Youjin Kim1, Boram Lee2, Joon Ho Shim2, Se-Hoon Lee3, Woong-Yang Park4, Yoon-La Choi5, Jong-Mu Sun1, Jin Seok Ahn1, Myung-Ju Ahn1, Keunchil Park1. 1. Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 2. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea; Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. 3. Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea. Electronic address: shlee119@skku.edu. 4. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea; Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; GENINUS Inc., Seoul, Korea. 5. Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul, Korea; Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Abstract
INTRODUCTION: EGFR-mutant NSCLC displays diverse outcomes to tyrosine kinase inhibitor (TKI) treatment. Because co-occurring genomic alterations might describe different biological subsets of patients with this cancer, exploring co-occurring genomic alterations that impact patients' outcomes using a comprehensive gene panel is potentially important. METHODS: This retrospective cohort study was conducted with the panel-sequencing data acquired from January 2014 to May 2017, and clinical outcome data collected until February 2018. This study includes all eligible patients who possess panel-sequencing data before treatment with first-/second-generation EGFR-TKIs (cohort 1) or third-generation EGFR-TKIs following initial EGFR-TKI failure (cohort 2). RESULTS: Seventy-five patients (mean [SD] age, 58.5 [11.0] years; 68.0% women) were included in cohort 1, and 82 patients (mean [SD] age, 57.3 [9.1] years; 67.1% women) were included in cohort 2. In cohort 1, alterations in TP53 were independently associated with worse progression-free survival (PFS) (hazard ratio [HR]: 2.02; 95% confidence interval [CI]: 1.04-3.93; p = 0.038) in multivariate analysis. In cohort 2, TP53 mutation was associated with significantly worse PFS (8.9 versus 12.8 months; p = 0.029). RB1 mutation was significantly associated with worse (median PFS, 1.9 versus 11.7 months; p < 0.001). PTEN mutation was associated with significantly worse PFS (2.6 versus 10.3 months; p = 0.001). MDM2 amplification was associated with worse PFS (6.6 versus 10.4 months; p = 0.025). In cohort 2, multivariate analysis revealed that alterations in TP53 (HR: 2.23; 95% CI: 1.16-4.29; p = 0.017), RB1 (HR: 5.62; 95% CI: 1.96-16.13; p = 0.001), PTEN (HR: 5.84; 95% CI: 1.56-21.85; p = 0.009), and MDM2 (HR: 2.46; 95% CI: 1.02-5.94; p = 0.046) were independently associated with worse PFS. CONCLUSIONS: Co-occurring genomic alterations detected by panel sequencing are associated with the clinical outcomes of EGFR-TKI treatment in NSCLC.
INTRODUCTION:EGFR-mutant NSCLC displays diverse outcomes to tyrosine kinase inhibitor (TKI) treatment. Because co-occurring genomic alterations might describe different biological subsets of patients with this cancer, exploring co-occurring genomic alterations that impact patients' outcomes using a comprehensive gene panel is potentially important. METHODS: This retrospective cohort study was conducted with the panel-sequencing data acquired from January 2014 to May 2017, and clinical outcome data collected until February 2018. This study includes all eligible patients who possess panel-sequencing data before treatment with first-/second-generation EGFR-TKIs (cohort 1) or third-generation EGFR-TKIs following initial EGFR-TKI failure (cohort 2). RESULTS: Seventy-five patients (mean [SD] age, 58.5 [11.0] years; 68.0% women) were included in cohort 1, and 82 patients (mean [SD] age, 57.3 [9.1] years; 67.1% women) were included in cohort 2. In cohort 1, alterations in TP53 were independently associated with worse progression-free survival (PFS) (hazard ratio [HR]: 2.02; 95% confidence interval [CI]: 1.04-3.93; p = 0.038) in multivariate analysis. In cohort 2, TP53 mutation was associated with significantly worse PFS (8.9 versus 12.8 months; p = 0.029). RB1 mutation was significantly associated with worse (median PFS, 1.9 versus 11.7 months; p < 0.001). PTEN mutation was associated with significantly worse PFS (2.6 versus 10.3 months; p = 0.001). MDM2 amplification was associated with worse PFS (6.6 versus 10.4 months; p = 0.025). In cohort 2, multivariate analysis revealed that alterations in TP53 (HR: 2.23; 95% CI: 1.16-4.29; p = 0.017), RB1 (HR: 5.62; 95% CI: 1.96-16.13; p = 0.001), PTEN (HR: 5.84; 95% CI: 1.56-21.85; p = 0.009), and MDM2 (HR: 2.46; 95% CI: 1.02-5.94; p = 0.046) were independently associated with worse PFS. CONCLUSIONS: Co-occurring genomic alterations detected by panel sequencing are associated with the clinical outcomes of EGFR-TKI treatment in NSCLC.
Authors: Xiaohong Han; Rongrong Luo; Lin Wang; Lei Zhang; Tao Wang; Yan Zhao; Shanshan Xiao; Nan Qiao; Chi Xu; Lieming Ding; Zhishang Zhang; Yuankai Shi Journal: Am J Cancer Res Date: 2020-12-01 Impact factor: 6.166