JCES01.04 Liquid Biopsy in Monitoring Dynamic Changes of Driver Genes in Advanced NSCLC

Abstract

Epidermal growth factor receptor (EGFR) activating mutations in the tyrosine kinase domain serve as predictive biomarkers for EGFR-tyrosine kinase inhibitor (EGFR-TKI) treatment outcome for patients with advanced non-small cell lung cancer (NSCLC).1 However, due to the invasive procedures required to obtain tumor tissues, not all patients can provide enough high-quality tissues for EGFR mutation analysis. Circulating free DNA (cfDNA) in plasma provides a noninvasive substitute for tumor tissues. Several studies have reported a concordance rate between tumor and plasma > 90%, even reaching 97%, demonstrating the feasibility of detecting EGFR mutations in cfDNA.2-4 EGFR mutation status detection in cfDNA has been approved by the European Society for Medical Oncology and by China to be used with EGFR-TKI treatment for NSCLC.5,6 In addition to providing pretreatment information, plasma-based EGFR mutation detection makes it possible to monitor dynamic changes in this mutation during treatment. Several studies have reported a quantitative change in EGFR mutations during EGFR-TKI treatment by comparing pre- and post-treatment plasma, in which various types of plasma EGFR mutations were found.7,8 The quantity of the plasma EGFR mutation sometimes decreases, or sometimes decreases slowly or rapidly. Patients whose plasma EGFR mutations decrease rapidly usually exhibit a better response to EGFR-TKI treatment.8 However, these studies were not based on prospective clinical trials, therefore the number of patients who had serial plasma specimens tested during EGFR-TKI treatments was limited, and very few plasma specimens were collected as part of a pre-planned schedule. The only recent study on plasma EGFR mutation changes based on a prospective clinical trial was reported by Mok et al.9 In this phase III trial (FASTACT-2), patients received gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation-specific cfDNA levels decreased at cycle 3 and increased at the time of disease progression. Positive plasma EGFR mutant DNA at cycle 3 predicted a worse clinical outcome. In this study, the treatment was chemotherapy plus EGFR-TKI or placebo, not EGFR-TKI, and there was no information on the plasma EGFR mutation at other time points except at baseline, cycle 3, and at disease progression. The dynamic changing types of plasma EGFR mutations during the whole course of EGFR-TKI treatment and its correlation with clinical outcomes were not determined. To measure changes of plasma EGFR L858R mutation during EGFR-TKI treatment, and to determine its correlation with the response and resistance to EGFR-TKI, we conducted a study. This study was a pre-planned exploratory analysis of a randomized phase III trial conducted from 2009 to 2014 comparing erlotinib with gefitinib in advanced NSCLC harboring EGFR mutations in tumor (CTONG0901). Serial plasma samples were collected as a pre-planned schedule. This trial was conducted in Guangdong Lung Cancer Institute, China. Totally, 256 patients were enrolled in CTONG0901. One hundred and eight patients harbored L858R mutation in tumors and 80 patients provided serial blood samples as pre-planned scheduled. Patients were randomized to receive erlotinib or gefitinib. Serial plasma L858R in 80 patients was detected using quantitative polymerase chain reaction. Changing types of plasma L858R were analyzed using Ward's Hierarchical Clustering Method. Progression-free survival (PFS) and overall survival (OS) were compared between different types. As a whole, the quantity of L858R decreased and reached the lowest level at the time of best response to EGFR-TKI. In 61 patients, L858R increased to its highest level when disease progressed (Ascend Type), while in 19 patients, L858R maintained a stable level when disease progressed (Stable Type). Median PFS was 11.1 (95%CI, 6.6–15.6) and 7.5 months (95%CI, 1.4–13.6) in patients with Ascend and Stable Types, respectively (P = .023). Median OS was 19.7 (95%CI, 16.5–22.9) and 16.0 months (95%CI, 13.4–18.5), respectively (P = .050). This is the first report finding two different changing types of plasma L858R mutation during EGFR-TKI treatment based on a prospective randomized study. Different changing types were correlated with benefits from EGFR-TKI. The impact of plasma L858R levels at disease progression on subsequent treatment strategy needs further exploration. This study was recently published in Journal of Hematology&Oncology.10 In summary, liquid biopsy is very promising in monitoring dynamic changes of driver genes in advanced NSCLC, which promotes the development of precision medicine. 1. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 2009;361(10):947-957. 2. Kimura H, Suminoe M, Kasahara K, et al. Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib (IRESSA). Br. J. Cancer. 2007;97(6):778-784. 3. Douillard JY, Ostoros G, Cobo M, et al. Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating-free tumor DNA as a surrogate for determination of EGFR status. J. Thorac. Oncol. 2014;9(9):1345-1353. 4. Couraud S, Vaca-Paniagua F, Villar S, et al. Noninvasive diagnosis of actionable mutations by deep sequencing of circulating free DNA in lung cancer from never-smokers: a proof-of-concept study from BioCAST/IFCT-1002. Clin. Cancer Res. 2014;20(17):4613-4624. 5. European Medicines Agency. Summary of Product Characteristics 2014 [EB/OL], 10/14 update. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001016/WC500036358.pdf. 6. Iressa 250mg Leaflet professional China. CN52-086A. 20150203. 7. Sacher AG, Oxnard GR, Mach SL, et al. Prediction of lung cancer genotype noninvasively using droplet digital PCR (ddPCR) analysis of cell-free plasma DNA (cfDNA). Paper presented at: Journal Of Clinical Oncology 2014. 8. Marchetti A, Palma JF, Felicioni L, et al. Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients. J. Thorac. Oncol. 2015;10(10):1437-1443. 9. Mok T, Wu YL, Lee JS, et al. Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy. Clin. Cancer Res. 2015;21(14):3196-3203. 10. Zhou Q, Yang JJ, Chen ZH, et al. Serial cfDNA assessment of response and resistance to EGFR-TKI for patients with EGFR-L858R mutant lung cancer from a prospective clinical trial. Journal of Hematology&Oncology. 2016;9:86. liquid biopsy, epidermal growth factor receptor (EGFR), non-small cell lung cancer (NSCLC)