A group of researchers has found a point mutation in the epidermal growth factor receptor (EGFR) gene that can predict tyrosine kinase inhibitor (TKI) sensitivity in patients with advanced lung adenocarcinoma.
TKI is a recent targeted therapy directed against cancer-specific molecules and signaling pathways, resulting in few nonspecific toxicities.
Tyrosine kinases are an especially important target because they play a crucial role in the modulation of growth factor signaling, a key aspect of cancer development.
In a study entitled “Mutant allele frequency predicts the efficacy of EGFR-TKIs in lung adenocarcinoma harboring the L858R mutation” and published in the Annals of Oncology journal, the team investigated the connection between the L858R mutation in patients with advanced EGFR-mutation positive lung cancer and their response to TKI therapy.
Using pyrosequencing and the Cycleave polymerase chain reaction (PCR) technique (two methods of DNA sequencing), the team analyzed 705 patients enrolled in the Shizuoka Lung Cancer Mutation Study between July 2011 and March 2013, and determined their EGFR mutation status using histological samples.
The researchers found that 94% of patients were positive for the L858R mutation, with a median L858R mutant allele frequency (MAF) of 18.5%, a parameter used to define the amount of genetic diversity in a particular population.
Additionally, analysis of 29 patients with advanced EGFR mutant-positive lung adenocarcinoma treated with gefitinib or erlotinib, two anti-EGFR TKI’s, demonstrated that the response rate to TKI treatment was significantly predicted by L858R MAF, with 79.1% of patients with a MAF of at least 9% vs 20.0% of patients with an MAF of less than 9% responding to TKI therapy.
The data from this study led researchers to conclude that, although patients with a MAF of 9% or less should not be automatically excluded from receiving TKI therapy, new treatment strategies, such as combination therapies, should be developed for these patients, since EGFR-TKI alone may not be effective enough.
Moreover, MAF should be carefully analyzed using sensitive and precise PCR techniques, since an adequate quantification can result in the identification of suitable candidates to decide whether or not a patient will present resistance during EGFR-TKI therapy.