting Epidermal Growth Factor Receptor by means of monoclonal antibodies (moAbs) (i.e., cetuximab and panitumumab) that inhibit endogenous ligands’ binding and lead to the inhibition of downstream signaling pathways, both as monotherapies or in combination with a chemotherapy backbone, allowed achieving clinically relevant therapeutic advances in metastatic colorectal cancer (mCRC) patients [1,2,3,4]. The optimization of the use of anti-EGFR agents in mCRC has acquired growing remark within the field From this perspective, a substantial improvement of the cost/benefit ratio was provided by the identification of RAS activating mutations, involving Kirsten Rat Sarcoma viral oncogene homolog (KRAS) and Neuroblastoma RAS viral oncogene homolog (NRAS) codons 12 and 13 of exon 2, 59 and 61 of exon 3, and 117 and 146 of exon 4, as predictors of intrinsic resistance to EGFR blockade [5,6]. We propose an updated literature review of the available evidence on molecular biomarkers (Figure 1), other than RAS status, which recently started their long winding roadmap toward implementation in clinical practice
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