Publications by authors named "Wan Teck Lim"

93 Publications

A phase II study of nimotuzumab (TheraCim-hR3) concurrent with cisplatin/radiotherapy in patients with locally advanced head and neck squamous cell carcinoma.

Head Neck 2021 Feb 5. Epub 2021 Feb 5.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Background: The efficacy of a combination of nimotuzumab, a humanized monoclonal antibody to the epidermal growth factor receptor, with chemoradiation in locally advanced head and neck squamous cell carcinoma (HNSCC) was evaluated in a phase II study.

Methods: Patients with stage III/IV HNSCC received 3-weekly cisplatin 100 mg/m for three cycles and weekly nimotuzumab 200 mg for 8 weeks concurrently with radiotherapy. Primary endpoint was best overall response (BOR) and secondary endpoint was progression-free survival (PFS).

Results: Thirty-seven patients were included; the majority were Chinese (76%), male (89%), and had stage IVA/IVB HNSCC (92%). BOR of complete and partial response was seen in 22/37 (59%) and 10/37 (27%) patients, respectively. Median PFS was 17.5 months (95% CI: 11.1-54.5) and 3-year PFS was 40.4% (95% CI: 24.3-55.9). The frequency and type of adverse events observed were similar to standard chemoradiation.

Conclusion: The combination of nimotuzumab with cisplatin and radiotherapy was safe and achieved high response rates in HNSCC.
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http://dx.doi.org/10.1002/hed.26635DOI Listing
February 2021

Cyclin D1 expression in mutant non-small cell lung cancer-old wine into new skins.

Transl Lung Cancer Res 2020 Dec;9(6):2302-2304

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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http://dx.doi.org/10.21037/tlcr-20-639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815367PMC
December 2020

Cost-effectiveness analysis of osimertinib for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small cell lung cancer in Singapore.

J Med Econ 2020 Nov 21;23(11):1330-1339. Epub 2020 Sep 21.

Agency for Care Effectiveness, Ministry of Health, Singapore, Singapore.

Objective: Non-small cell lung cancer (NSCLC) accounts for 80-90% of all lung cancer cases and is usually associated with a poor prognosis. However, targeted therapy with first and second generation tyrosine kinase inhibitors (TKIs) has so far improved progression-free survival of epidermal growth factor receptor (EGFR) mutant NSCLC patients. Osimertinib, a third generation EGFR TKI has recently shown improved overall survival of 6.8 months in previously untreated EGFR mutant NSCLC patients. We assessed the cost-effectiveness of osimertinib versus standard EGFR TKIs (gefitinib or erlotinib) as first-line treatment for advanced or metastatic EGFR mutant NSCLC patients in Singapore.

Methods: A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from the Singapore healthcare payer perspective. Survival curves based on the overall trial population from the FLAURA trial were extrapolated beyond trial period over a 10-year time horizon to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from public healthcare institutions in Singapore. Deterministic and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results.

Results: Compared with first or second generation TKI, osimertinib had a base-case incremental cost-effectiveness ratio (ICER) of SG$418,839 (US$304,277) per quality-adjusted life year gained. One-way sensitivity analysis showed the ICER was most sensitive to time horizon and variations in progression-free utility values. Scenario analyses showed that a 50% reduction in the cost of osimertinib was still associated with a high ICER that was unlikely to be deemed cost effective.

Conclusions: Osimertinib is not cost effective as a first-line treatment compared to standard EGFR TKIs in advanced EGFR mutant NSCLC patients in Singapore. The findings from our evaluation, alongside other considerations including the lack of survival benefit in the Asian subgroup of the FLAURA trial, will be useful to inform policy makers on funding decisions for NSCLC treatments in Singapore.
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http://dx.doi.org/10.1080/13696998.2020.1819822DOI Listing
November 2020

Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC.

J Thorac Oncol 2020 12 28;15(12):1928-1934. Epub 2020 Aug 28.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore, Singapore. Electronic address:

Introduction: RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes.

Methods: This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected.

Results: A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009).

Conclusions: In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance.
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http://dx.doi.org/10.1016/j.jtho.2020.08.011DOI Listing
December 2020

An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Thyroid 2020 09 29;30(9):1254-1262. Epub 2020 Jul 29.

Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided  = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test:  = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test -value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.
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http://dx.doi.org/10.1089/thy.2019.0269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482116PMC
September 2020

Genomic landscape of lung adenocarcinoma in East Asians.

Nat Genet 2020 02 3;52(2):177-186. Epub 2020 Feb 3.

Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.
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http://dx.doi.org/10.1038/s41588-019-0569-6DOI Listing
February 2020

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

Lung Cancer 2020 01 26;139:207-215. Epub 2019 Nov 26.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore. Electronic address:

Objectives: 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.

Materials And Methods: We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples 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.

Results: A total of 174 samples 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.

Conclusions: 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.
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http://dx.doi.org/10.1016/j.lungcan.2019.11.022DOI Listing
January 2020

Phase 1 study of capmatinib in MET-positive solid tumor patients: Dose escalation and expansion of selected cohorts.

Cancer Sci 2020 Feb 30;111(2):536-547. Epub 2019 Dec 30.

State Key Laboratory of Translational Oncology, Phase 1 Clinical Trial Centre, The Chinese University of Hong Kong, Hong Kong, China.

Capmatinib is an oral, ATP-competitive, and highly potent, type 1b MET inhibitor. Herein, we report phase 1 dose-escalation results for capmatinib in advanced MET-positive solid tumor patients and dose expansion in advanced non-lung tumors. Capmatinib was well tolerated with a manageable safety profile across all explored doses. Dose-limiting toxicities (DLT) occurred at 200 mg twice daily (bid), 250 mg bid, and 450 mg bid capsules; however, no DLT were reported at 600 mg bid (capsules). Capmatinib tablets at 400 mg bid had comparable tolerability and exposure to that of 600 mg bid capsules. Maximum tolerated dose was not reached; recommended phase 2 dose was 400 mg bid tablets/600 mg bid capsules; at this dose, C >EC (90% inhibition of c-MET phosphorylation in animal models) is expected to be achieved and maintained. Among the dose-expansion patients (N = 38), best overall response across all cohorts was stable disease (gastric cancer 22%, hepatocellular carcinoma 46%, other indications 28%); two other indication patients with gene copy number (GCN) ≥6 achieved substantial tumor reduction. Near-complete immunohistochemically determined phospho-MET inhibition (H-score = 2) was shown following capmatinib 450 mg bid capsule in paired biopsies obtained from one advanced colorectal cancer patient. Incidence of high-level MET GCN (GCN ≥6) and MET-overexpressing (immunohistochemistry 3+) tumors in the expansion cohorts was 8% and 13%, respectively; no MET mutations were observed. Thus, the recommended phase 2 dose (RP2D) of capmatinib was 600 mg bid capsule/400 mg bid tablet. Capmatinib was well tolerated and showed antitumor activity and acceptable safety profile at the RP2D. (ClinicalTrials.gov Identifier: NCT01324479).
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http://dx.doi.org/10.1111/cas.14254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004521PMC
February 2020

Single-Cell Analysis of Circulating Tumor Cells: Why Heterogeneity Matters.

Cancers (Basel) 2019 Oct 19;11(10). Epub 2019 Oct 19.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.

Unlike bulk-cell analysis, single-cell approaches have the advantage of assessing cellular heterogeneity that governs key aspects of tumor biology. Yet, their applications to circulating tumor cells (CTCs) are relatively limited, due mainly to the technical challenges resulting from extreme rarity of CTCs. Nevertheless, recent advances in microfluidics and immunoaffinity enrichment technologies along with sequencing platforms have fueled studies aiming to enrich, isolate, and sequence whole genomes of CTCs with high fidelity across various malignancies. Here, we review recent single-cell CTC (scCTC) sequencing efforts, and the integrated workflows, that have successfully characterized patient-derived CTCs. We examine how these studies uncover DNA alterations occurring at multiple molecular levels ranging from point mutations to chromosomal rearrangements from a single CTC, and discuss their cellular heterogeneity and clinical consequences. Finally, we highlight emerging strategies to address key challenges currently limiting the translation of these findings to clinical practice.
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http://dx.doi.org/10.3390/cancers11101595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826423PMC
October 2019

Liquid biopsy: one cell at a time.

NPJ Precis Oncol 2019 2;3:23. Epub 2019 Oct 2.

1NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore, Singapore.

As an alternative target to surgically resected tissue specimens, liquid biopsy has gained much attention over the past decade. Of the various circulating biomarkers, circulating tumor cells (CTCs) have particularly opened new windows into the metastatic cascade, with their functional, biochemical, and biophysical properties. Given the extreme rarity of intact CTCs and the associated technical challenges, however, analyses have been limited to bulk-cell strategies, missing out on clinically significant sources of information from cellular heterogeneity. With recent technological developments, it is now possible to probe genetic material of CTCs at the single-cell resolution to study spatial and temporal dynamics in circulation. Here, we discuss recent transcriptomic profiling efforts that enabled single-cell characterization of patient-derived CTCs spanning diverse cancer types. We further highlight how expression data of these biomarkers have advanced our understanding of metastatic spectrum and provided a basis for the development of CTC-based liquid biopsies to track, monitor, and predict the efficacy of therapy and any emergent resistance.
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http://dx.doi.org/10.1038/s41698-019-0095-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775080PMC
October 2019

Compendiums of cancer transcriptomes for machine learning applications.

Sci Data 2019 10 8;6(1):194. Epub 2019 Oct 8.

NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore, Singapore.

There are massive transcriptome profiles in the form of microarray. The challenge is that they are processed using diverse platforms and preprocessing tools, requiring considerable time and informatics expertise for cross-dataset analyses. If there exists a single, integrated data source, data-reuse can be facilitated for discovery, analysis, and validation of biomarker-based clinical strategy. Here, we present merged microarray-acquired datasets (MMDs) across 11 major cancer types, curating 8,386 patient-derived tumor and tumor-free samples from 95 GEO datasets. Using machine learning algorithms, we show that diagnostic models trained from MMDs can be directly applied to RNA-seq-acquired TCGA data with high classification accuracy. Machine learning optimized MMD further aids to reveal immune landscape across various carcinomas critically needed in disease management and clinical interventions. This unified data source may serve as an excellent training or test set to apply, develop, and refine machine learning algorithms that can be tapped to better define genomic landscape of human cancers.
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http://dx.doi.org/10.1038/s41597-019-0207-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783425PMC
October 2019

Addressing cellular heterogeneity in tumor and circulation for refined prognostication.

Proc Natl Acad Sci U S A 2019 09 15;116(36):17957-17962. Epub 2019 Aug 15.

NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, 117456 Singapore, Singapore;

Despite pronounced genomic and transcriptomic heterogeneity in non-small-cell lung cancer (NSCLC) not only between tumors, but also within a tumor, validation of clinically relevant gene signatures for prognostication has relied upon single-tissue samples, including 2 commercially available multigene tests (MGTs). Here we report an unanticipated impact of intratumor heterogeneity (ITH) on risk prediction of recurrence in NSCLC, underscoring the need for a better genomic strategy to refine prognostication. By leveraging label-free, inertial-focusing microfluidic approaches in retrieving circulating tumor cells (CTCs) at single-cell resolution, we further identified specific gene signatures with distinct expression profiles in CTCs from patients with differing metastatic potential. Notably, a refined prognostic risk model that reconciles the level of ITH and CTC-derived gene expression data outperformed the initial classifier in predicting recurrence-free survival (RFS). We propose tailored approaches to providing reliable risk estimates while accounting for ITH-driven variance in NSCLC.
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http://dx.doi.org/10.1073/pnas.1907904116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731691PMC
September 2019

Pan-cancer analysis connects tumor matrisome to immune response.

NPJ Precis Oncol 2019 22;3:15. Epub 2019 May 22.

1NUS Graduate School for Integrative Sciences & Engineering, National University of Singapore, Singapore, Singapore.

Recent sequencing efforts unveil genomic landscapes of tumor microenvironment. A key compartment in this is the extracellular matrix (ECM) and its related components - matrisome. Yet, little is known about the extent to which matrisome pattern is conserved in progressive tumors across diverse cancer types. Using integrative genomic approaches, we conducted multi-platform assessment of a measure of deregulated matrisome associated with tumor progression, termed as tumor matrisome index (TMI), in over 30,000 patient-derived samples. Combined quantitative analyses of genomics and proteomics reveal that TMI is closely associated with mutational load, tumor pathology, and predicts survival across different malignancies. Interestingly, we observed an enrichment of specific tumor-infiltrating immune cell populations, along with signatures predictive of resistance to immune checkpoint blockade immunotherapy, and clinically targetable immune checkpoints in TMI tumors. B7-H3 emerged as a particularly promising target for anti-tumor immunity in these tumors. Here, we show that matrisomal abnormalities could represent a potential clinically useful biomarker for prognostication and prediction of immunotherapy response.
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http://dx.doi.org/10.1038/s41698-019-0087-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531473PMC
May 2019

Publisher Correction: Methionine is a metabolic dependency of tumor-initiating cells.

Nat Med 2019 Jun;25(6):1022

Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

In the version of this article originally published, there is an error in Fig. 5a. Originally, 'MAT2A' appeared between 'Methionine' and 'Homocysteine'. 'MAT2A' should have been 'MTR'. The error has been corrected in the PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-019-0486-3DOI Listing
June 2019

Methionine is a metabolic dependency of tumor-initiating cells.

Nat Med 2019 05 6;25(5):825-837. Epub 2019 May 6.

Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

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.
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http://dx.doi.org/10.1038/s41591-019-0423-5DOI Listing
May 2019

First-line afatinib for the treatment of mutation-positive non-small-cell lung cancer in the 'real-world' clinical setting.

Ther Adv Med Oncol 2019 15;11:1758835919836374. Epub 2019 Apr 15.

Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.

Afatinib is an ErbB family blocker that is approved for the treatment of epidermal growth factor receptor ( mutation-positive non-small-cell lung cancer (NSCLC). Pivotal randomized clinical studies demonstrated that afatinib significantly prolonged progression-free survival compared with platinum-based chemotherapy (LUX-Lung 3, LUX-Lung 6), and with gefitinib (LUX-Lung 7), with manageable side effects. However, these results were derived from controlled studies conducted in selected patients and are not necessarily representative of real-world use of afatinib. To gain a broader understanding of the effectiveness and safety of first-line afatinib, we have undertaken a literature review of real-world studies that have assessed its use in a variety of patient populations. We focused on patients with uncommon mutations, brain metastases, or those of advanced age, as these patients are often excluded from clinical studies but are regularly seen in routine clinical practice. The available real-world studies suggest that afatinib has clinical activity, and is tolerable, in diverse patient populations in an everyday clinical practice setting. Moreover, consistent with LUX-Lung 7, several real-world comparative studies indicate that afatinib might confer better efficacy than first-generation EGFR tyrosine kinase inhibitors. Tolerability-guided dose adjustment, undertaken in 21-68% of patients in clinical practice, did not appear to reduce the efficacy of afatinib. Taken together, these findings provide further support for the use of afatinib as a treatment option in patients with mutation-positive NSCLC.
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http://dx.doi.org/10.1177/1758835919836374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466470PMC
April 2019

Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.

J Clin Oncol 2019 04 24;37(11):876-884. Epub 2019 Jan 24.

1 National Cancer Centre Singapore, Singapore.

Purpose: Mesenchymal epithelial transition factor ( MET) activation has been implicated as an oncogenic driver in epidermal growth factor receptor ( EGFR)-mutant non-small-cell lung cancer (NSCLC) and can mediate primary and secondary resistance to EGFR tyrosine kinase inhibitors (TKI). High copy number thresholds have been suggested to enrich for response to MET inhibitors. We examined the clinical relevance of MET copy number gain (CNG) in the setting of treatment-naive metastatic EGFR-mutant-positive NSCLC.

Patients And Methods: MET fluorescence in situ hybridization was performed in 200 consecutive patients identified as metastatic treatment-naïve EGFR-mutant-positive. We defined MET-high as CNG greater than or equal to 5, with an additional criterion of MET/centromeric portion of chromosome 7 ratiο greater than or equal to 2 for amplification. Time-to-treatment failure (TTF) to EGFR TKI in patients identified as MET-high and -low was estimated by Kaplan-Meier method and compared using log-rank test. Multiregion single-nucleotide polymorphism array analysis was performed on 13 early-stage resected EGFR-mutant-positive NSCLC across 59 sectors to investigate intratumoral heterogeneity of MET CNG.

Results: Fifty-two (26%) of 200 patients in the metastatic cohort were MET-high at diagnosis; 46 (23%) had polysomy and six (3%) had amplification. Median TTF was 12.2 months (95% CI, 5.7 to 22.6 months) versus 13.1 months (95% CI, 10.6 to 15.0 months) for MET-high and -low, respectively ( P = .566), with no significant difference in response rate regardless of copy number thresholds. Loss of MET was observed in three of six patients identified as MET-high who underwent postprogression biopsies, which is consistent with marked intratumoral heterogeneity in MET CNG observed in early-stage tumors. Suboptimal response (TTF, 1.0 to 6.4 months) to EGFR TKI was observed in patients with coexisting MET amplification (five [3.2%] of 154).

Conclusion: Although up to 26% of TKI-naïve EGFR-mutant-positive NSCLC harbor high MET CNG by fluorescence in situ hybridization, this did not significantly affect response to TKI, except in patients identified as MET-amplified. Our data underscore the limitations of adopting arbitrary copy number thresholds and the need for cross-assay validation to define therapeutically tractable MET pathway dysregulation in EGFR-mutant-positive NSCLC.
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http://dx.doi.org/10.1200/JCO.18.00177DOI Listing
April 2019

A merged lung cancer transcriptome dataset for clinical predictive modeling.

Sci Data 2018 07 24;5:180136. Epub 2018 Jul 24.

NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, #05-01, 28 Medical Drive, Singapore 117456, Singapore.

The Gene Expression Omnibus (GEO) database is an excellent public source of whole transcriptomic profiles of multiple cancers. The main challenge is the limited accessibility of such large-scale genomic data to people without a background in bioinformatics or computer science. This presents difficulties in data analysis, sharing and visualization. Here, we present an integrated bioinformatics pipeline and a normalized dataset that has been preprocessed using a robust statistical methodology; allowing others to perform large-scale meta-analysis, without having to conduct time-consuming data mining and statistical correction. Comprising 1,118 patient-derived samples, the normalized dataset includes primary non-small cell lung cancer (NSCLC) tumors and paired normal lung tissues from ten independent GEO datasets, facilitating differential expression analysis. The data has been merged, normalized, batch effect-corrected and filtered for genes with low variance via multiple open source R packages integrated into our workflow. Overall this dataset (with associated clinical metadata) better represents the diseased population and serves as a powerful tool for early predictive biomarker discovery.
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http://dx.doi.org/10.1038/sdata.2018.136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057440PMC
July 2018

Bystander CD8 T cells are abundant and phenotypically distinct in human tumour infiltrates.

Nature 2018 05 16;557(7706):575-579. Epub 2018 May 16.

Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore, Singapore.

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. Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients. Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control, in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown. Here we show that human lung and colorectal cancer CD8 TILs can not only be specific for tumour antigens (for example, neoantigens), but also recognize a wide range of epitopes unrelated to cancer (such as those from Epstein-Barr virus, human cytomegalovirus or influenza virus). We found that these bystander CD8 TILs have diverse phenotypes that overlap with tumour-specific cells, but lack CD39 expression. In colorectal and lung tumours, the absence of CD39 in CD8 TILs defines populations that lack hallmarks of chronic antigen stimulation at the tumour site, supporting their classification as bystanders. Expression of CD39 varied markedly between patients, with some patients having predominantly CD39 CD8 TILs. Furthermore, frequencies of CD39 expression among CD8 TILs correlated with several important clinical parameters, such as the mutation status of lung tumour epidermal growth factor receptors. Our results demonstrate that not all tumour-infiltrating T cells are specific for tumour antigens, and suggest that measuring CD39 expression could be a straightforward way to quantify or isolate bystander T cells.
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http://dx.doi.org/10.1038/s41586-018-0130-2DOI Listing
May 2018

A Decade of Never-smokers Among Lung Cancer Patients-Increasing Trend and Improved Survival.

Clin Lung Cancer 2018 09 17;19(5):e539-e550. Epub 2018 Mar 17.

Division of Medical Oncology, National Cancer Centre, Singapore.

Background: It is not known whether clinicopathologic characteristics, treatment, and survival of never-smokers among lung cancer incident cases have changed over time. We assessed the trend and overall survival (OS) of these patients within our institution during a 10-year period.

Patients And Methods: We reviewed 2 cohorts of non-small-cell lung cancer patients with a diagnosis from 1999 to 2002 and from 2008 to 2011. The patient characteristics and OS were compared by smoking status within each cohort and between the 2 cohorts over time.

Results: Of the 992 patients in the 1999-2002 cohort and the 1318 patients in the 2008-2011 cohort, 902 and 1272 had a known smoking status, respectively. The proportion of never-smokers increased from 31% in 1999-2002 to 48% in 2008-2011 (P < .001). Within both cohorts, the differences in characteristics among never-, former-, and current-smokers have remained largely constant over time. A greater proportion of never-smokers had Eastern Cooperative Oncology Group performance status 0 to 1 and adenocarcinoma. The median OS increased from 15.5 months in 1999-2002 to 24.9 months in 2008-2011 (P = .001) for never-smokers, 12.3 to 15.9 months (P = .150) for former-smokers, and 10.5 to 13.9 months (P = .011) for current-smokers. The larger survival improvement among never-smokers was likely accounted for by the larger increase in never-smokers who were treated with tyrosine kinase inhibitors and pemetrexed over time.

Conclusion: We found an increasing trend of never-smokers among incident lung cancer cases and improved survival for these patients during a 10-year period. The documentation of smoking status in any national cancer registry is vital to estimate the true incidence of lung cancer among never-smokers over time.
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http://dx.doi.org/10.1016/j.cllc.2018.03.013DOI Listing
September 2018

Cost effectiveness analysis of afatinib versus pemetrexed-cisplatin for first-line treatment of locally advanced or metastatic EGFR mutation positive non-small-cell lung cancer from the Singapore healthcare payer's perspective.

BMC Cancer 2018 03 27;18(1):352. Epub 2018 Mar 27.

Agency for Care Effectiveness, Ministry of Health, Harrower Hall, 14 College Road, Singapore, 169853, Singapore.

Background: Non-small-cell lung cancer (NSCLC) accounts for 85% of all lung cancers and is associated with a poor prognosis. Afatinib is an irreversible ErbB family blocker recommended in clinical guidelines as a first-line treatment for NSCLC which harbours an epidermal growth factor receptor (EGFR) mutation. The objective of this study was to evaluate the cost-effectiveness of afatinib versus pemetrexed-cisplatin for first-line treatment of locally advanced or metastatic EGFR mutation positive NSCLC in Singapore.

Methods: A partitioned survival model with three health states (progression-free, progressive disease and death) was developed from a healthcare payer perspective. Survival curves from the LUX-Lung 3 trial (afatinib versus pemetrexed-cisplatin chemotherapy) were extrapolated beyond the trial period to estimate the underlying progression-free survival and overall survival parametric distributions. Rates of adverse reactions were also estimated from LUX-Lung 3 while health utilities from overseas were derived from the literature in the absence of local estimates. Direct costs were sourced from public healthcare institutions in Singapore. Incremental cost-effectiveness ratios (ICERs) were calculated over a 5 year time horizon. Deterministic and probabilistic sensitivity analyses and additional scenario analyses were conducted to explore the impact of uncertainties and assumptions on the cost-effectiveness results.

Results: In the base-case analysis, the ICER for afatinib versus pemetrexed-cisplatin was SG$137,648 per quality-adjusted life year (QALY) gained and SG$109,172 per life-year gained. One-way sensitivity analysis showed the ICER was most sensitive to variations in the utility values, the cost of afatinib and time horizon. Scenario analyses showed that even reducing the cost of afatinib by 50% led to a high ICER which was unlikely to represent a cost-effective use of healthcare resources.

Conclusions: Compared with pemetrexed-cisplatin, afatinib is not cost-effective as a first-line treatment for advanced EGFR mutation-positive NSCLC in Singapore. The findings from our study will be useful to inform local healthcare decision-making and resource allocations for NSCLC treatments, together with other considerations such as clinical effectiveness, safety and affordability of TKIs.
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http://dx.doi.org/10.1186/s12885-018-4223-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872570PMC
March 2018

Antitumor Activity of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma: An International, Multicenter Study of the Mayo Clinic Phase 2 Consortium (NCI-9742).

J Clin Oncol 2018 05 27;36(14):1412-1418. Epub 2018 Mar 27.

Brigette B.Y. Ma, Edwin P. Hui, Kwok-Wai Lo, Ka-Fai To, K.C. Allen Chan, Y.M. Dennis Lo, Ann D. King, and Anthony T.C. Chan, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Region, People's Republic of China; Wan-Teck Lim, National Cancer Centre; Boon-Cher Goh, National University Cancer Institute of Singapore; Alex Y.C. Chang, Johns Hopkins University School of Medicine; Akhil Chopra, OncoCare Cancer Centre, Singapore; Adam Pettinger, Nathan R. Foster, Charles Erlichman, Jun Yin, and Brian A. Costello, Mayo Clinic, Rochester, MN; Jonathan W. Riess, University of California Davis Comprehensive Cancer Center, Sacramento; Barbara J. Gitlitz, University of Southern California Keck School of Medicine, Los Angeles; Dean W. Lim, City of Hope Comprehensive Cancer Center, Duarte, CA; Mark Agulnik, Northwestern University, Evanston, IL; Julie A. Kish and Christine H. Chung, Moffitt Cancer Center, University of South Florida, Tampa, FL; Douglas R. Adkins, Washington University School of Medicine, St Louis, MO; Kevin J. Cullen, University of Maryland, Baltimore, MD.

Purpose This multinational study evaluated the antitumor activity of nivolumab in nasopharyngeal carcinoma (NPC). Tumor and plasma-based biomarkers were investigated in an exploratory analysis. Patients and Methods Patients with multiply pretreated recurrent or metastatic NPC were treated with nivolumab until disease progression. The primary end point was objective response rate (ORR) and secondary end points included survival and toxicity. The expression of programmed death-ligand 1 (PD-L1) and human leukocyte antigens A and B in archived tumors and plasma clearance of Epstein-Barr virus DNA were correlated with ORR and survival. Results A total of 44 patients were evaluated and the overall ORR was 20.5% (complete response, n = 1; partial response, n = 8). Nine patients received nivolumab for > 12 months (20%). The 1-year overall survival rate was 59% (95% CI, 44.3% to 78.5%) and 1-year progression-free survival (PFS) rate was 19.3% (95% CI, 10.1% to 37.2%). There was no statistical correlation between ORR and the biomarkers; however, a descriptive analysis showed that the proportion of patients who responded was higher among those with PD-L1 positive tumors (> 1% expression) than those with PD-L1-negative tumors. The loss of expression of one or both human leukocyte antigen class 1 proteins was associated with better PFS than when both proteins were expressed (1-year PFS, 30.9% v 5.6%; log-rank P = .01). There was no association between survival and PD-L1 expression or plasma Epstein-Barr virus DNA clearance. There was no unexpected toxicity to nivolumab. Conclusion Nivolumab has promising activity in NPC and the 1-year overall survival rate compares favorably with historic data in similar populations. Additional evaluation in a randomized setting is warranted. The biomarker results were hypothesis generating and validation in larger cohorts is needed.
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http://dx.doi.org/10.1200/JCO.2017.77.0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941615PMC
May 2018

Primary pulmonary lymphoepithelioma-like carcinoma in Singapore.

Ann Thorac Med 2018 Jan-Mar;13(1):30-35

Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore.

Background: Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype of nonsmall cell lung cancer (NSCLC) predominantly reported in East Asia. We aimed to evaluate clinical characteristics, diagnosis, treatment, and prognosis of PPLELC in Singapore.

Methods: Retrospective review of all patients diagnosed with PPLELC at our center between 2000 and 2014.

Results: All 28 patients were Chinese, 67.9% were female, and the median age was 58 years (range37-76 years). Majority (89.3%) were never smokers and 53.6% asymptomatic at diagnosis. About 28.6% presented with Stage I/II disease, 25% had Stage III disease, and 46.4% had Stage IV disease. All patients with Stage I/II disease underwent lobectomy without adjuvant treatment. Four out of 7 patients with Stage III disease underwent surgery with or without adjuvant therapy while the rest received chemoradiation. Twelve out of 13 patients with Stage IV disease received chemotherapy with or without radiotherapy. At the end of 2016, survival data were available for all 28 patients. Two-year survival rates for Stage I/II, Stage III, and Stage IV disease were 100%, 85.7%, and 61.5%, respectively, while survival was 100%, 85.7%, and 9.6%, respectively, at five years.

Conclusion: The majority (46.4%) of patients presented with metastatic disease. For those with Stage I-III disease, 5-year survival for PPLELC was better than other NSCLC subtypes. Multimodality treatment including surgery could be considered in locally advanced disease. In Stage IV disease, it tended to approximate that of NSCLC.
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http://dx.doi.org/10.4103/atm.ATM_304_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772105PMC
February 2018

Phase 1b Trial of Ficlatuzumab, a Humanized Hepatocyte Growth Factor Inhibitory Monoclonal Antibody, in Combination With Gefitinib in Asian Patients With NSCLC.

Clin Pharmacol Drug Dev 2018 06 18;7(5):532-542. Epub 2018 Jan 18.

Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Hepatocyte growth factor (HGF)/c-Met pathway dysregulation is a mechanism for epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Ficlatuzumab (AV-299; SCH 900105), a humanized IgG κ HGF inhibitory monoclonal antibody, prevents HGF/c-Met pathway ligand-mediated activation. This phase 1b study assessed the safety/tolerability, pharmacokinetics/pharmacodynamics, and antitumor activity of ficlatuzumab plus gefitinib in Asian patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients received intravenous ficlatuzumab either 10 mg/kg (cohort 1; n = 3) or 20 mg/kg (cohort 2; n = 12) every 2 weeks plus oral gefitinib 250 mg daily. Patients tolerated the drug combination well. Four treatment-related grade 3/4 adverse events were reported in 3 patients (cohort 2). Pharmacokinetic profiles for ficlatuzumab and gefitinib were consistent with prior single-agent trials. Partial responses were achieved in 5 patients (4 confirmed), all in cohort 2; objective response rate (ORR) was 33% (duration, 1.9-6.4 months). Responding patients had no prior EGFR TKI treatment, 2 without an EGFR mutation. Four additional patients had disease stabilization (cohort 2; duration, 2.7-9.1 months; 42% ORR). The recommended phase 2 dose for ficlatuzumab plus gefitinib 250 mg/day was 20 mg/kg every 2 weeks. This drug combination has shown preliminary dose-related antitumor activity in advanced NSCLC.
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http://dx.doi.org/10.1002/cpdd.427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032914PMC
June 2018

Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing.

Nat Commun 2018 01 15;9(1):216. Epub 2018 Jan 15.

Cancer Stem Cell Biology, Genome Institute of Singapore, Singapore, 138672, Singapore.

EGFR-mutant lung adenocarcinomas (LUAD) display diverse clinical trajectories and are characterized by rapid but short-lived responses to EGFR tyrosine kinase inhibitors (TKIs). Through sequencing of 79 spatially distinct regions from 16 early stage tumors, we show that despite low mutation burdens, EGFR-mutant Asian LUADs unexpectedly exhibit a complex genomic landscape with frequent and early whole-genome doubling, aneuploidy, and high clonal diversity. Multiple truncal alterations, including TP53 mutations and loss of CDKN2A and RB1, converge on cell cycle dysregulation, with late sector-specific high-amplitude amplifications and deletions that potentially beget drug resistant clones. We highlight the association between genomic architecture and clinical phenotypes, such as co-occurring truncal drivers and primary TKI resistance. Through comparative analysis with published smoking-related LUAD, we postulate that the high intra-tumor heterogeneity observed in Asian EGFR-mutant LUAD may be contributed by an early dominant driver, genomic instability, and low background mutation rates.
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http://dx.doi.org/10.1038/s41467-017-02584-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768770PMC
January 2018

An extracellular matrix-related prognostic and predictive indicator for early-stage non-small cell lung cancer.

Nat Commun 2017 11 23;8(1):1734. Epub 2017 Nov 23.

NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, #05-01, 28 Medical Drive, Singapore, 117456, Singapore.

The prognosis and prediction of adjuvant chemotherapy (ACT) response in early-stage non-small cell lung cancer (NSCLC) patients remain poor in this era of personalized medicine. We hypothesize that extracellular matrix (ECM)-associated components could be potential markers for better diagnosis and prognosis due to their differential expression in 1,943 primary NSCLC tumors as compared to 303 normal lung tissues. Here we develop a 29-gene ECM-related prognostic and predictive indicator (EPPI). We validate a robust performance of the EPPI risk scoring system in multiple independent data sets, comprising a total of 2,071 early-stage NSCLC tumors. Patients are stratified according to the universal cutoff score based on the EPPI when applied in the clinical setting; the low-risk group has significantly better survival outcome. The functional EPPI gene set represents a potential genomic tool to improve patient selection in early-stage NSCLC to further derive the best benefits of ACT and prevent unnecessary treatment or ACT-associated morbidity.
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http://dx.doi.org/10.1038/s41467-017-01430-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700969PMC
November 2017

Improved Survival of Advanced Lung Cancer in Singapore Over the Past Decade.

Ann Acad Med Singap 2017 Sep;46(9):333-338

Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.

Introduction: We reviewed changes in clinical characteristics, treatment and survival of lung cancer patients in Singapore over the past decade.

Materials And Methods: We reviewed all primary lung cancer cases from January 2004 to December 2013. Basic demographic, clinical and treatment data were extracted from the database. Overall survival (OS) was calculated using Kaplan-Meier method; survival curves were compared using log-rank test. Linear regression trend lines were estimated using least squares approach, and Cox regression analyses were performed to identify prognostic factors.

Results: Among 6006 lung cancer patients, the median age was 68 years old, 65% were males, 88% were Chinese, 92% had non-small-cell lung cancer and 76% had advanced stage IIIB/IV. There were proportionally more adenocarcinomas diagnosed over the years, while that of squamous cell carcinoma (SCC) and small-cell-lung cancer (SCLC) have remained stable. The median OS of all patients increased from 9.2 months in 2004 to 11.5 months in 2013. This survival improvement was statistically significant among patients with stage IIIB/IV (6.7 to 8.7 months; = 0.005) and adenocarcinoma (12.7 to 15.4 months; = 0.041). There was no improvement in median OS for SCC or SCLC. The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) (hazard ratio [HR] 0.68; 95% CI, 0.63 to 0.73) and pemetrexed (HR, 0.69; 95% CI, 0.63 to 0.76) were significantly associated with improved OS.

Conclusion: Survival of patients with advanced stage IIIB/IV lung adenocarcinoma has improved over the past decade, and is potentially associated with the use of EGFR TKI and pemetrexed.
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September 2017

Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma.

Nat Med 2017 Oct 18;23(10):1167-1175. Epub 2017 Sep 18.

Cancer Therapeutics Research Laboratory, National Cancer Centre Singapore, Singapore.

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.
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http://dx.doi.org/10.1038/nm.4401DOI Listing
October 2017

Personalized Treatment Through Detection and Monitoring of Genetic Aberrations in Single Circulating Tumor Cells.

Adv Exp Med Biol 2017 ;994:255-273

Mechanobiology Institute of Singapore, 5A Engineering Drive 1, Singapore, 117411, Singapore.

Circulating tumor cells (CTCs) present a viable alternative to access tumor materials other than primary biopsies in cancer. This disease is among the most widespread in the world and is difficult to target because of its complex nature, challenges in getting quality samples and dynamic temporal changes in response to treatment. Conventional methods of detection and monitoring the disease profile do not suffice to be able to target the heterogeneity that exists at the cellular level. CTCs have been identified as a possible substitute for tumor tissue samples, and can be used to complement current disease management. Challenges in CTCs molecular analysis lie in the purity of the sample, which is masked by the presence of large quantities of white blood cells (WBCs) . In this chapter, we present a microfluidic biochip platform that performs secondary purification to isolate single CTCs efficiently. Studying single CTCs will allow for sensitive detection of critical mutations and addressing intercellular variances that will be otherwise missed easily due to low mutation frequencies when evaluating bulk cell retrieval. Using the biochip, we isolated single CTCs, and conducted personalized integrated EGFR mutational analysis using conventional polymerase chain reaction (PCR) and Sanger sequencing. We also demonstrated that high quality next generation sequencing (NGS) libraries can be readily generated from these samples. In our initial study, we revealed that the dominant EGFR mutations such as L858R and T790M could be detected in Non Small Cell Lung Cancer (NSCLC) patients with low CTC counts. We envision the biochip will enable efficient isolation of rare single cells from samples. This technology coupled with downstream molecular characterization of CTCs will aid in realizing the personalized medicine for cancer patients.
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http://dx.doi.org/10.1007/978-3-319-55947-6_14DOI Listing
October 2017

A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer.

Oncotarget 2017 Jun;8(25):41474-41486

Division of Medical Oncology, National Cancer Centre, Singapore.

Background: A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue.

Results: In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06-2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251-2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603-4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063-1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS.

Materials And Methods: 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS.

Conclusions: In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.
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http://dx.doi.org/10.18632/oncotarget.17102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522319PMC
June 2017