Circulating tumor DNA profiling to reveal heterogeneity of EGFR-TKI resistance mechanisms in lung adenocarcinoma patients

Sub-category:
Circulating Biomarkers
Category:
Tumor Biology
Meeting:
2017 ASCO Annual Meeting
Abstract No:
11527
Poster Board Number:
Poster Session (Board #227)
Citation:
J Clin Oncol 35, 2017 (suppl; abstr 11527)
Author(s): Rongrong Chen, Jun Zhao, Xingsheng Hu, Pingping Dai, Yuting Yi, Zhenzhen Zhou,Yanfang Guan, Meiru Zhao, Tao Liu, Ling Yang, Xin Yi, Xuefeng Xia; Geneplus-Beijing, Beijing, China;Beijing University School of Oncology Beijing Institute for Cancer Research, Beijing, China;National Cancer Center /Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing Key Laboratory of Chinical Study on Anticancer Molecular Targeted Drugs,Beijing, China; Dalian Medical University, Dalian, China; The Methodist Hospital Research Institute,Houston, TX

Abstract Disclosures

Abstract

Background
EGFR-TKI therapy has significantly improved prognosis of NSCLC patients with EGFR sensitive mutation. However, almost all patients ultimately develop PD while receiving TKI treatment.Circulating tumor DNA (ctDNA) is promising as a minimally-invasive liquid biopsy for comprehensive analysis of molecular abnormalities.

Methods
A total of 254 advanced lung adenocarcinoma patients with signs of EGFR-TKI resistance were enrolled in the study. ctDNA was analyzed using next-generation sequencing based ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions,rearrangements, and somatic copy-number alterations across 59 genes.

Results
ctDNA profiling was possible for all patients, 172 patients had ≥ 1 ctDNA alteration(s). Median number of plasma somatic mutations was 2, predominantly located in EGFR and TP53, with MET,ERBB2 and PIK3CA followed. Of that, 30.6% of mutations detected in ctDNA were at a frequency below 1%. In exploring the mechanisms of TKI-resistance, we found TKI-sensitizing mutations were not detected in plasma of 138 patients (54.3%). Known mechanisms such as EGFR T790M/C797S mutation, activating mutations of PI3K-AKT-mTOR signaling, amplification of MET,activating mutation / amplification of ERBB2, activating mutation of KRAS, BRAF or mutations in EGFR EX20 other than T790M/C797S were identified in 59, 16, 8, 7, 3, 2, and 2 patients respectively. T790M/C797S was detected in 50.8% of patients with plasma positive for TKI-sensitizing mutations. Of note, C797S was only detected in patients treated with AZD9291.EGFR amplification were identified in 15 patients, though whether it would result in TKI-resistance was still controversial. Co-occurrence of resistance mechanisms were observed in 22 patients including 13 patients without TKI-sensitizing mutations.

Conclusions
There was a high frequency of inter and intra-patient heterogeneity of resistance mechanisms after EGFR TKI therapy. ctDNA can be used as a ‘ liquid biopsy ’ to facilitate the broad exploration of potential resistance mechanisms.