Journal
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
Volume 88, Issue 3, Pages 477-493Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.critrevonc.2013.06.009
Keywords
EGFR mutations; Secondary resistance; Gefitinib; Erlotinib; Afatinib; Dacomitinib; Tyrosine kinase inhibitors; Non-small-cell lung cancer
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Funding
- [GRC-04]
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Activating mutation in exons 19 or 21 of epidermal growth factor receptor (EGFR) in non-small-cell lung cancers (NSCLC) are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib. Cancer patients harboring activating EGFR mutations benefit from first-line TKI therapy. Yet 10% of patients present a primary TKI resistance, while 50% of the others develop a secondary resistance within 9-12 months after starting TKI. The RECIST's definition of progression appears flawed when applied to EGFR-mutated NSCLC patients. Most often, tumor volume shrinking widely exceeds 30% during TKI response and kinetics of growth is low during relapse. At present, secondary resistance mechanisms associated with progression are better known: clonal selection of EGFR resistance mutation (T790M mutation in exon 20), amplification of transmembrane receptors for other growth factors (c-met, HER family, IGF1R, or AXL), downstream molecular alterations in EGFR signaling pathway (PI3K or PTEN), and epithelial mesenchymal transition or transdifferentiation to small-cell cancer. The best strategy for secondary resistance is not well-defined: maintaining TKI therapy, switching to chemotherapy, combining both treatments, or using new therapies targeting other signaling pathways. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
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