ORCID Profile
0000-0002-4655-0206
Current Organisation
National Cancer Centre Singapore
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Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-07-2011
Publisher: Springer Science and Business Media LLC
Date: 05-2018
DOI: 10.1038/S41586-018-0130-2
Abstract: Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types
Publisher: Springer International Publishing
Date: 2014
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: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C4AN00355A
Abstract: We demonstrate the high-throughput and high-resolution separation of rare circulating tumor cells (CTCs) from blood using a multiplexed spiral microfluidic device.
Publisher: Royal Society of Chemistry (RSC)
Date: 2014
DOI: 10.1039/C3LC50617G
Abstract: The enumeration and characterization of circulating tumor cells (CTCs), found in the peripheral blood of cancer patients, provide a potentially accessible source for cancer diagnosis and prognosis. This work reports on a novel spiral microfluidic device with a trapezoidal cross-section for ultra-fast, label-free enrichment of CTCs from clinically relevant blood volumes. The technique utilizes the inherent Dean vortex flows present in curvilinear microchannels under continuous flow, along with inertial lift forces which focus larger CTCs against the inner wall. Using a trapezoidal cross-section as opposed to a traditional rectangular cross-section, the position of the Dean vortex core can be altered to achieve separation. Smaller hematologic components are trapped in the Dean vortices skewed towards the outer channel walls and eventually removed at the outer outlet, while the larger CTCs equilibrate near the inner channel wall and are collected from the inner outlet. By using a single spiral microchannel with one inlet and two outlets, we have successfully isolated and recovered more than 80% of the tested cancer cell line cells (MCF-7, T24 and MDA-MB-231) spiked in 7.5 mL of blood within 8 min with extremely high purity (400-680 WBCs mL(-1) ~4 log depletion of WBCs). Putative CTCs were detected and isolated from 100% of the patient s les (n = 10) with advanced stage metastatic breast and lung cancer using standard biomarkers (CK, CD45 and DAPI) with the frequencies ranging from 3-125 CTCs mL(-1). We expect this simple and elegant approach can surmount the shortcomings of traditional affinity-based CTC isolation techniques as well as enable fundamental studies on CTCs to guide treatment and enhance patient care.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-2022
DOI: 10.1200/PO.22.00278
Abstract: HER2-altered non–small-cell lung cancer (NSCLC) represents a erse subgroup, including mutations, lifications, and overexpression. However, HER2 exon 20 insertion mutations are emerging as a distinct molecular subtype with expanding therapeutic options. We describe the molecular epidemiology and genomic features of HER2-altered NSCLC in an Asian tertiary cancer center. We identified patients with HER2-mutated NSCLC in our institutional database, collating clinicopathological features and treatment outcomes. The genomic landscape of human epidermal growth factor receptor 2 ( HER2)–mutated NSCLC was further evaluated using whole-exome sequencing (WES) data from combined local and publicly available data sets. HER2 lification and overexpression as selection biomarkers in NSCLC were further interrogated using HER2 immunohistochemistry and correlations with WES and RNA sequencing data. Among 1,252 patients with consecutive lung adenocarcinoma undergoing routine next-generation sequencing, the prevalence of HER2 mutations was 3.1%—exon 20 insertion mutations comprised 2.7%. We examined the clinicopathological features in 55 patients with HER2-mutated NSCLC comprising 40 exon 20 insertion and 15 nonexon 20 insertion mutations. The most common exon 20 insertion mutation was HER2 Y772_A775dup in 30 (75%), followed by HER2 G776delinsVC in five patients (13%). There were limited responses to HER2-directed therapies apart from trastuzumab-deruxtecan, and no responses were seen with immunotherapy monotherapy. Evaluating the genomics features of HER2 exon 20 insertion mutations using WES data revealed low tumor mutational burden (TMB), low incidence of cancer driver comutations, and a predominance of aging mutational signature—similar to EGFR-mutated tumors. In contrast, uncommon (or nonexon 20 insertion) HER2-mutated tumors resembled EGFR wild-type tumors with higher TMB, higher frequency of cancer driver comutations, and greater presence of smoking and APOBEC mutational signature. Finally, in evaluating HER2 immunohistochemistry in all lung adenocarcinoma, there was significant discordance comparing different scoring systems and poor correlation with HER2 RNA expression and HER2 lification. The incidence of HER2 mutations is 3.1% in East Asian nonsquamous NSCLC. HER2 exon 20 insertion–mutated tumors appear genomically distinct from uncommon (nonexon 20 insertion) HER2 mutations, the latter demonstrating higher TMB, co-occurring drivers, and predominant nonaging mutational signature. The therapeutic implications of the genomic and clinical features of HER2-mutated NSCLC warrant further investigation.
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: Public Library of Science (PLoS)
Date: 07-07-2014
Publisher: Informa UK Limited
Date: 30-11-2022
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2021
DOI: 10.1200/PO.20.00261
Abstract: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the In idualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. In idualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.
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: Elsevier BV
Date: 2023
DOI: 10.1016/J.EJCA.2022.10.012
Abstract: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC. Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method. 455 patients were included (267 EGFR-mutated, EGFR-M+ 188 EGFR-wildtype, wt). Median age at diagnosis was 65 years, 52.3% (238/455) of patients were males, 62.9% (286/455) of patients were never-smokers and 92.5% (421/455) of patients had R0 resection. Stage IA comprised 42.4% (193/455) of patients, Stage IB comprised 23.1% (105/455) of patients, Stage IIA comprised 10.8% of patients (49/455), Stage IIB comprised 5.1% of patients (23/455) and Stage IIIA comprised 18.7% (85/455) of patients. Among EGFR-M+, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-M+ and EGFR-wt was 45.3% (121/267) and 54.8% (103/188) respectively (p = 0.047). At median follow-up of 47 months, 178 patients had relapsed. Among EGFR-M+, 2-year DFS comparing PD-L1 <1% and PD-L1 ≥1% was 78.1% and 67.6% (p = 0.007) while 5-year OS was 59.5% and 42.8% (p = 0.001), respectively. Controlling for age, gender, lymphovascular invasion, adjuvant therapy and resection margin status, PD-L1 ≥1% (hazard ratio, HR 2.18, 95% CI 1.04-4.54, p = 0.038), stage IIB (HR 7.78, 95% CI 1.72-35.27, p = 0.008) and stage IIIA (HR 4.45, 95% CI 1.44-13.80, p = 0.01) emerged as independent predictors of inferior OS on multivariable analysis. In exploratory analysis, genomic analysis of 81 EGFR-M+ tumours was performed. PD-L1 ≥1% tumours had significantly higher rates of TP53 mutations (36.1% versus 15.6%, p = 0.04), with predominantly missense mutations. PD-L1 ≥1% is an independent predictor of worse OS among early-stage EGFR-mutated NSCLC and is associated with inferior DFS regardless of EGFR status. PD-L1 score as a risk stratification factor should be evaluated in prospective adjuvant studies among EGFR-mutated NSCLC.
Publisher: Springer Science and Business Media LLC
Date: 12-02-2013
DOI: 10.1038/SREP01259
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. /
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: 10.1158/1078-0432.22480718.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: Elsevier BV
Date: 2010
Publisher: Springer Science and Business Media LLC
Date: 18-09-2017
DOI: 10.1038/NM.4401
Abstract: Targeting EGFR is a validated approach in the treatment of squamous-cell cancers (SCCs), although there are no established biomarkers for predicting response. We have identified a synonymous mutation in EGFR, c.2361G>A (encoding p.Gln787Gln), in two patients with head and neck SCC (HNSCC) who were exceptional responders to gefitinib, and we showed in patient-derived cultures that the A/A genotype was associated with greater sensitivity to tyrosine kinase inhibitors (TKIs) as compared to the G/A and G/G genotypes. Remarkably, single-copy G>A nucleotide editing in isogenic models conferred a 70-fold increase in sensitivity due to decreased stability of the EGFR-AS1 long noncoding RNA (lncRNA). In the appropriate context, sensitivity could be recapitulated through EGFR-AS1 knockdown in vitro and in vivo, whereas overexpression was sufficient to induce resistance to TKIs. Reduced EGFR-AS1 levels shifted splicing toward EGFR isoform D, leading to ligand-mediated pathway activation. In co-clinical trials involving patients and patient-derived xenograft (PDX) models, tumor shrinkage was most pronounced in the context of the A/A genotype for EGFR-Q787Q, low expression of EGFR-AS1 and high expression of EGFR isoform D. Our study reveals how a 'silent' mutation influences the levels of a lncRNA, resulting in noncanonical EGFR addiction, and delineates a new predictive biomarker suite for response to EGFR TKIs.
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: Springer Science and Business Media LLC
Date: 05-2019
DOI: 10.1038/S41591-019-0423-5
Abstract: Understanding cellular metabolism holds immense potential for developing new classes of therapeutics that target metabolic pathways in cancer. Metabolic pathways are altered in bulk neoplastic cells in comparison to normal tissues. However, carcinoma cells within tumors are heterogeneous, and tumor-initiating cells (TICs) are important therapeutic targets that have remained metabolically uncharacterized. To understand their metabolic alterations, we performed metabolomics and metabolite tracing analyses, which revealed that TICs have highly elevated methionine cycle activity and transmethylation rates that are driven by MAT2A. High methionine cycle activity causes methionine consumption to far outstrip its regeneration, leading to addiction to exogenous methionine. Pharmacological inhibition of the methionine cycle, even transiently, is sufficient to cripple the tumor-initiating capability of these cells. Methionine cycle flux specifically influences the epigenetic state of cancer cells and drives tumor initiation. Methionine cycle enzymes are also enriched in other tumor types, and MAT2A expression impinges upon the sensitivity of certain cancer cells to therapeutic inhibition.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.LUNGCAN.2019.11.022
Abstract: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients. We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue s les were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted. A total of 174 s les were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time. This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.
Publisher: Elsevier BV
Date: 12-2020
No related grants have been discovered for Darren Wan-Teck Lim.