Non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show a dramatic response to EGFR tyrosine kinase inhibitors (EGFR TKIs). However, most patients have a relapse within 1 year after the initiation of therapy. An EGFR secondary mutation T790M has been observed in approximately 50 % of such lung cancers that acquire resistance to EGFR TKIs. A critical question is whether the T790M mutation occurs as a result of treatment with EGFR TKIs or whether it exists prior to treatment and is selected during the course of therapy. However, its assessment can be challenging due to limited tissue availability and low sensitivity of the previously available methods. Here, we sought to detect the T790M using colony hybridization (CH) assay. This assay is able to detect mutant allele of 0.01 % in the background of wild-type allele. We assessed the T790M mutation in pretreatment specimens from 39 EGFR-TKI-treated patients with activating EGFR mutations. The T790M mutation was detected by CH in 31 of 39 patients (79 %). Median time to treatment failure (TTF) was 9 months in patients with pretreatment T790M, whereas it was 7 months in patients without the T790M mutation (P = 0.44). When we subdivided the patients with T790M into a strong and a modest positive subgroups in terms of the frequency of positive signals observed by our colony hybridization technique, seven patients with strong positivity had a TTF significantly longer than 8 patients without T790M (P = 0.0097) and 24 patients with modest positivity (P = 0.0019). Thus, the use of our highly sensitive method showed that a subgroup of patients with the EGFR mutation harbor rare T790M alleles before exposure to EGFR TKIs. However, contrary to our expectation, such patients had longer TTF.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1209. doi:1538-7445.AM2012-1209