T790M mutation was first discovered in patients who acquired resistance to gefitinib or erlotinib. It has then been shown to be a “second-site mutation” in approximately 50% of EGFR-mutant lung cancers that have developed acquired resistance to EGFR-TKI. However, in some patients, the T790M mutation was also detected as a primary event before drug exposure, at a frequency that is highly dependent on the technique used.
6554 DNA samples from lung cancer patients in Guangdong General Hospital during 2005-2014 was retrospectively collected for both EGFR sensitive mutation (exon 19 deletion and L858R mutation) and T790M mutation analysis, by either direct DNA sequencing or amplification refractory mutation system (ARMS).
Of 6046 patients whose tumor samples were collected before EGFR-TKI exposure, the frequency of de novo T790M mutation was as low as 0.5%. Gender (p = 0.026) and smoking status (p = 0.020) correlated significantly with T790M mutation frequency, whereas age, disease stage and histology type were not. The T790M mutation frequency was higher in female non-smoking patients compared with male smoking patients. Of 508 patients who had a post-TKI biopsy, the incidence of T790M mutation was 22.5%. And ARMS was shown to be more sensitive than direct DNA sequencing (27.8% vs 19.6%, p = 0.034). In mutation-positive subgroup, the prevalence of concomitant T790M was 1.4% in TKI-naÃ¯ve samples and 39.9% in TKI-treated samples. No difference between exon 19 deletions and L858R mutations existed in pre-TKI samples (1.1% vs 1.6%, p = 0.438), whereas a higher frequency of T790M mutation was found in exon 19 deletions in post-TKI samples (40.1% vs 28.3%, p = 0.034).
Tumors with a preexisting EGFR T790M mutation are extremely rare when tested by the traditional techniques. The observed mutation frequency suggests that the majority of T790M mutation emerge during EGFR-TKI exposure and it might occur more frequently in exon 19 deletions.
Clinical trial identification
All authors have declared no conflicts of interest.
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