ORCID Profile
0000-0003-1004-6048
Current Organisation
Genome Institute of Singapore
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480718
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2021
DOI: 10.1158/1078-0432.CCR-20-4607
Abstract: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance. We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M−) disease. Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M− tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal lifications, whole-genome doubling and nonaging mutational signatures in T790M− tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M− and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping ergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480712.V1
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480718.V1
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480715
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480715.V1
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530516
Abstract: AbstractPurpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in i EGFR /i -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in i EGFR /i sup T790M /sup -negative resistance. Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic i EGFR /i -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M sup + /sup ) and -negative (T790M sup − /sup ) disease. Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M sup − /sup tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as i TP53 /i alterations, 3q chromosomal lifications, whole-genome doubling and nonaging mutational signatures in T790M sup − /sup tumors. Almost half of resistant tumors were further classified as immune sup hot /sup , with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M sup − /sup and T790M sup + /sup disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping ergent TKI resistance and outcome trajectories in i EGFR /i -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22480712
Abstract: Supplementary Data from Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-05-2022
DOI: 10.1200/JCO.21.01647
Abstract: With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women. In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration. Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non- BRCA pathogenic variant carriers (area under receiver operating curve, 0.80 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( P value = .003), thereby improving the overall efficacy. Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530516.V1
Abstract: AbstractPurpose: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in i EGFR /i -mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in i EGFR /i sup T790M /sup -negative resistance. Experimental Design: We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic i EGFR /i -mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M sup + /sup ) and -negative (T790M sup − /sup ) disease. Results: Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M sup − /sup tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as i TP53 /i alterations, 3q chromosomal lifications, whole-genome doubling and nonaging mutational signatures in T790M sup − /sup tumors. Almost half of resistant tumors were further classified as immune sup hot /sup , with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M sup − /sup and T790M sup + /sup disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients. Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping ergent TKI resistance and outcome trajectories in i EGFR /i -mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential. /
No related grants have been discovered for Alexis Khng.