Abstract 2906: Intratumor heterogeneity of non-small-cell lung cancer with EGFR mutations
Authors: Qiao Sitan , Zhao Xin , Zhou Xinlan , Zhang Yaxiong , Zhang Li , Wu Kui 
Published: August 2019

Abstract
The mutation frequency of epidermal growth factor receptor (EGFR) is approximately 40% among Asian patients with NSCLC. Guidelines for the diagnosis and treatment of primary lung cancer in China recommended epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) as a first-line therapy for advanced NSCLC patients carrying EGFR mutation including exon 19 deletion (19Del) and L858R mutation on exon 21 (L858R). Although survival periods in clinical practice of EGFR-TKIs treatment have been getting longer, the patients with different subtype of EGFR mutations exhibited diverse drug response to EGFR-TKIs. The reasons why are still unclear.
In this study, we performed whole genome and panel sequencing of 239 spatially distinct regions from 42 lung adenocarcinoma of Chinese patients, of which 14 patients carried EGFR 19del mutation (EGFR-19Del), 15 patients carried L858R mutation (EGFR-L858R) and 13 patients did not carry any of these two mutation types (Control). We found the intra-tumor heterogeneity (ITH) levels were significantly higher in EGFR-mutant patients compared with control (P&lt;0.05). Average fraction of nonubiquitous mutation was 93.63%, 93.87% and 71.34% in EGFR-19Del, EGFR-L858R and Control, respectively. Remarkably, mutational process preferentially associated with different genes on different pathways were observed between two EGFR mutant subtypes, in which cell cycle related pathways were more likely to mutate in EGFR-L858R patients, while cell adhesion associated pathways were more susceptible to mutations in EGFR-19Del patients. Furthermore, two distinct evolutionary patterns were identified in EGFR-mutant patients based on whether TP53 mutations occurred simultaneously. In EGFR-mutant patients with stage I, the prognosis of patients with TP53 mutations was significantly worse than those without TP53 mutations. Meanwhile, we found that in the absence of TP53 mutations, more than 70% of EGFR-L858R patients showed multiple recurrent clonal driver mutations regardless of the stage of the patients. In contrast, EGFR-19Del patients only carried recurrent clonal driver mutation of EGFR in stage I, and began to accumulate other clonal driver mutations in later stage, which may indicate different evolutionary strategies underlying these two subtypes.
These preliminary results suggested that intratumor genetic diversity provided a substrate for tumor adaptation and evolution in the subtype of EGFR mutation. It could provide genetic basis for diagnosis and prognosis in EGFR-TKIs therapeutic response and to guide stratification of lung cancer treatment and clinical research in future.
Citation Format: Sitan Qiao, Xin Zhao, Xinlan Zhou, Yaxiong Zhang, Li Zhang, Kui Wu. Intratumor heterogeneity of non-small-cell lung cancer with EGFR mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2906.