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Shuchen Chen
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.21 - Activating IDH Mutation as Resistance Mechanism to EGFR TKI in EGFR+ NSCLC (ID 835)
00:00 - 00:00 | Presenting Author(s): Shuchen Chen
- Abstract
Introduction
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are important enzymes in the tricarboxylic acid cycle, which catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate. The most frequent mutations, R132 (IDH1) , R100 (IDH1) , R140 (IDH2) and R172 (IDH2) involve the active site and result in neomorphic enzyme activity. IDH mutations have been observed as mutually exclusive in a number of cancer types, including sarcomas, hematologic malignancies, brain cancer and bile duct carcinoma. Implications of IDH mutations vary greatly by cancer type. In myelodysplastic syndromes and acute myeloid leukemia (AML), IDH1 mutations have been associated with worse outcome, shorter overall survival. However, in glioblastoma and astrocytoma, patients with IDH1 mutations have shown better overall survival than patients with wild-type IDH1. Up to now, IDH mutations are rarely reported in non-small cell lung cancer (NSCLC). The aim of this study is to investigate the mutation spectrum and prognosis of NSCLC patients harboring IDH mutations.
Methods
A total of 476 patients with NSCLC were recruited between July 2016 and November 2019 in Liaoning Cancer Hospital. Lung cancer tissue specimens and/or circulating cell-free DNA from patients were detected using hybridization-based targeted next-generation sequencing. The patients' clinical characteristics and treatment history were retrieved from the hospital database for further evaluation.
Results
8 patients (1.68%) with activating IDH gene mutations（IDH1_R132, IDH1_R100, IDH2_R140 and IDH2_R172）were detected in our study. 4 of which had concurrent activating EGFR mutations and had received EGFR tyrosine kinase inhibitors (TKIs). Patient 1 with IDH1_R132C and EGFR_L861Q had experienced disease progression after only 3.4 months (PFS) of gefitinib and then died in 3.6 months(OS: 7 months). Patient 2 with IDH2_R140W and EGFR_L858R had PFS of 4.3 months and OS of 9.5 months after gefitinib treatment. However, the PFS and OS of the first line EGFR-TKIs were 9~18.9 months and >24 months respectively. Patient 3 was firstly detected with EGFR_L858R (no IDH mutation) and treated with gefitinib. After acquiring gefitinib resistance, the patient was further treated with osimertinib. However, IDH1_R132C mutation appeared after osimertinib resistance, and then died in 2 months. Different from the patients above, patient 4 is an early stage (IIIA) lung adenocarcinoma with IDH1_R132C and EGFR_L858R diagnosed in July 2019. EGFR-TKI were used for postoperative adjuvant treatment and we were following up closely.
Conclusion
IDH mutations occurred rarely in NSCLC. Activating IDH mutations have been associated with short PFS and short OS. Additionally, they might act as a resistance mechanism to EGFR TKIs. When performing comprehensive analysis of primary and acquired resistance to EGFR TKIs, detecting IDH mutations will be important.
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P89 - Targeted Therapy - Clinically Focused - Translational (ID 266)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P89.07 - A Large-Scale Survey of IDH1/2 Mutation in Chinese Patients With NSCLC (ID 1452)
00:00 - 00:00 | Author(s): Shuchen Chen
- Abstract
Introduction
Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes, which catalyzes isocitrate to α-ketoglutarate (αKG). Mutations of IDH family were identified in multiple tumor types, including sarcomas, hematologic malignancies, brain cancer and bile duct carcinoma. And the IDH mutation proteins confer neomorphic activity, resulting in the conversion of αKG to D-2-hydroxyglutarate (2-HG) and epigenetic dysregulation via accumulation of 2-HG. Increasing preclinical studies and clinical trials indicating that IDH mutation inhibitors could reverse epigenetic dysregulation and induce cellular differentiation by decrease intracellular 2-HG accumulation. Recently, FDA have approved the first IDH1 Inhibitor, ivosidenib, for AML treatment. In previous study, we found the potential role of activating IDH1/2 mutations in mediating resistance to EGFR-TKI. Here we provide an overview of IDH1/2 mutations in a large-scale chinese lung carcinomas.
Methods
Lung cancer tissue specimens and/or circulating cell-free DNA from patients who had undergone molecular profiling at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory in China were retrospectively reviewed. IDH1, IDH2 and other lung cancer related genes were detected using hybridization-based targeted next-generation sequencing. Some patients’ clinical characteristics and treatment history were retrieved from the database for further evaluation.
Results
A total of 14429 Chinese lung cancer cases had undergone molecular profiling from January 2017 to November 2019. IDH gene mutation rate was 2.25% (324/14429), including IDH1_R132 (80 patients), IDH2_R140(47 patients), IDH1_I99(13 patients), IDH1_R100(7 patients), IDH1_L44 (7 patients) , IDH2_N136 (7 patients), IDH1_N53 (6 patients), IDH1_D79 (5 patients), IDH2_R172 (4 patients) and 166 others, which mainly occurred in exon 4(IDH1exon4: 45%, IDH2exon4: 27%). Activating IDH mutations（IDH1_R132, IDH1_R100, IDH2_R140 and IDH2_R172）were detected in 131 patients (0.86%), including 95 (73%) males and 36 (27%) females, with a median age of 63 (range 29-90). Among them, co-variations in TP53 (80, 61%), EGFR mut (44, 34%), EGFR amp (7, 5.3%), ERBB2 (19, 15%), RB1 (11, 8%), and ALK fusion (3, 2.3%) were observed. Analysis of IDH1/2 mutations from 1144 NSCLC patients, including 660 lung adenocarcinoma and 484 lung squamous cell carcinoma from TCGA cohort, 12 IDH1/2 mutations (1.05%) and 2 activating IDH1/2 mutations (0.18%) patients were found.
Conclusion
The IDH1/2 mutation rate in Chinese NSCLC patients is much higher than that in North American, which may define a subset of patients with NSCLC. In our another study, We found activating IDH1/2 mutation might act as a resistance mechanism to EGFR TKIs and have been associated with short PFS and short OS. Whether inhibition of mutant IDH1/2 activity might offer therapeutic benefits is unclear. The detail mechanism of resistance and appropriate therapeutic strategies remain to be further study.
