Application of Liquid Biopsy to Non-small- Cell Lung Cancer Lung
المؤلف:
Marcello Ciaccio
المصدر:
Clinical and Laboratory Medicine Textbook 2021
الجزء والصفحة:
p471-472
2025-12-06
17
cancer is characterized by several driver mutations, the best known of which are EGFR point mutations, ALK-EML4 translocations, and RAS mutations. There are now targeted drugs, Tyrosine Kinase Inhibitors (TKIs), which act only if the tumor has some of these mutations (target therapy). These therapies have doubled patient survival. However, after treatment with these drugs, it is possible to observe a tumor progression caused by developing resistance mechanisms that make these therapies ineffective. In some cases, the molecular mechanisms of resistance have been identified and include specific mutations in the molecular targets of the drug itself. This is the case of EGFR in Non-small-Cell Lung Cancer (NSCLC). It has been shown that the molecular alterations of these tumors are not homogeneously distributed (tumor heterogeneity) and that metastases may present a mutational profile completely different from that of the primary tumor, making molecular analysis crucial when tumor progression is observed. Until now, tissue biopsy is considered the gold standard for molecular investigations but is limited by some factors, including its invasiveness, the impossibility of accessing some sites, tumor heterogeneity, and reduced patient compliance. In contrast, searching for specific mutations of the EGFR gene on plasma (ctDNA) is a noninvasive investigation that allows longitudinal monitoring by serial sampling over time. For these reasons, liquid biopsy is a valuable tool for selecting those patients with NSCLC who could benefit from treatment with TKIs.
The EGFR gene encodes for a transmembrane protein with an extracellular ligand-binding domain (EGF, TGFα), a single transmembrane hydrophobic domain, and an intracellular domain with tyrosine kinase activity. The activation of the receptor is followed by dimerization, autophosphorylation, and subsequent activation of several signal transduction pathways that regulate the processes of cell survival and/or apoptosis, angiogenesis (PIK3-AKT, JAK-STAT), cell differentiation and migration (RAS-RAF-MEK). The mechanism of action of TKI drugs involves their competition with ATP for binding to the receptor and blocking signal trans duction. However, in unselected patients, the response to TKIs is limited to 10% of cases. These therapies’ success depends on activating mutations, including exon 19 deletions (Ex19Del) and L858R, which account for 85% of EGFR mutations. These mutations are considered oncogenic. They constitutively activate the EGFR receptor without ligand, supporting the survival and antiapoptotic signal via PI3K- AKT and ERK-MAPK.
These mutations, in addition to being “activating” against EGFR, make the cell sensitive to TKIs because they increase the affinity of EGFR for the drug by 5–10 times compared to the wild-type receptor. This allows the inhibition of EGFR without toxicity at an epidermal and gastrointestinal level due to the blockade of EGFR in healthy cells. As already mentioned, using TKIs over time leads to the establishment of resistance in 60% of treated patients. From a molecular point of view, a possible cause is the occurrence of some mutations in EGFR, among which the best known is T790M. This mutation alters the ATP binding site to which TKIs also bind, thus canceling the sensitization induced by the other activating mutations. In addition to the mutations mentioned above, dozens of other mutations in the EGFR gene have been described whose effect on the activation status of the EGFR receptor and the action of TKIs has not yet been fully elucidated. These are uncommon and often associated with more frequent mutations, such as L858R or exon 19 deletions (Table 1).
Table1. Mutations affecting EGFR and indications for the TKI use
In 2014, the European Medicine Agency (EMA) approved the use of plasma to assess EGFR mutational status in patient candidates for TKIs treatment. Patients with locally advanced or metastatic NSCLC and positive for L858R activating mutations or exon 19 deletions on plasma are eligible for treatment with TKIs. Patients with TKI-treated NSCLC who have the T790M mutation on plasma are eligible for treatment with new third-generation TKIs, which have been shown to be effective in progression after treatment with first- and second-line TKIs caused by the occurrence of the EGFR T790M mutation.
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