Clinical implication and usefulness of de novo EGFR T790M mutation in lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutation

Abstract

Detection rate of de novo EGFR T790 M mutation was increased up to 80% through recent ultrasensitive detection methods. Here, we investigated the clinical significance and its usefulness of detecting de novo EGFR T790 M using ultrasensitive droplet-digital polymerase chain reaction (ddPCR) method.In total, 102 cases diagnosed as lung adenocarcinoma with EGFR-tyrosine kinase inhibitor (TKI) sensitizing mutations (mEGFR) and had been treated with 1 st ~ 2 nd generation EGFR-TKI alone were enrolled for this study. De novo T790 M status was tested using the tissues at the initial diagnosis and positivity was defined as the ratio of T790 M/wild-type copies over 0.00294 by ddPCR.Seventy patients (68.6%) harbored the de novo T790 M. De novo T790 M was more frequently detected in cases with EGFR L858 R mutation than those with EGFR exon 19 deletion (E19d) mutations (P = 0.024). Forty-three patients underwent rebiopsy due to disease progression. The cases who experienced progression due to acquired T790 M were more likely to have E19d at initial diagnosis and the presence of de novo T790 M and the ratio of T790 M/wild-type copies did not relate to the emergence of acquired T790 M. On the other hand, the cases with a longer duration of disease-control by EGFR-TKI had higher change to get acquired T790 M mutation (P-value = 0.040).The presence of de novo T790 M has limitation in predicting disease progression by acquired T790 M, suggesting that identifying de novo T790 M through the ultrasensitive methods may not be necessary identifying patients who would be beneficial by 3rd-generation EGFR-TKI as the 1st line treatment.

Treatment pattern and outcomes in de novo T790M-mutated non-small cell lung cancer

“…The reported incidence of CNS involvement in EGFR -positive NSCLC ranges from 20% to 55% [ 22 – 26 ]. A co-existing EGFR mutation was noted in approximately half of the patients (19/40, 47.5%) in our study, similar to other studies [ 27 , 28 ].…”

Overcoming Resistance to Osimertinib by T790M Loss and C797S Acquisition Using Gefitinib in a Patient With EGFR-Mutant NSCLC: A Case Report

“…By conventional methods, the frequency reported is between 1% and 8% of all EGFR-mutant NSCLCs, although using PCR ultrasensitive methods the prevalence can increase to 34% to 80%. 8 Nevertheless, the exact frequency of de novo T790M mutation remains controversial.…”

The Role of De Novo T790M Mutation in The Origin of T790M Resistance Clone and in The Clinical Outcomes For Advanced EGFR-Mutant NSCLC Patients Receiving EGFR-TKIs

“…The most common EGFR-activating mutations are EGFR 19del and 21L858R [5], but the probability of pretreatment de novo T790M that coexists with 19del or 21L858R remains controversial. Several reports showed that the de novo T790M mutation likely coexists with EGFR 21L858R mutation [24,[30][31][32][33][34].…”

“…These techniques include matrix-assisted laser desorption ionization-time of ight mass spectrometry (MALDI-TOF MS), TaqMan assay, colony hybridization, peptide nucleic acid (PNA)-clamping PCR, and scorpion ampli ed refractory mutation system (ARMS). Droplet digital PCR (ddPCR) is a novel method that can detect rare mutations with ultra-sensitive quanti cation [13,14,[16][17][18][19][20][21][22][23][24]. De novo T790M has low frequency and the highest reported MAF for the mutation is between 0.01% and 0.1% [14,[21][22][23].…”