Abstract 559: Next-generation sequencing of circulating tumor DNA in advanced lung cancer patients treated with the immune checkpoint inhibitor
Authors: Cho William C. , Hsiao Wen , Tan Kien Thiam , Li Jacky Y. , Chen Shu-Jen 
Published: July 2021

Introduction: Advanced lung cancer is a highly lethal disease worldwide. Recently, immune checkpoint inhibitors (ICIs) have made a significant breakthrough in the management of advanced lung cancer. Even though only a proportion of patients respond to ICI, the duration of such responders due to immunological memory is remarkable and is longer than other agents in refractory disease. Circulating tumor DNA (ctDNA) exhibits the potential in identifying genomic alterations and monitoring ICI treatment in advanced lung cancer patients. Identification of these genomic alterations may help to triage patients who will achieve better clinical benefit with minimal toxicity in therapies with ICIs.

Materials and Methods: ctDNA mutational changes were monitored in the longitudinal blood samples (n = 39) of seven stage IV lung adenocarcinoma patients between baseline and after ICI therapy (complete monitoring until disease progression or the end of follow-up). The mutation spectrum in these patients was detected by a next-generation sequencing panel consisting of 50 cancer-related genes.

Results: Among the seven patients, 15 variants were identified. All patients harbored at least one mutation, with an average of 2.1 mutations per patient. The most frequently mutated genes were TP53 (42.9%) and EGFR (42.9%). Baseline measurement showed eight mutations (EGFR E746V, L747P, A763_Y764insFQEA; TP53 R158C, A159S; ATM V2439G; ERBB2 Y772_A755dup; KRAS Q61H) in five patients. Seven mutations (TP53 I254fs, I255del, A276P, R280S; EGFR I740_K745dup; FGFR2 G261fs; STK11 D162fs) were observed in four patients following ICI therapy, suggesting that these alterations might be acquired during treatment. Most importantly, all patients harbored at least one clinically targetable gene mutation, including ATM, EGFR, ERBB2, STK11, and KRAS. Among these genes, the oncogenic mutations of EGFR and ERBB2 are FDA-recognized biomarkers predictive of response to specific targeted drugs in non-small cell lung cancer.

Conclusion: This study demonstrates that ctDNA monitoring is a useful method for molecular genotyping of advanced lung cancer patients. Genomic profiling of liquid biopsy may help to identify gene signatures for biomarkers predictive of response to treatment. The gene mutations identified in the individual patient of this study may help access the clinical benefit of therapy with ICIs or other drugs. The identification of druggable genes may potentially help to develop more effective treatment strategies. Considering the small percentage of patients receiving ICI therapy, this is a small-scale pilot study and a larger study is warranted.

Citation Format: William C. Cho, Wen Hsiao, Kien Thiam Tan, Jacky Y. Li, Shu-Jen Chen. Next-generation sequencing of circulating tumor DNA in advanced lung cancer patients treated with the immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 559.