82 results on '"Ang MK"'
Search Results
2. Different cellular p16(INK4a) localisation may signal different survival outcomes in head and neck cancer.
- Author
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Zhao N, Ang MK, Yin XY, Patel MR, Fritchie K, Thorne L, Muldrew KL, Hayward MC, Sun W, Wilkerson MD, Chera BS, Hackman T, Zanation AM, Grilley-Olson JE, Couch ME, Shockley WW, Weissler MC, Shores CG, Funkhouser WK, and Olshan AF
- Abstract
Background: Recently, the management of head and neck squamous cell carcinoma (HNSCC) has focused considerable attention on biomarkers, which may influence outcomes. Tests for human papilloma infection, including direct assessment of the virus as well as an associated tumour suppressor gene p16, are considered reproducible. Tumours from familial melanoma syndromes have suggested that nuclear localisation of p16 might have a further role in risk stratification. We hypothesised p16 staining that considered nuclear localisation might be informative for predicting outcomes in a broader set of HNSCC tumours not limited to the oropharynx, human papilloma virus (HPV) status or by smoking status.Methods: Patients treated for HNSCC from 2002 to 2006 at UNC (University of North Carolina at Chapel Hill) hospitals that had banked tissue available were eligible for this study. Tissue microarrays (TMA) were generated in triplicate. Immunohistochemical (IHC) staining for p16 was performed and scored separately for nuclear and cytoplasmic staining. Human papilloma virus staining was also carried out using monoclonal antibody E6H4. p16 expression, HPV status and other clinical features were correlated with progression-free (PFS) and overall survival (OS).Results: A total of 135 patients had sufficient sample for this analysis. Median age at diagnosis was 57 years (range 20-82), with 68.9% males, 8.9% never smokers and 32.6% never drinkers. Three-year OS rate and PFS rate was 63.0% and 54.1%, respectively. Based on the p16 staining score, patients were divided into three groups: high nuclear, high cytoplasmic staining group (HN), low nuclear, low cytoplasmic staining group (LS) and high cytoplasmic, low nuclear staining group (HC). The HN and the LS groups had significantly better OS than the HC group with hazard ratios of 0.10 and 0.37, respectively, after controlling for other factors, including HPV status. These two groups also had significantly better PFS than the HC staining group. This finding was consistent for sites outside the oropharynx and did not require adjustment for smoking status.Conclusion: Different p16 protein localisation suggested different survival outcomes in a manner that does not require limiting the biomarker to the oropharynx and does not require assessment of smoking status. [ABSTRACT FROM AUTHOR]- Published
- 2012
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3. Imaging: Mass spectrometry in HNSCC--a peek at response prediction?
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Ang MK, Hayes DN, Ang, Mei-Kim, and Hayes, D Neil
- Abstract
EGFR inhibitors provide benefit in patients with advanced and metastatic head and neck squamous cell carcinoma (HNSCC). Mass spectrometry profiling has been used to predict outcome in patients with HNSCC after EGFR inhibitor treatment, and may enable prior identification of patients most likely to benefit from these therapies. however, further validation in prospective studies is needed. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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4. Gemcitabine, carboplatin, and Epstein Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized Phase 3 trial.
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Toh HC, Yang MH, Wang HM, Hsieh CY, Chitapanarux I, Ho KF, Hong RL, Ang MK, Colevas AD, Sirachainan E, Lertbutsayanukul C, Ho GF, Nadler E, Algazi A, Lulla P, Wirth LJ, Wirasorn K, Liu YC, Ang SF, Low SHJ, Tho LM, Hasbullah HH, Brenner MK, Wang WW, Ong WS, Tan SH, Horak I, Ding C, Myo A, and Samol J
- Abstract
Background: Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous Phase 2 trial of locally recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective anti-tumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared to conventional chemotherapy treatment., Patients and Methods: This multicenter, randomized, Phase 3 trial evaluated the efficacy and safety of GC followed by EBV-CTL vs. GC alone as first-line treatment for R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the United States (US) were included. Subjects were randomized to first-line GC (4 cycles) and EBV-CTL (6 cycles) or GC (6 cycles) in a 1:1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety., Clinicaltrials: gov identifier: NCT02578641., Results: 330 subjects with NPC were enrolled. Most subjects in both treatment arms received ≥4 cycles of chemotherapy and most subjects in the GC+EBV-CTL group received ≥2 infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC+EBV-CTL subjects. The median OS was 25.0 months in the GC+EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% CI: 0.91, 1.56; P = 0.194). Only 1 subject experienced a Grade 2 serious adverse event related to EBV-CTL., Conclusion: GC+EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS vs. chemotherapy. This is the largest adoptive T cell therapy trial reported in solid tumors to date., (Copyright © 2024. Published by Elsevier Ltd.)
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- 2024
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5. VEXAS Syndrome and Thrombosis: Findings of Inflammation, Hypercoagulability, and Endothelial Dysfunction.
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Fan BE, Sum CLL, Leung BPL, Ang MK, Lim XR, Lee SSM, Koh LW, Goh LL, Chan WL, Wang LD, Wong SL, and Tay SH
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- Humans, Endothelium, Vascular physiopathology, Female, Thrombophilia blood, Inflammation blood, Thrombosis blood
- Abstract
Competing Interests: None declared.
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- 2024
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6. Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.
- Author
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Saw SPL, Low YF, Lai GGY, Chan LL, Wong WKY, Tsui G, Chen OH, Seet AOL, Tan WC, Tan AC, Chan JWK, Teh YL, Tan WL, Ng QS, Ang MK, Kanesvaran R, Lim DWT, Tan DSW, Mok TSK, and Li MSC
- Subjects
- Female, Humans, Male, Middle Aged, Disease Progression, Indoles, Platinum therapeutic use, Platinum administration & dosage, Pyrimidines, Retrospective Studies, Treatment Outcome, Acrylamides therapeutic use, Aniline Compounds therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, ErbB Receptors genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms mortality, Lung Neoplasms pathology, Mutation, Pemetrexed therapeutic use, Pemetrexed administration & dosage
- Abstract
Objectives: First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure., Materials and Methods: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS)., Results: A total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0-652) after progression on osimertinib. Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65). TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis., Conclusions: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr Saw reports grants from Astra Zeneca, consulting fees from Pfizer, Bayer, Astra Zeneca and Daiichi Sankyo, honoraria from Astra Zeneca, MSD, Bristol-Myers Squibb, Daiichi Sankyo, Roche and Takeda, meeting support from MSD and Astra Zeneca from Pfizer, advisory board participation from Astra Zeneca, Daiichi Sankyo and Pfizer, outside the submitted work. Dr Lai reports grants from Astra Zeneca, Roche and Amgen and meeting support from Astra Zeneca, outside the submitted work. Dr Chan reports meeting support from Roche, Astra Zeneca and Ipsen, outside the submitted work. Dr W.C. Tan reports grants from Singhealth, honoraria from Merck & Co, MSD and Astra Zeneca, meeting support from Ipsen Pharmaceuticals and Merck & Co, outside the submitted work. Dr A. Tan reports consulting fees from Amgen, Bayer and Pfizer, honoraria from Amgen, Guardant Health, Takeda, Juniper Biologics and Astra Zeneca, outside the submitted work. Dr W.L. Tan reports grants from Astra Zeneca, honoraria from Novartis and Merck, meeting support from Astra Zeneca, MSD, Boehringer Ingelheim and Ipsen, outside the submitted work. Dr Kanesvaran reports honoraria from Astellas, MSD and Ipsen, leadership roles in ESMO and SIOG, outside the submitted work. Dr Lim reports grants from Taiho Pharmaceuticals, consulting fees from Daiichi Sankyo, Amgen, Janssen and Alentis Therapeutics, honoraria from MSD and Takeda, meeting support from Astra Zeneca and Alentis Therapeutics, outside the submitted work. Dr. Tan reports grants from ACM Biolabs, Amgen, Astra Zeneca, Bayer and Pfizer, consulting fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche and Takeda, honoraria from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, Beigene, Regeneron, Zymeworks, meeting support from Bayer, Merck, Pfizer, Regeneron and Zymeworks, outside the submitted work. Dr Mok reportsgrantsfrom AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery, consulting fees from Abbvie Inc, ACEA Pharma, Adagene, Alentis Therapeutics AG, Alpha Biopharma Co., Ltd, Amgen, Amoy Diagnostics Co,AnHeart Therapeutics Inc,AVEO Pharmaceuticals, Inc,Bayer Healthcare Pharmaceuticals Ltd,BeiGene,BerGenBio ASA,Berry Oncology,Boehringer Ingelheim,Blueprint Medicines Corporation,Bristol Myers Squibb,Bowtie Life Insurance Company Limited,Bridge Biotherapeutics Inc,Covidien LP,C4 Therapeutics Inc,Cirina Ltd,CStone Pharmaceuticals,Curio Science,D3 Bio Ltd,Da Volterra,Daiichi Sankyo,Eisai,Elevation Oncology,F. Hoffmann-La Roche Ltd./ Genentech,Fishawack Facilitate Ltd,G1 Therapeutics Inc,geneDecode Co., Ltd,Gilead Sciences, Inc,GLG’s Healthcare,Gritstone Oncology, Inc,Guardant Health,Hengrui Therapeutics Inc,HiberCell, Inc.,HutchMed,Ignyta Inc.,Illumina Inc.,IncyteCorporation,Inivata,IQVIA,Janssen,Lakeshore Biotech Ltd,Lilly,Lunit USA, Inc,Loxo-Oncology,Lucence Health Inc,Medscape LLC/ WebMD,Medtronic,Merck Serono,MSD,Mirati Therapeutics Inc,MiRXES,MoreHealth,Novartis,Novocure GmbH,Omega Therapeutics Inc,OrigiMed,OSE Immunotherapeutics,PeerVoice,Pfizer,PrIME Oncology,Prenetics Global Limited,Puma Biotechnology Inc,Qiming Development (HK) Ltd,Regen Medtech Holdings Limited,Regeneron Pharmaceuticals Inc.,Roche Pharmaceuticals/ Diagnostics/ Foundation One,Sanofi-Aventis,SFJ Pharmaceutical Ltd,Simcere of America Inc,Synergy Research,Summit Therapeutics Sub, Inc,Takeda Pharmaceuticals HK Ltd,Tigermed,Vertex Pharmaceuticals,Virtus Medical Group,XENCOR, Inc,Yuhan Corporation,honorariafromACEA Pharma,Alpha Biopharma Co.Ltd,Amgen,Amoy Diagnostics Co. Ltd,AstraZeneca (before 1/1/19),BeiGene,BI,BMS,Daiichi Sankyo,Daz Group,Fishawack Facilitate Ltd.,InMed Medical Communication,Janssen Pharmaceutica NV,Jiahui Holdings Co. Limited,LiangYiHui Healthcare,Lilly,Lucence Health Inc.,MD Health Brazil,Medscape LLC,Merck Pharmaceuticals HK Ltd.,Merck Sharp & Dohme,MiRXES,Novartis,OrigiMed Co. Ltd.,P. Permanyer SL,PeerVoice, Physicians’ Education Resource,Pfizer,PrIME Oncology,Research to Practice,Roche Pharmaceuticals/ Diagnostics/ Foundation One,Sanofi-Aventis,Shanghai BeBirds Translation & Consulting Co. Ltd,Taiho Pharmaceutical Co. Ltd,Takeda Oncology,Touch Independent Medical Education Ltd,meeting support fromNovartis,Roche,Pfizer, AstraZeneca,Daiichi Sankyo,BI,MiRXES,BMS,MSD,Abbvie,Zai Lab,Liangyihui,advisory boardforAbbVie Inc.,ACEA Pharma,Amgen,AstraZeneca,Alentis Therapeutics AG,BerGenBio ASA,Berry Oncology,Blueprint Medicines Corporation,Boehringer Ingelheim,Bowtie Life Insurance Co Ltd,Bristol Myers Squibb,C4 Therapeutics Inc,Covidien LP,CStone Pharmaceuticals,Curio Science,D3 Bio Ltd.,Daiichi Sankyo Inc.,Eisai,Fishawack Facilitate Ltd.,G1 Therapeutics Inc.,Gilead Sciences Inc.,Gritstone Oncology Inc,Guardant Health,geneDecode Co. Ltd. (uncompensated),Hengrui Therapeutics Inc.,HutchMed,Ignyta Inc.,Incyte Corporation,Imagene AI Ltd.,Inivata,IQVIA,Janssen,Lakeshore Biotech,Lily,Loxo-Oncology Inc.,Lunit Inc,Merck Serono,Merck Sharp & Dohme,Mirati Therapeutics Inc.,MiRXES Group,Novartis,OrigiMed,Pfizer,Prenetics Global Limited,Puma Biotechnology Inc.,Roche/Genentech,Regeneron Pharmaceuticals Inc,Sanofi-Aventis R&D,SFJ Pharmaceutical,Simcere of America Inc.,Simcere Zaiming, Inc.,Takeda,Vertex Pharmaceuticals,Virtus Medical Group,XENCOR, Inc,Yuhan Corporation,being member in the Board of DirectorsforAstraZeneca PLC,HutchMed,Aurora,Insighta,holding stock / stock optionofAstraZeneca,Aurora Tele-Oncology Ltd.,Biolidics Ltd.,HutchMed,Prenetics Global Limited,D3 Bio,Lunit,Bowtie Life Insurance, Lakeshore Biotech Ltd,Loxo-oncology,Virtus Medical Group,Yinson Capital Pte. Ltd.,Phanes Therapeutics, Inc.,Insighta,Alentis Therapeutics AG, outside the submitted work. Dr Li reports grants from Gilead, MSD and Astra Zeneca, honoraria from Astra Zeneca, Novartis, Amgen, Pfizer. Takeda, ACE Oncology, Merck, Guardant Health, Gilead, Janssen and MSD, meeting support from Astra Zeneca, Pfizer, Daiichi Sankyo, MSD, Amgen, advisory board for Astra Zeneca, Pfizer, AnHeart Therapeutics, Amgen, Takeda, Yuhan and Blossomhill therapeutics, outside the submitted work. No other conflicts of interest were declared.]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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7. Oncogene-Driven Non-Small Cell Lung Cancers in Patients with a History of Smoking Lack Smoking-Induced Mutations.
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Huang CY, Jiang N, Shen M, Lai GG, Tan AC, Jain A, Saw SP, Ang MK, Ng QS, Lim DW, Kanesvaran R, Tan EH, Tan WL, Ong BH, Chua KL, Anantham D, Takano AM, Lim KH, Tam WL, Sim NL, Skanderup AJ, Tan DS, and Rozen SG
- Subjects
- Humans, Male, Female, Middle Aged, Aged, Adult, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms genetics, Lung Neoplasms pathology, Mutation, Oncogenes genetics, Smoking adverse effects, Smoking genetics
- Abstract
Non-small cell lung cancers (NSCLC) in nonsmokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in nonsmokers, alterations in these "nonsmoking-related oncogenes" (NSRO) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared with typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and nonsmokers had similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs, which was confirmed in two large NSCLC data sets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to the regulation of the cell cycle. These findings suggest that, whereas the genomic landscape is similar between NSRO-driven NSCLC in smokers and nonsmokers, smoking still affects the tumor phenotype independently of genomic alterations., Significance: Non-small cell lung cancers driven by nonsmoking-related oncogenes do not harbor genomic scars caused by smoking regardless of smoking history, indicating that the impact of smoking on these tumors is mainly nongenomic., (©2024 American Association for Cancer Research.)
- Published
- 2024
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8. Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.
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Tan AC, Lai GGY, Saw SPL, Chua KLM, Takano A, Ong BH, Koh TPT, Jain A, Tan WL, Ng QS, Kanesvaran R, Rajasekaran T, Kalashnikova E, Renner D, Sudhaman S, Malhotra M, Sethi H, Liu MC, Aleshin A, Lim WT, Tan EH, Skanderup AJ, Ang MK, and Tan DSW
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- Humans, Male, Female, Middle Aged, Aged, Retrospective Studies, Early Detection of Cancer methods, Biomarkers, Tumor genetics, Biomarkers, Tumor blood, Adult, Aged, 80 and over, Multiplex Polymerase Chain Reaction methods, Lung Neoplasms genetics, Lung Neoplasms blood, Lung Neoplasms pathology, Circulating Tumor DNA blood, Circulating Tumor DNA genetics, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local diagnosis, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung blood, Carcinoma, Non-Small-Cell Lung pathology, High-Throughput Nucleotide Sequencing methods, Neoplasm, Residual genetics, Neoplasm, Residual diagnosis, Neoplasm Staging
- Abstract
Background: In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay., Methods: This retrospective cohort study included patients with stage I-III NSCLC. Recruited patients received standard-of-care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole-exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient-specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single-nucleotide variants in plasma samples., Results: The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence-free survival (RFS; hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.00-12.62; p = .009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0-12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63-158.9; p < .0001)., Conclusions: ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
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- 2024
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9. Longitudinal post-radiotherapy plasma Epstein-Barr virus DNA trends inform on optimal risk stratification in endemic nasopharyngeal carcinoma.
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Neo J, Yip PL, Ong EHW, Miao J, Chow WM, Wee JTS, Fong KW, Soong YL, Tan TWK, Tan JSH, Sin SY, Liu J, Loh KS, Tay JK, Ang MK, Tan SH, Lim DWT, and Chua MLK
- Subjects
- Humans, Nasopharyngeal Carcinoma pathology, Herpesvirus 4, Human genetics, Prognosis, DNA, Viral, Recurrence, Risk Assessment, Epstein-Barr Virus Infections complications, Nasopharyngeal Neoplasms pathology
- Abstract
Objectives: To characterize longitudinal changes in Epstein-Barr virus (EBV) DNA post-radiotherapy in nasopharyngeal carcinoma (NPC) patients, and investigate whether an early (0-2 weeks) or delayed (8-12 weeks) EBV DNA result better predicts for disease-free survival (DFS)., Materials and Methods: Histologically-confirmed NPC patients with ≥1 EBV DNA test quantified using the harmonized BamHI-W polymerase chain reaction-based assay at 0-2 and 8-12 weeks post-radiotherapy were included., Results: We identified 302 patients with EBV DNA measured at 0-2 weeks post-radiotherapy; of which, 110 (36.4 %) underwent a repeat test at 8-12 weeks post-treatment. Patients harboring a detectable EBV DNA at 0-2 weeks experienced an inferior DFS (adjusted HR
1-264 copies 1.72 [95 %CI: 1.05-2.83], P = 0.031; AHR≥265 copies 4.39 [95 %CI: 1.68-11.44], P = 0.002 relative to 0 copies/mL). At 8-12 weeks, we observed substantial shifts in EBV DNA readings from 0 to 2 weeks; 76/110 (69.1 %) and 34/110 (30.9 %) patients at 0-2 weeks versus 90/110 (81.8 %) and 20/110 (18.2 %) at 8-12 weeks recorded undetectable and detectable EBV DNA, respectively. Positive EBV DNA at 8-12 weeks was strongly associated with relapse (73.3 % [11/15] for 1-264; 80.0 % [4/5] for ≥265 subgroups had relapses versus 15.6 % [14/90] for 0 copies/mL). Area under receiver operating curve values for 2-year relapse rates were 0.817 (95 %CI: 0.725-0.909) for stage + EBV DNA8-12w versus 0.654 (95 %CI: 0.542-0.765) for stage + EBV DNA0-2w. CONCLUSION: EBV DNA is dynamic post-radiotherapy, and delayed EBV DNA testing better enriched for higher-risk NPC patients. This implicates trials investigating adjuvant chemotherapy intensification based on early EBV DNA testing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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10. Combinatorial Hypofractionated Radiotherapy and Pembrolizumab in Anaplastic Thyroid Cancer.
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Tan JSH, Tay TKY, Ong EHW, Fehlings M, Tan DS, Sukma NB, Chen EX, Sng JH, Yip CSP, Lim KH, Lim DW, Iyer NG, Hwang JSG, Chua MLK, and Ang MK
- Abstract
Objectives Anaplastic thyroid cancer (ATC) is an aggressive disease associated with poor outcomes and resistance to therapies. Our study aim was to evaluate the activity of a combinatorial regimen of sandwich sequencing of pembrolizumab immunotherapy and hypofractionated radiotherapy (RT). Methods In this case series, patients with ATC received hypofractionated RT (QUAD-shot) and intravenous pembrolizumab 200mg every 3-4 weeks. Pembrolizumab was continued until disease progression or up till 24 months. Concurrent Lenvatinib treatment was allowed. Primary endpoint was best overall response (BOR) and progression-free survival (PFS). Additionally, we performed immune profiling of circulating T cells in a responder to investigate the immune response to our combinatorial treatment. Results At median follow-up of 32.6 months (IQR: 26.4-38.8), of a cohort of 5 patients, BOR was 80%; with 2 complete responses (CR) and 2 partial responses (PR). Patients who achieved CR remained disease-free at last follow-up. Median PFS was 7.6 months (IQR: 6.2-NR), and 1-year PFS and overall survival rate was 40% (95% CI: 13.7-100) for both. Treatment was well-tolerated, with mostly grade 1-2 adverse events. Immune profiling of one partial responder revealed an increase in activated CD4 and CD8 T cells post-QUAD-shot RT, which was further enhanced during the maintenance phase of pembrolizumab. Conclusions Herein, we reported a case series of 5 patients with ATC, with 2 long-term survivors who were treated with surgical debulking followed by QUAD-shot RT and pembrolizumab, possibly due to synergy of local and systemic treatments in activating anti-tumour immunogenic cytotoxicity. This regimen warrants further investigation in a larger cohort of patients.
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- 2024
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11. Response to fam-Trastuzumab-Deruxtecan in patients with metastatic HER2-positive salivary duct carcinoma: A case series.
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Boey JJH, Ng KYY, Krisnadi C, Lim DW, and Ang MK
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- Humans, Trastuzumab therapeutic use, Salivary Ducts, Carcinoma
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2023
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12. Boosted abscopal effect from radiotherapy and pembrolizumab in anaplastic thyroid cancer: a mini-review and case report.
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Goh D, Lim KH, Sudirman SRB, Ang MK, Chua MLK, and Lim CM
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- Female, Humans, Middle Aged, B7-H1 Antigen, Positron Emission Tomography Computed Tomography, Thyroid Carcinoma, Anaplastic drug therapy, Thyroid Carcinoma, Anaplastic pathology, Thyroid Neoplasms drug therapy, Thyroid Neoplasms diagnosis, Thyroid Neoplasms pathology, Antibodies, Monoclonal, Humanized
- Abstract
Background: The abscopal effect, in which radiation induces a systemic anti-tumour immune response, has been demonstrated with radiotherapy. Immunotherapy boosts the abscopal effect by facilitating the immune response to radiation. Radiotherapy and programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockade has resulted in the boosted abscopal effect in solid cancers, but its role in anaplastic thyroid cancer (ATC) is unknown. In this mini-review, we describe the abscopal effect and summarise its proposed underlying mechanisms. We then present a potential case of boosted abscopal effect in ATC., Case Description: In our case presentation, we describe a 51-year-old female who presented with 3 weeks of rapidly enlarging thyroid mass. Examination revealed a 3-cm thyroid nodule which was Bethesda V on fine needle aspiration cytology (FNAC). Intraoperatively, there was a gross extrathyroidal extension into the cricoid cartilage. After total thyroidectomy, post-operative histopathology showed widely invasive follicular thyroid cancer with anaplastic transformation (>50%). Immunohistochemistry showed high PD-L1 expression [combined positive score (CPS) >70%]. Due to residual cricoid cartilage disease and several peri-hilar and lung metastases on positron emission tomography-computed tomography (PET-CT) scan, she underwent post-operative palliative radiotherapy and pembrolizumab. After two cycles of pembrolizumab, repeat PET-CT scan showed complete response (CR) of local and distant disease. She remained well for 32 months, before recent discovery of a right mandible bony metastasis planned for radiotherapy., Conclusions: This case demonstrates exceptional response to radiotherapy and anti-PD-1 immunotherapy in ATC, potentially illustrating the first known abscopal effect in ATC with this treatment.
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- 2023
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13. Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma.
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Lim DW, Kao HF, Suteja L, Li CH, Quah HS, Tan DS, Tan SH, Tan EH, Tan WL, Lee JN, Wee FY, Jain A, Goh BC, Chua MLK, Liao BC, Ng QS, Hong RL, Ang MK, Yeong JP, and Iyer NG
- Subjects
- Humans, Nasopharyngeal Carcinoma pathology, Herpesvirus 4, Human genetics, Programmed Cell Death 1 Receptor, CTLA-4 Antigen, Neoplasm Recurrence, Local drug therapy, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols, Epstein-Barr Virus Infections, Nasopharyngeal Neoplasms pathology
- Abstract
Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC., (© 2023. The Author(s).)
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- 2023
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14. Real world efficacy of osimertinib in second line/beyond in patients with metastatic EGFR+ non-small cell lung cancer and role of paired tumour-plasma T790M testing at tyrosine kinase inhibitor resistance.
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Ma J, Tan SH, Yin DXC, Tran NTA, Tan GS, Lai GGY, Ang MK, Kanesvaran R, Jain A, Rajasekaran T, Tan EH, Lim TKH, Tan DS, Lim DW, Ng QS, and Tan WL
- Abstract
Background: Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) approved for use in EGFR-mutant lung cancer. We examined its performance in the second/subsequent line after resistance to first- and second-generation (1/2G) EGFR-TKI., Methods: We reviewed electronic records of 202 patients who received osimertinib from July 2015 to January 2019 in the second/subsequent line after progression on prior EGFR-TKI. Of these, complete data from 193 patients were available. Clinical data including patient characteristics, primary EGFR mutation, T790M mutation status, presence of baseline brain metastases (BM), first-line EGFR-TKI use, and survival outcomes were extracted, and results retrospectively analyzed., Results: Of 193 evaluable patients, 151 (78.2%) were T790M+ (T790M positive) with 96 (49.2%) tissue confirmed; 52% of patients received osimertinib in the second line setting. After median follow up of 37 months, median progression-free survival (PFS) of the entire cohort was 10.3 [95% confidence interval (CI): 8.64-11.50] months and median overall survival (OS) was 20 (95% CI: 15.61-23.13) months. Overall response rate (ORR) to osimertinib was 43% (95% CI: 35.9-50.3%); 48.3% in T790M+ vs . 20% in T790M- (T790M negative) patients. OS in T790M+ patients was 22.6 vs . 7.9 months in T790M- patients (HR 0.43, P=0.001), and PFS was 11.2 vs . 3.1 months respectively (HR 0.52, P=0.01). Tumour T790M+ was significantly associated with longer PFS (P=0.007) and OS (P=0.01) compared to tumour T790M- patients, however this association was not seen with plasma T790M+. Of the 22 patients with paired tumor/plasma T790M testing, response rate (RR) to osimertinib was 30% for those plasma T790M+/tumour T790M-, compared to 63% and 67% for those who were plasma T790M+/tumour T790M+ and plasma T790M-/tumour T790M+, respectively. By multivariable analysis (MVA), Eastern Cooperative Oncology Group (ECOG) performance status ≥2 was associated with shorter OS (HR 2.53, P<0.001) and PFS (HR 2.10, P<0.001), whereas presence of T790M+ was associated with longer OS (HR 0.50, P=0.008) and PFS (HR 0.57, P=0.027)., Conclusions: This cohort demonstrated the efficacy of osimertinib in second line/beyond for EGFR+ (EGFR mutation-positive) non-small cell lung cancer (NSCLC). Tissue T790M result appeared more predictive of osimertinib efficacy compared to plasma, highlighting potential T790M heterogeneity and the advantage with paired tumor-plasma T790M testing at TKI resistance. T790M- disease at resistance remains an unmet treatment need., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-661/coif). JM reports travel support for meetings from AstraZeneca. GGYL reports honoraria from Amgen and consulting/advisory role for Merck, AstraZeneca, Pfizer, Bristol Myers Squibb and Roche. MKA reports support for meetings from AstraZeneca, Boehringer Ingelheim, Ipsen; honoraria from Boston Scientific and consulting/advisory role for Merck. RK reports research funding support from Sanofi (Inst), Janssen Pharmaceuticals (Inst); honoraria from Astellas Pharma, Novartis, Janssen Pharmaceuticals, MSD Oncology, Bristol-Myers Squibb, consulting/advisory role for Pfizer, Astellas Pharma, Novartis, Mundipharma. TR reports honoraria and Speakers’ Bureau from Novartis, consulting/advisory role for Ipsen and Eisai. TKHL reports honoraria for AstraZeneca and consulting/advisory role for MSD. DSWT reports research funding from Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst); honoraria from Bristol-Myers Squibb, Takeda Pharmaceuticals, Novartis, Roche and Pfizer; consulting/advisory role for Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer. DWTL reports research funding from Bristol-Myers Squibb (Inst), honoraria from Boehringer Ingelheim, consulting/advisory role for Roche, AstraZeneca, MSD Oncology, Novartis and Boehringer Ingelheim and stock ownership from Clearbridge Biomedics. QSN reports research funding from Novartis, MSD Oncology and Bayer; honoraria from MSD Oncology, AstraZeneca and Pierre Fabre and consulting/advisory role for Boehringer Ingelheim. WLT reports educational grant support from AstraZeneca; honoraria from Novartis, Merck, and Amgen; support for meetings from AstraZeneca, Ipsen, Boehringer Ingelheim, Bristol-Myers Squibb (Inst), and DKSH. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)
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- 2023
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15. PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer.
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Saw SPL, Ng WP, Zhou S, Lai GGY, Tan AC, Ang MK, Lim WT, Kanesvaran R, Ng QS, Jain A, Tan WL, Rajasekaran T, Chan JWK, Teh YL, Pang M, Yeo JC, Takano A, Ong BH, Tan EH, Tan SH, Skanderup AJ, and Tan DSW
- Subjects
- Female, Humans, Male, B7-H1 Antigen metabolism, Biomarkers, ErbB Receptors genetics, ErbB Receptors metabolism, Mutation, Prognosis, Retrospective Studies, Aged, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
- Abstract
Aim: 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., Methods: 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., Results: 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., Conclusion: 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., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Saw reported receiving personal fees from Pfizer, Bayer, AstraZeneca and MSD outside the submitted work. Dr A. Tan reported receiving personal fees from Amgen and Pfizer outside the submitted work. Dr Lai reported receiving personal fees from Amgen and grants from Merck, Astra Zeneca, Pfizer, Bristol Myers Squibb, and Roche outside the submitted work. Dr D.W.T. Lim reported receiving grants from Bristol Myers Squibb and Boehringer-Ingelheim and personal fees from Merck, Roche, Pfizer, Taiho, and Astra-Zeneca outside the submitted work. Dr Kanesvaran reported receiving personal fees from Merck, Bristol Myers Squibb, Astellas, Johnson & Johnson, Eisai, Ipsen and Novartis outside the submitted work. Dr Ng reported serving on advisory boards for Boehringer Ingelheim and Merck outside the submitted work. Dr W.L. Tan reported receiving personal fees from Amgen, Merck and Novartis outside the submitted work. Dr. Ong reported receiving personal fees from AstraZeneca, MSD and Medtronic, non-financial support from Johnson & Johnson, personal fees and non-financial support from Stryker outside the submitted work. Dr D.S.W. Tan reported grants from AstraZeneca and Amgen and personal fees from Novartis, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Amgen, and C4 Therapeutics outside the submitted work. No other disclosures were reported., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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16. Efficacy of Anti-PD1 Blockade in Treating Recurrent or Metastatic Nasopharyngeal Cancer: A Systematic Review and Meta-analysis.
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Yeo BSY, Song HJJMD, Soong YL, Chua MLK, Ang MK, Lim DWT, See A, and Lim CM
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- Humans, Cisplatin therapeutic use, Neoplasm Recurrence, Local drug therapy, Nasopharyngeal Carcinoma drug therapy, Progression-Free Survival, Deoxycytidine therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Nasopharyngeal Neoplasms pathology
- Abstract
Objectives: Anti-PD1 antibody has emerged as a promising immunotherapeutic option in patients with recurrent and/or metastatic nasopharyngeal cancers (RM-NPC). We aim to summarise existing evidence on the use of anti-PD1 antibodies in the treatment of these patients and compare its effectiveness with standard-of-care palliative chemotherapy. Our secondary aim is to explore potential combination therapies with anti-PD1 antibodies., Materials and Methods: PubMed, Embase and Cochrane databases were systematically searched for studies comparing the efficacy of various anti-PD1 antibodies in the treatment of RM-NPC (either as first or second line treatment) from inception to 2 September 2022. Meta-analyses were performed to correlate the various anti-PD1 antibodies with primary endpoints including overall response rate disease control rate (DCR), progression free survival (PFS) and overall survival (OS)., Results: Eighteen studies with 1,887 patients met the inclusion criteria. The use of anti-PD1 antibody monotherapy as second-line treatment of RM-NPC revealed an ORR of 23 % (95 % CI = 19 %-28 %) and DCR of 51 % (95 % CI = 42 %-60 %). The ORRs for first-line as well as a combination of first and second-line treatments were 21 % (95 % CI = 15 % - 30 %) and 22 % (95 % CI = 6 % - 56 %, I
2 = 75 %) respectively. The 12-month PFS and 12-month OS was also 27 % (95 % CI = 21 %-33 %) and 63 % (95 % CI = 53 %-72 %) respectively. ORR was much higher at 73 % (95 % CI = 32 %-94 %) when anti-PD1 antibodies were combined with Gemcitabine plus Cisplatin., Conclusion: Anti-PD1 antibody demonstrate considerable activity in previously treated RM-NPC patients. Combining anti-PD1 antibodies with gemcitabine and cisplatin chemotherapy enhanced the efficacy of treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2023
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17. Multidisciplinary lung cancer clinic: An emerging model of care.
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Saw SPL, Chua KLM, Ong BH, Lim DWT, Lai GGY, Tan DSW, and Ang MK
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- Humans, Ambulatory Care Facilities, Lung Neoplasms diagnosis, Lung Neoplasms therapy
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- 2022
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18. Adjuvant Immunotherapy in Patients with Early-Stage Non-small Cell Lung Cancer and Future Directions.
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Saw SP, Ang MK, and Tan DS
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- Humans, Cisplatin therapeutic use, Adjuvants, Immunologic therapeutic use, Immunotherapy, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung therapy, Lung Neoplasms genetics, Lung Neoplasms therapy, Small Cell Lung Carcinoma
- Abstract
Opinion Statement: While cisplatin-based adjuvant chemotherapy has been the standard of care for the past two decades, the recent introduction of immunotherapy has heralded an important milestone in the adjuvant landscape of early-stage non-small cell lung cancer (NSCLC). The landmark approval of adjuvant atezolizumab based on disease-free survival (DFS) benefit in IMpower010 was swiftly followed by the recent data for use of adjuvant pembrolizumab in PEARLS/KEYNOTE-091, and similar trials involving other immune checkpoint inhibitors are eagerly anticipated. Although both atezolizumab and pembrolizumab demonstrated a significant DFS benefit in the intention-to-treat population, key subgroup analyses have raised questions about the role of predictive biomarkers such as PD-L1 expression and EGFR-mutation status. In this review, we examine the data from the two important trials (IMpower010 and PEARLS/KEYNOTE-091), discuss the controversies surrounding adjuvant immunotherapy including appropriate endpoints, biomarker selection and highlight key considerations in oncogene-driven NSCLC. Finally, we propose future directions including the impact of neoadjuvant therapy on developments in the adjuvant immunotherapy paradigm and role of minimal residual disease (MRD)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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19. Clinical and Genomic Features of HER2 Exon 20 Insertion Mutations and Characterization of HER2 Expression by Immunohistochemistry in East Asian Non-Small-Cell Lung Cancer.
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Tan AC, Saw SPL, Chen J, Lai GGY, Oo HN, Takano A, Lau DPX, Yeong JPS, Tan GS, Lim KH, Skanderup AJ, Chan JWK, Teh YL, Rajasekaran T, Jain A, Tan WL, Ng QS, Kanesvaran R, Lim WT, Ang MK, and Tan DSW
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- Exons genetics, Genomics, Humans, Immunohistochemistry, Mutagenesis, Insertional genetics, RNA therapeutic use, Receptor, ErbB-2 genetics, Trastuzumab genetics, Adenocarcinoma of Lung genetics, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
- Abstract
Purpose: HER2 -altered non-small-cell lung cancer (NSCLC) represents a diverse subgroup, including mutations, amplifications, 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., Methods: 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 amplification and overexpression as selection biomarkers in NSCLC were further interrogated using HER2 immunohistochemistry and correlations with WES and RNA sequencing data., Results: 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 HER2G776delinsVC 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 amplification., Conclusion: 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.- Published
- 2022
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20. A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.
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Lai GGY, Yeo JC, Jain A, Zhou S, Pang M, Alvarez JJS, Sim NL, Tan AC, Suteja L, Lim TW, Guo YA, Shen M, Saw SPL, Rohatgi N, Yeong JPS, Takano A, Lim KH, Gogna A, Too CW, Da Zhuang K, Tan WL, Kanesvaran R, Ng QS, Ang MK, Rajasekaran T, Wang L, Toh CK, Lim WT, Tam WL, Tan SH, Skanderup AMJ, Tan EH, and Tan DSW
- Abstract
Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC., Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI., Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15-1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events., Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI-resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients., (© 2022 by the International Association for the Study of Lung Cancer.)
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- 2022
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21. Global haemostatic tests demonstrate the absence of parameters of hypercoagulability in non-hypoxic mild COVID-19 patients: a prospective matched study.
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Fan BE, Ramanathan K, Sum CLL, Christopher D, Chan SSW, Lim GH, Bok CF, Wong SW, Lye DC, Young BE, Lim JY, Lee RM, Lim SP, Tan HT, Ang MK, Lau SL, Kuperan P, Ong KH, and Chia YW
- Subjects
- Anticoagulants therapeutic use, Factor VIII, Fibrinogen analysis, Humans, Prospective Studies, Thrombelastography, von Willebrand Factor, COVID-19 complications, Hemostatics, Thrombophilia diagnosis, Thrombophilia etiology, Thrombosis drug therapy, Venous Thromboembolism drug therapy
- Abstract
Severe COVID-19 patients demonstrate hypercoagulability, necessitating thromboprophylaxis. However, less is known about the haemostatic profile in mild COVID-19 patients. We performed an age and gender-matched prospective study of 10 severe and 10 mild COVID-19 patients. Comprehensive coagulation profiling together with Thromboelastography and Clot Waveform Analysis were performed. FBC, PT, APTT, D-dimer, fibrinogen and CWA were repeated every 3 days for both groups and repeat TEG was performed for severe patients up till 15 days. On recruitment, severe patients had markers reflecting hypercoagulability including raised median D-dimer 1.0 μg/mL (IQR 0.6, 1.4) (p = 0.0004), fibrinogen 5.6 g/L (IQR 4.9, 6.6) (p = 0.002), Factor VIII 206% (IQR 171, 203) and vWF levels 265.5% (IQR 206, 321). Mild patients had normal values of PT, aPTT, fibrinogen and D-dimer, and slightly elevated median Factor VIII and von Willebrand factor (vWF) levels. Repeated 3-day assessments for both groups showed declining trends in D-dimer and Fibrinogen. CWA of severe COVID-19 group demonstrated hypercoagulability with an elevated median values of aPTT delta change 78.8% (IQR 69.8, 85.2) (p = 0.001), aPTT clot velocity (min1) 7.8%/s (IQR 6.7, 8.3) (p = 0.001), PT delta change 22.4% (IQR 19.4, 29.5) (p = 0.004), PT min1 7.1%/s (IQR 6.3, 9.0) (p = 0.02), PT clot acceleration (min 2) 3.6%/s
2 (IQR 3.2, 4.5) (p = 0.02) and PT clot deceleration (max2) 2.9%/s2 (IQR 2.5, 3.5) (p = 0.02). TEG of severe patients reflected hypercoagulability with significant increases in the median values of CFF MA 34.6 mm (IQR 27.4,38.6) (p = 0.003), CRT Angle 78.9° (IQR 78.3, 80.0) (p = 0.0006), CRT A10 67.6 mm (IQR 65.8, 69.6) (p = 0.007) and CFF A10 32.0 mm (IQR 26.8, 34.0) (p = 0.003). Mild COVID-19 patients had absent hypercoagulability in both CWA and TEG. 2 severe patients developed thromboembolic events while none occurred in the mild COVID-19 group. Mild COVID-19 patients show absent parameters of hypercoagulability in global haemostatic tests while those with severe COVID-19 demonstrated parameters associated with hypercoagulability on the global haemostatic tests together with raised D-Dimer, fibrinogen, Factor VIII and vWF levels., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2022
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22. Pan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck.
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Keam B, Machiels JP, Kim HR, Licitra L, Golusinski W, Gregoire V, Lee YG, Belka C, Guo Y, Rajappa SJ, Tahara M, Azrif M, Ang MK, Yang MH, Wang CH, Ng QS, Wan Zamaniah WI, Kiyota N, Babu S, Yang K, Curigliano G, Peters S, Kim TW, Yoshino T, and Pentheroudakis G
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- Follow-Up Studies, Humans, Medical Oncology, Squamous Cell Carcinoma of Head and Neck diagnosis, Squamous Cell Carcinoma of Head and Neck therapy, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell therapy, Head and Neck Neoplasms diagnosis, Head and Neck Neoplasms therapy
- Abstract
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia., Competing Interests: Disclosure BK declares grants or contracts from Merck Sharp & Dohme (MSD) Oncology, Ono Pharmaceutical and AstraZeneca, consulting fees from AstraZeneca, MSD Oncology, ABL Bio, Genexine, Cellid, Handok, Celid, Trial Informatics and CBS Bio, payment or honoraria from MSD Oncology and Merck. J-PM declares consulting fees/honoraria from Pfizer, Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer, Bristol Myers Squibb (BMS), Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology, iTEOS, TheRNA and NEKTAR, support for attending meetings and/or travel from Amgen, Pfizer and MSD and participation at a Safety or Advisory Board for PsiOxus. LL declares institutional grants or contracts from AstraZeneca, BMS, Boehringer Ingelheim, Celgene International, Eisai, Exelixis Inc, Debiopharm International SA, Hoffman-La Roche Ltd., IRX Therapeutics Inc., Medpace Inc., Merck-Serono, MSD, Novartis, Pfizer, Roche Spa and Buran and receipt of honoraria or fees (for public speaking/teaching in medical meetings and/or for providing expert opinion in Advisory Boards) for AstraZeneca, Bayer, BMS, Eisai, MSD, Merck-Serono, Boehringer Ingelheim, Hoffman La Roche Ltd., Novartis, Roche, Debiopharm International SA, Sobi, Incyte Biosciences Italy SRL, Doxa Pharma, Amgen, Nanobiotics and GlaxoSmithKline (GSK). CB declares payment or honoraria from Merck KGaA, BMS and Roche. MT declares consulting fees from Ono Pharmaceuticals, MSD, BMS and Merck Biopharma, and honoraria from Eisai, Ono Pharmaceuticals, BMS and Merck Biopharma. MA declares consulting fees from MSD, AstraZeneca, Eli Lilly, DKSH, Eisai, Roche, Novartis and Merck, payment or honoraria from MSD, AstraZeneca, Eli Lilly, DKSH, Eisai, Roche, Novartis and Merck, support for attending meetings and/or travel from MSD, Roche, Elekta/Abex and AstraZeneca, and is the president of the Malaysian Oncological Society. MKA declares honoraria for presentations from Pfizer and Boehringer Ingelheim, sponsorship for meetings from AstraZeneca, Boehringer Ingelheim and DKSH. QSNg declares support for attending meetings and or travel from BMS, Boehringer Ingelheim, MSD and Astellas, and participation in Safety or Advisory Boards for MSD and Boehringer Ingelheim. WIWZ declares honoraria for lectures from Amgen Malaysia, DKSH Malaysia, Eisai Malaysia, Eli Lilly Malaysia, Ipsen Malaysia, MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck Serono Malaysia, Pfizer Malaysia and Roche Malaysia, travel grants from Amgen Malaysia, Celgene Malaysia, Eisai Malaysia, Eli Lilly Malaysia, MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche Malaysia, participation on an Advisory Board for Celgene Malaysia, Roche Malaysia, Eli Lilly Malaysia, Eisai Malaysia and MSD Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and is a member of ASCO AP Regional Council and Greater Petaling Cancer City Challenge UICC. NK declares institutional grants or contracts from Ono Pharmaceutical, BMS, AstraZeneca, Pfizer, Chugai Pharmaceutical, Rakuten Medical, Bayer and Adlai Nortye, payment or honoraria from Ono Pharmaceutical, BMS, Merck Biopharma, MSD, Eisai and Bayer, participation on a Data Safety Monitoring Board or Advisory Board for Bayer and Adlai Nortye. GC declares institutional grants from Merck, consulting fees from BMS, Pfizer, MSD, AstraZeneca, Daichii Sankyo, Lilly, Novartis and Seattle Genetics, payment or honoraria from AstraZeneca, Roche and Daichii Sankyo. SP declares fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Imedex, Medscape, MSD, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda and the receipt of grants/research support: (Sub) investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics, Roche/Genentech. TWK declares institutional grants or contracts from Roche, and sanofi-aventis. TY declares institutional grants or contracts from Taiho Pharmaceutical, Sumitomo Dainippon, Ono Pharmaceutical, Chugai Pharmaceutical, Amgen, Parexel International, MSD, Daiichi-Sankyo and Sanofi. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2021
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23. Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities.
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Chua KP, Teng YHF, Tan AC, Takano A, Alvarez JJS, Nahar R, Rohatgi N, Lai GGY, Aung ZW, Yeong JPS, Lim KH, Naeini MM, Kassam I, Jain A, Tan WL, Gogna A, Too CW, Kanesvaran R, Ng QS, Ang MK, Rajasekaran T, Anantham D, Phua GC, Tan BS, Lee YY, Wang L, Teo ASM, Khng AJ, Lim MJ, Suteja L, Toh CK, Lim WT, Iyer NG, Tam WL, Tan EH, Zhai W, Hillmer AM, Skanderup AJ, and Tan DSW
- Subjects
- ErbB Receptors genetics, Humans, Protein-Tyrosine Kinases genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Mutation
- Abstract
Purpose: 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 EGFR
T790M -negative resistance., Experimental Design: 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., Results: 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 amplifications, 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., Conclusions: Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent 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., (©2021 The Authors; Published by the American Association for Cancer Research.)- Published
- 2021
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24. Association of Clinicopathologic and Molecular Tumor Features With Recurrence in Resected Early-Stage Epidermal Growth Factor Receptor-Positive Non-Small Cell Lung Cancer.
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Saw SPL, Zhou S, Chen J, Lai G, Ang MK, Chua K, Kanesvaran R, Ng QS, Jain A, Tan WL, Rajasekaran T, Lim DWT, Tan A, Fong KW, Takano A, Cheng XM, Lim KH, Koh T, Ong BH, Tan EH, Toh CK, Skanderup AJ, Tan SH, and Tan DSW
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- Acrylamides therapeutic use, Adult, Aged, Aged, 80 and over, Aniline Compounds therapeutic use, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung epidemiology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung therapy, Cohort Studies, Disease-Free Survival, ErbB Receptors genetics, Female, Humans, Lung Neoplasms epidemiology, Lung Neoplasms pathology, Lung Neoplasms therapy, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local therapy, Neoplasm Staging, Singapore epidemiology, Young Adult, Carcinoma, Non-Small-Cell Lung genetics, Carrier Proteins genetics, Lung Neoplasms genetics, Neoplasm Recurrence, Local epidemiology, Neoplasm Recurrence, Local genetics
- Abstract
Importance: The recently published ADAURA study has posed a significant dilemma for clinicians in selecting patients for adjuvant osimertinib. Risk factors for recurrence in early-stage epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) also remain undefined., Objective: To determine clinicopathologic characteristics and recurrence patterns of resected early-stage EGFR-positive NSCLC, using wildtype EGFR as a comparator cohort, and identify features associated with recurrence., Design, Setting, and Participants: This is a cohort study including patients diagnosed with AJCC7 Stage IA to IIIA NSCLC between January 1, 2010, and June 30, 2018, who underwent curative surgical procedures at a specialist cancer center in Singapore. The cutoff for data analysis was October 15, 2020. Patient demographic characteristics, treatment history, and survival data were collated. In exploratory analysis, whole-exome sequencing was performed in a subset of 86 patients. Data were analyzed from September 3, 2020, to June 6, 2021., Exposures: Adjuvant treatment was administered per investigator's discretion., Main Outcomes and Measures: The main outcome was 2-year disease-free survival (DFS)., Results: A total of 723 patients were included (389 patients with EGFR-positive NSCLC; 334 patients with wildtype EGFR NSCLC). There were 366 women (50.6%) and 357 men (49.4%), and the median (range) age was 64 (22-88) years. A total of 299 patients (41.4%) had stage IA NSCLC, 155 patients (21.4%) had stage IB NSCLC, 141 patients (19.5%) had stage II NSCLC, and 125 patients (17.3%) had stage IIIA NSCLC. Compared with patients with wildtype EGFR NSCLC, patients with EGFR-positive NSCLC were more likely to be women (106 women [31.7%] vs 251 women [64.5%]) and never smokers (121 never smokers [36.2%] vs 317 never smokers [81.5%]). At median (range) follow up of 46 (0-123) months, 299 patients (41.4%) had cancer recurrence. There was no statistically significant difference in 2-year DFS for EGFR-positive and wildtype EGFR NSCLC (70.2% [95% CI, 65.3%-74.5%] vs 67.6% [95% CI, 62.2%-72.4%]; P = .70), although patients with EGFR-positive NSCLC had significantly better 5-year overall survival (77.7% [95% CI, 72.4%-82.1%] vs 66.6% [95% CI, 60.5%-72.0%]; P = .004). Among patients with EGFR-positive NSCLC, 2-year DFS was 81.0% (95% CI, 74.0%-86.3%) for stage IA, 78.4% (95% CI, 68.2%-85.6%) for stage IB, 57.1% (95% CI, 43.7%-68.4%) for stage II, and 46.6% (95% CI, 34.7%-57.7%) for stage IIIA. Overall, 5-year DFS among patients with stage IB through IIIA was 37.2% (95% CI, 30.1%-44.3%). Sites of disease at recurrence were similar between EGFR-positive and wildtype EGFR NSCLC, with locoregional (64 patients [16.5%] vs 56 patients [16.8%]), lung (41 patients [10.5%] vs 40 patients [12.0%]), and intracranial (37 patients [9.5%] vs 22 patients [6.6%]) metastases being the most common. A risk estimation model incorporating genomic data and an individual patient nomogram using clinicopathologic features for stage I EGFR-positive NSCLC was developed to improve risk stratification., Conclusions and Relevance: This cohort study found that recurrence rates were high in early-stage EGFR-positive NSCLC including stage IA, yet 37.2% of patients with stage IB through IIIA were cured without adjuvant osimertinib. Further studies are needed to elucidate individualized surveillance and adjuvant treatment strategies for early-stage EGFR-positive NSCLC.
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- 2021
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25. Complementary Sequential Circulating Tumor Cell (CTC) and Cell-Free Tumor DNA (ctDNA) Profiling Reveals Metastatic Heterogeneity and Genomic Changes in Lung Cancer and Breast Cancer.
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Kong SL, Liu X, Tan SJ, Tai JA, Phua LY, Poh HM, Yeo T, Chua YW, Haw YX, Ling WH, Ng RCH, Tan TJ, Loh KWJ, Tan DS, Ng QS, Ang MK, Toh CK, Lee YF, Lim CT, Lim TKH, Hillmer AM, Yap YS, and Lim WT
- Abstract
Introduction: Circulating tumor cells (CTCs) and cell-free tumor DNA (ctDNA) are tumor components present in circulation. Due to the limited access to both CTC enrichment platforms and ctDNA sequencing in most laboratories, they are rarely analyzed together., Methods: Concurrent isolation of ctDNA and single CTCs were isolated from lung cancer and breast cancer patients using the combination of size-based and CD45-negative selection method via DropCell platform. We performed targeted amplicon sequencing to evaluate the genomic heterogeneity of CTCs and ctDNA in lung cancer and breast cancer patients., Results: Higher degrees of genomic heterogeneity were observed in CTCs as compared to ctDNA. Several shared alterations present in CTCs and ctDNA were undetected in the primary tumor, highlighting the intra-tumoral heterogeneity of tumor components that were shed into systemic circulation. Accordingly, CTCs and ctDNA displayed higher degree of concordance with the metastatic tumor than the primary tumor. The alterations detected in circulation correlated with worse survival outcome for both lung and breast cancer patients emphasizing the impact of the metastatic phenotype. Notably, evolving genetic signatures were detected in the CTCs and ctDNA samples during the course of treatment and disease progression., Conclusions: A standardized sample processing and data analysis workflow for concurrent analysis of CTCs and ctDNA successfully dissected the heterogeneity of metastatic tumor in circulation as well as the progressive genomic changes that may potentially guide the selection of appropriate therapy against evolving tumor clonality., Competing Interests: ST is the current employee of Sysmex and ex-employee of Clearbridge mFluidics Pte Ltd. YL is ex-employee of Biolidics Ltd. CL is a cofounder and shareholder of Biolidics Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kong, Liu, Tan, Tai, Phua, Poh, Yeo, Chua, Haw, Ling, Ng, Tan, Loh, Tan, Ng, Ang, Toh, Lee, Lim, Lim, Hillmer, Yap and Lim.)
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- 2021
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26. Individualized Molecular Profiling for Allocation to Clinical Trials Singapore Study-An Asian Tertiary Cancer Center Experience.
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Seet AOL, Tan AC, Tan TJ, Ng MCH, Tai DWM, Lam JYC, Tan GS, Gogna A, Too CW, Tan BS, Takano A, Lim A, Lim TH, Lim ST, Dent RA, Ang MK, Yap YS, Tan IBH, Choo SP, Toh CK, Lim EH, Farid M, Skanderup AJ, Iyer NG, Lim WT, Tan EH, Lim TKH, and Tan DSW
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- Adult, Aged, Aged, 80 and over, Cancer Care Facilities, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Prospective Studies, Singapore, Tertiary Care Centers, Young Adult, Clinical Trials as Topic, Gene Expression Profiling, Neoplasms genetics, Neoplasms therapy, Precision Medicine
- Abstract
Purpose: 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 and Methods: Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized 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., Results: 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., Conclusion: Individualized 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., Competing Interests: Aaron C. Tan Honoraria: Amgen, Thermo Fisher Scientific Travel, Accommodations, Expenses: ASLAN Pharmaceuticals, Illumina Tira J. Tan Stock and Other Ownership Interests: Immunomedics Honoraria: AstraZeneca, Roche/Genentech Consulting or Advisory Role: AstraZeneca, Lilly, Pfizer, DKSH, Novartis Speakers' Bureau: Novartis Research Funding: Bayer, Novartis, AstraZeneca, Odonate Therapeutics, Synthon Travel, Accommodations, Expenses: AstraZeneca, Eisai Matthew C. H. Ng Honoraria: MSD Oncology, Taiho Pharmaceutical, ASLAN Pharmaceuticals, Lilly Consulting or Advisory Role: MSD Oncology, Bristol Myers Squibb, Novartis, Merck Speakers' Bureau: Lilly Research Funding: ASLAN Pharmaceuticals Travel, Accommodations, Expenses: MSD Oncology, Taiho Pharmaceutical, Bristol Myers Squibb David W. M. Tai Honoraria: Bristol Myers Squibb, Eisai Consulting or Advisory Role: Bristol Myers Squibb, Eisai Speakers' Bureau: Ipsen, Bristol Myers Squibb, Eisai, Roche Research Funding: Bristol-Myers Squibb, Sirtex Medical, Novartis. Justina Y. C. Lam Honoraria: AstraZeneca Consulting or Advisory Role: AstraZeneca Research Funding: Bayer, Merus, Bristol Myers Squibb Travel, Accommodations, Expenses: Lilly Bien-Soo Tan Research Funding: Boston Scientific Rebecca Alexandra Dent Honoraria: Roche/Genentech, AstraZeneca, Pfizer, MSD Consulting or Advisory Role: Roche, Pfizer, Merck, Eisai, AstraZeneca, Novartis Travel, Accommodations, Expenses: Roche, Pfizer, Amgen, Merck Yoon-Sim Yap Honoraria: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Consulting or Advisory Role: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Travel, Accommodations, Expenses: Pfizer, AstraZeneca, Eisai, Lilly, Roche, Novartis Iain B. H. Tan Honoraria: Amgen, Roche, Merck Serono, MSD Consulting or Advisory Role: Amgen, Roche, Merck Serono, MSD, Novartis Research Funding: MSD Travel, Accommodations, Expenses: Merck Serono, Amgen Su Pin Choo Honoraria: Bristol Myers Squibb, AstraZeneca Consulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Bayer, MSD Oncology, Eisai, Roche Travel, Accommodations, Expenses: Taiho Pharmaceutical, Bristol Myers Squibb Chee-Keong Toh Stock and Other Ownership Interests: Nektar Consulting or Advisory Role: Merck, Bristol Myers Squibb/Celgene, Astellas Pharma, MSD Oncology, Roche, DKSH, Natera, Eisai, Pfizer Speakers' Bureau: Ipsen, AstraZeneca, Merck, Astellas Pharma Mohamad Farid Honoraria: Bayer Consulting or Advisory Role: Bayer N. Gopalakrishna Iyer Consulting or Advisory Role: InvitroCue Patents, Royalties, Other Intellectual Property: A device and method of providing lighting during surgeries in deep and narrow cavities Inventors: N. C. Tan, W. S. Tan, M. H. Chew, H. K. Tan, P. Sunkeri, R. S. L. Lieu, F. W. L. Loke, N. G. Iyer. PCTSG2016-050231. Licensed to Vivo Surgical Pte Ltd Wan Teck Lim Consulting or Advisory Role: Roche, AstraZeneca, MSD Oncology, Novartis, Boehringer Ingelheim Research Funding: Bristol Myers Squibb Travel, Accommodations, Expenses: AstraZeneca, Taiho Pharmaceutical Daniel S. W. Tan Honoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, Pfizer Consulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer Research Funding: Novartis, GlaxoSmithKline, AstraZeneca Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche No other potential conflicts of interest were reported.Aaron C. Tan Honoraria: Amgen, Thermo Fisher Scientific Travel, Accommodations, Expenses: ASLAN Pharmaceuticals, Illumina Tira J. Tan Stock and Other Ownership Interests: Immunomedics Honoraria: AstraZeneca, Roche/Genentech Consulting or Advisory Role: AstraZeneca, Lilly, Pfizer, DKSH, Novartis Speakers' Bureau: Novartis Research Funding: Bayer, Novartis, AstraZeneca, Odonate Therapeutics, Synthon Travel, Accommodations, Expenses: AstraZeneca, Eisai Matthew C. H. Ng Honoraria: MSD Oncology, Taiho Pharmaceutical, ASLAN Pharmaceuticals, Lilly Consulting or Advisory Role: MSD Oncology, Bristol Myers Squibb, Novartis, Merck Speakers' Bureau: Lilly Research Funding: ASLAN Pharmaceuticals Travel, Accommodations, Expenses: MSD Oncology, Taiho Pharmaceutical, Bristol Myers Squibb David W. M. Tai Honoraria: Bristol Myers Squibb, Eisai Consulting or Advisory Role: Bristol Myers Squibb, Eisai Speakers' Bureau: Ipsen, Bristol Myers Squibb, Eisai, Roche Research Funding: Bristol-Myers Squibb, Sirtex Medical, Novartis. Justina Y. C. Lam Honoraria: AstraZeneca Consulting or Advisory Role: AstraZeneca Research Funding: Bayer, Merus, Bristol Myers Squibb Travel, Accommodations, Expenses: Lilly Bien-Soo Tan Research Funding: Boston Scientific Rebecca Alexandra Dent Honoraria: Roche/Genentech, AstraZeneca, Pfizer, MSD Consulting or Advisory Role: Roche, Pfizer, Merck, Eisai, AstraZeneca, Novartis Travel, Accommodations, Expenses: Roche, Pfizer, Amgen, Merck Yoon-Sim Yap Honoraria: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Consulting or Advisory Role: Novartis, Lilly, Pfizer, AstraZeneca, Eisai, MSD, Inivata Travel, Accommodations, Expenses: Pfizer, AstraZeneca, Eisai, Lilly, Roche, Novartis Iain B. H. Tan Honoraria: Amgen, Roche, Merck Serono, MSD Consulting or Advisory Role: Amgen, Roche, Merck Serono, MSD, Novartis Research Funding: MSD Travel, Accommodations, Expenses: Merck Serono, Amgen Su Pin Choo Honoraria: Bristol Myers Squibb, AstraZeneca Consulting or Advisory Role: Bristol Myers Squibb, AstraZeneca, Bayer, MSD Oncology, Eisai, Roche Travel, Accommodations, Expenses: Taiho Pharmaceutical, Bristol Myers Squibb Chee-Keong Toh Stock and Other Ownership Interests: Nektar Consulting or Advisory Role: Merck, Bristol Myers Squibb/Celgene, Astellas Pharma, MSD Oncology, Roche, DKSH, Natera, Eisai, Pfizer Speakers' Bureau: Ipsen, AstraZeneca, Merck, Astellas Pharma Mohamad Farid Honoraria: Bayer Consulting or Advisory Role: Bayer N. Gopalakrishna Iyer Consulting or Advisory Role: InvitroCue Patents, Royalties, Other Intellectual Property: A device and method of providing lighting during surgeries in deep and narrow cavities Inventors: N. C. Tan, W. S. Tan, M. H. Chew, H. K. Tan, P. Sunkeri, R. S. L. Lieu, F. W. L. Loke, N. G. Iyer. PCTSG2016-050231. Licensed to Vivo Surgical Pte Ltd Wan Teck Lim Consulting or Advisory Role: Roche, AstraZeneca, MSD Oncology, Novartis, Boehringer Ingelheim Research Funding: Bristol Myers Squibb Travel, Accommodations, Expenses: AstraZeneca, Taiho Pharmaceutical Daniel S. W. Tan Honoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, Pfizer Consulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer Research Funding: Novartis, GlaxoSmithKline, AstraZeneca Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)
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- 2021
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27. Phase II study of nimotuzumab (TheraCim-hR3) concurrent with cisplatin/radiotherapy in patients with locally advanced head and neck squamous cell carcinoma.
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Ang MK, Montoya JE, Tharavichitkul E, Lim C, Tan T, Wang LY, Wee J, Soong YL, Fong KW, Ng QS, Tan DS, Toh CK, Tan EH, and Lim WT
- Subjects
- Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chemoradiotherapy, Cisplatin therapeutic use, Female, Humans, Male, Squamous Cell Carcinoma of Head and Neck therapy, Carcinoma, Squamous Cell drug therapy, Head and Neck Neoplasms therapy
- Abstract
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
2 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., (© 2021 Wiley Periodicals LLC.)- Published
- 2021
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28. COVID-19 associated coagulopathy in critically ill patients: A hypercoagulable state demonstrated by parameters of haemostasis and clot waveform analysis.
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Fan BE, Ng J, Chan SSW, Christopher D, Tso ACY, Ling LM, Young BE, Wong LJL, Sum CLL, Tan HT, Ang MK, Lim GH, Ong KH, Kuperan P, and Chia YW
- Subjects
- Adult, Blood Coagulation Tests, COVID-19 complications, COVID-19 physiopathology, Critical Illness, Female, Humans, Lupus Coagulation Inhibitor blood, Male, Middle Aged, Retrospective Studies, Thrombophilia blood, Blood Coagulation, COVID-19 blood, Thrombophilia virology
- Abstract
Patients with COVID-19 are known to be at risk of developing both venous, arterial and microvascular thrombosis, due to an excessive immuno-thrombogenic response to the SARS-CoV-2 infection. Overlapping syndromes of COVID-19 associated coagulopathy with consumptive coagulopathy and microangiopathy can be seen in critically ill patients as well. Blood was collected from 12 Intensive Care Unit (ICU) patients with severe COVID-19 who were on either mechanical ventilation or on high flow oxygen with a PaO2/FiO2 ratio of <300 mmHg. Laboratory tests were performed for parameters of haemostasis, clot waveform analysis and anti-phospholipid antibodies. CWA parameters were raised with elevated aPTT median Min1 (clot velocity) 9.3%/s (IQR 7.1-9.9%/s), elevated PT median Min1 10.3%/s (IQR 7.1-11.1%/s), elevated aPTT median Min2 (clot acceleration) 1.5%/s
2 (IQR 1.0-1.6%/s2 ), elevated PT median Min2 5.2%/s2 (3.6-5.7%/s2 ), elevated aPTT median Max2 (clot deceleration) 1.3%/s2 (IQR 0.8-1.4%/s2 ) elevated PT median Max2 3.8%/s2 (IQR 2.6-4.2%/s2 ), increased aPTT median Delta change (decreased light transmission due to increased clot formation) 87.8% (IQR 70.2-91.8%) and PT median Delta change 33.0%. This together with raised median Factor VIII levels of 262.5%, hyperfibrinogenemia (median fibrinogen levels 7.5 g/L), increased median von Willebrand factor antigen levels 320% and elevated median D-dimer levels 1.7 μg/dl support the diagnosis of COVID-19 associated coagulopathy. A lupus anticoagulant was present in 50% of patients. Our laboratory findings further support the view that severe SARS-CoV-2 infection is associated with a state of hypercoagulability.- Published
- 2021
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29. Pairing a prognostic target with potential therapeutic strategy for head and neck cancer.
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Lek SM, Li K, Tan QX, Shannon NB, Ng WH, Hendrikson J, Tan JWS, Lim HJ, Chen Y, Koh KKN, Skanthakumar T, Kwang XL, Chong FT, Leong HS, Tay G, Putri NE, Lim TKH, Hwang JSG, Ang MK, Tan DSW, Tan NC, Tan HK, Kon OL, Soo KC, Iyer NG, and Ong CJ
- Subjects
- Adenosine Triphosphatases genetics, Aurora Kinase A antagonists & inhibitors, Cell Line, Tumor, Female, Gene Silencing, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Humans, Immunohistochemistry, Male, Membrane Transport Proteins genetics, Molecular Targeted Therapy methods, Prognosis, RNA, Small Interfering, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck genetics, Squamous Cell Carcinoma of Head and Neck pathology, Tissue Array Analysis, Adenosine Triphosphatases metabolism, Aurora Kinase A metabolism, Head and Neck Neoplasms metabolism, Membrane Transport Proteins metabolism, Protein Kinase Inhibitors therapeutic use, Signal Transduction genetics, Squamous Cell Carcinoma of Head and Neck metabolism
- Abstract
Objectives: We have previously identified and validated a panel of molecular prognostic markers (ATP13A3, SSR3, and ANO1) for Head and Neck Squamous Cell Carcinoma (HNSCC). The aim of this study was to investigate the consequence of ATP13A3 dysregulation on signaling pathways, to aid in formulating a therapeutic strategy targeting ATP13A3-overexpressing HNSCC., Materials and Methods: Gene Set Enrichment Analysis (GSEA) was performed on HNSCC microarray expression data (Internal local dataset [n = 92], TCGA [n = 232], EMBL [n = 81]) to identify pathways associated with high expression of ATP13A3. Validation was performed using immunohistochemistry (IHC) on tissue microarrays (TMAs) of head and neck cancers (n = 333), staining for ATP13A3 and phosphorylated Aurora kinase A (phospho-T288). Short interfering RNA was used to knockdown ATP13A3 expression in patient derived HNSCC cell lines. Protein expression of ATP13A3 and Aurora kinase A was then assessed by immunoblotting., Results: GSEA identified Aurora kinase pathway to be associated with high expression of ATP13A3 (p = 0.026). The Aurora kinase pathway was also associated with a trend towards poor prognosis and tumor aggressiveness (p = 0.086, 0.094, respectively). Furthermore, the immunohistochemical staining results revealed a significant association between Aurora kinase activity and high ATP13A3 expression (p < 0.001). Knockdown of ATP13A3 in human head and neck cell lines showed decrease in Aurora kinase A levels., Conclusion: Tumors with high ATP13A3 are associated with high Aurora kinase activity. This suggests a potential therapeutic role of Aurora kinase inhibitors in a subset of poor prognosis HNSCC patients with overexpression of ATP13A3., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2020
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30. Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC.
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Tan AC, Seet AOL, Lai GGY, Lim TH, Lim AST, Tan GS, Takano A, Tai DWM, Tan TJY, Lam JYC, Ng MCH, Tan WL, Ang MK, Kanesvaran R, Ng QS, Jain A, Rajasekaran T, Lim WT, Tan EH, Lim TKH, and Tan DSW
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Gene Rearrangement, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Proto-Oncogene Proteins c-ret genetics, Retrospective Studies, Lung Neoplasms genetics, Lung Neoplasms therapy
- Abstract
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., (Copyright © 2020. Published by Elsevier Inc.)
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- 2020
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31. High-Dimensional Characterization of the Systemic Immune Landscape Informs on Synergism Between Radiation Therapy and Immune Checkpoint Blockade.
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Chua KLM, Fehlings M, Yeo ELL, Nardin A, Sumatoh H, Chu PL, Nei WL, Ong EHW, Woo WY, Low KP, Wang H, Poon DJJ, Liang ZG, Yao K, Huang L, Toh CK, Ang MK, Farid M, Cheng XM, Kanesvaran R, Dent R, Wee JTS, Lim TKH, Iyer NG, Tan DSW, Soo KC, Newell EW, and Chua MLK
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- B7-H1 Antigen metabolism, Cell Line, Tumor, Cell Survival immunology, Cell Survival radiation effects, Combined Modality Therapy, Humans, Immunophenotyping, Killer Cells, Natural cytology, Killer Cells, Natural immunology, Killer Cells, Natural radiation effects, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes radiation effects, Immune Checkpoint Inhibitors pharmacology, Radiotherapy
- Abstract
Purpose: Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated., Methods and Materials: In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry-based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses., Results: Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype., Conclusions: Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2020
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32. Global haemostatic tests in rapid diagnosis and management of COVID-19 associated coagulopathy in acute limb ischaemia.
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Fan BE, Chia YW, Sum CLL, Kuperan P, Chan SSW, Ling LM, Tan GWL, Goh SSN, Wong LH, Lim SP, Lim KGE, Tan HT, Ang MK, Lau SL, Ong KH, and Ng J
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- Adult, Anticoagulants, Arterial Occlusive Diseases blood, Arterial Occlusive Diseases therapy, Arterial Occlusive Diseases virology, COVID-19, Coronavirus Infections blood, Coronavirus Infections therapy, Coronavirus Infections virology, Endovascular Procedures, Host-Pathogen Interactions, Humans, Ischemia blood, Ischemia therapy, Ischemia virology, Male, Pandemics, Pneumonia, Viral blood, Pneumonia, Viral therapy, Pneumonia, Viral virology, Predictive Value of Tests, SARS-CoV-2, Thromboembolism blood, Thromboembolism therapy, Thromboembolism virology, Time Factors, Treatment Outcome, Workflow, Arterial Occlusive Diseases diagnosis, Betacoronavirus pathogenicity, Coronavirus Infections diagnosis, Hemostasis drug effects, Ischemia diagnosis, Lower Extremity blood supply, Pneumonia, Viral diagnosis, Thrombelastography, Thromboembolism diagnosis
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- 2020
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33. Twenty-five years of Respirology: Advances in lung cancer.
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Ang MK and Mok TSK
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- 2020
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34. 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.
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Tan AC, Lai GGY, Tan GS, Poon SY, Doble B, Lim TH, Aung ZW, Takano A, Tan WL, Ang MK, Tan BS, Devanand A, Too CW, Gogna A, Ong BH, Koh TPT, Kanesvaran R, Ng QS, Jain A, Rajasekaran T, Lim AST, Lim WT, Toh CK, Tan EH, Lim TKH, and Tan DSW
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- Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung economics, Adenocarcinoma of Lung genetics, Adult, Aged, Aged, 80 and over, Asia, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung economics, Carcinoma, Non-Small-Cell Lung genetics, ErbB Receptors genetics, Female, Follow-Up Studies, Humans, Lung Neoplasms drug therapy, Lung Neoplasms economics, Lung Neoplasms genetics, Male, Middle Aged, Mutation, Prognosis, Retrospective Studies, Adenocarcinoma of Lung pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung pathology, Cost-Benefit Analysis, High-Throughput Nucleotide Sequencing methods, Lung Neoplasms pathology, Molecular Targeted Therapy
- Abstract
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., (Copyright © 2019. Published by Elsevier B.V.)
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- 2020
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35. Association of clinical factors with survival outcomes in laryngeal squamous cell carcinoma (LSCC).
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Fong PY, Tan SH, Lim DWT, Tan EH, Ng QS, Sommat K, Tan DSW, and Ang MK
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- Adult, Age Factors, Aged, Aged, 80 and over, Chemoradiotherapy, Adjuvant statistics & numerical data, Comorbidity, Female, Humans, Kaplan-Meier Estimate, Laryngeal Neoplasms pathology, Laryngeal Neoplasms therapy, Larynx pathology, Larynx radiation effects, Larynx surgery, Lymphatic Metastasis pathology, Lymphatic Metastasis therapy, Male, Middle Aged, Neoadjuvant Therapy statistics & numerical data, Neoplasm Staging, Prognosis, Progression-Free Survival, Retrospective Studies, Singapore epidemiology, Squamous Cell Carcinoma of Head and Neck pathology, Squamous Cell Carcinoma of Head and Neck therapy, Laryngeal Neoplasms mortality, Laryngectomy statistics & numerical data, Organ Sparing Treatments statistics & numerical data, Squamous Cell Carcinoma of Head and Neck mortality
- Abstract
Aim: Treatment strategies in laryngeal squamous cell cancer (LSCC) straddle the need for long term survival and tumor control as well as preservation of laryngeal function as far as possible. We sought to identify prognostic factors affecting LSCC outcomes in our population., Methods: Clinical characteristics, treatments and survival outcomes of patients with LSCC were analysed. Baseline comorbidity data was collected and age-adjusted Charlson Comorbidity Index (aCCI) was calculated. Outcomes of overall survival (OS), progression-free survival (PFS) and laryngectomy-free survival (LFS) were evaluated., Results: Two hundred and fifteen patients were included, 170 (79%) underwent primary radiation/ chemoradiation and the remainder upfront surgery with adjuvant therapy where indicated. The majority of patients were male, Chinese and current/ex-smokers. Presence of comorbidity was common with median aCCI of 3. Median OS was 5.8 years. On multivariable analyses, high aCCI and advanced nodal status were associated with inferior OS (HR 1.24 per one point increase in aCCI, P<0.001 and HR 3.52; p<0.001 respectively), inferior PFS (HR 1.14; p = 0.007 and HR 3.23; p<0.001 respectively) and poorer LFS (HR 1.19; p = 0.001 and HR 2.95; p<0.001 respectively). Higher tumor (T) stage was associated with inferior OS and LFS (HR 1.61; p = 0.02 and HR 1.91; p = 0.01 respectively)., Conclusion: In our Asian population, the presence of comorbidities and high nodal status were associated with inferior OS, PFS and LFS whilst high T stage was associated with inferior LFS and OS., Competing Interests: The authors have declared that no competing interests exist.
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- 2019
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36. Clonal MET Amplification as a Determinant of Tyrosine Kinase Inhibitor Resistance in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.
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Lai GGY, Lim TH, Lim J, Liew PJR, Kwang XL, Nahar R, Aung ZW, Takano A, Lee YY, Lau DPX, Tan GS, Tan SH, Tan WL, Ang MK, Toh CK, Tan BS, Devanand A, Too CW, Gogna A, Ong BH, Koh TPT, Kanesvaran R, Ng QS, Jain A, Rajasekaran T, Yuan J, Lim TKH, Lim AST, Hillmer AM, Lim WT, Iyer NG, Tam WL, Zhai W, Tan EH, and Tan DSW
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- Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung enzymology, Carcinoma, Non-Small-Cell Lung secondary, Cell Line, Tumor, Databases, Factual, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, ErbB Receptors metabolism, Genetic Heterogeneity, Humans, In Situ Hybridization, Fluorescence, Lung Neoplasms drug therapy, Lung Neoplasms enzymology, Lung Neoplasms pathology, Predictive Value of Tests, Protein Kinase Inhibitors therapeutic use, Reproducibility of Results, Retrospective Studies, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung genetics, Drug Resistance, Neoplasm genetics, Gene Amplification, Gene Dosage, Lung Neoplasms genetics, Mutation, Proto-Oncogene Proteins c-met genetics
- Abstract
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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- 2019
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37. Correction to: Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases.
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Tan WL, Ng QS, Lim C, Tan EH, Toh CK, Ang MK, Kanesvaran R, Jain A, Tan DSW, and Lim DW
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ᅟ.
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- 2018
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38. Influence of afatinib dose on outcomes of advanced EGFR-mutant NSCLC patients with brain metastases.
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Tan WL, Ng QS, Lim C, Tan EH, Toh CK, Ang MK, Kanesvaran R, Jain A, Tan DSW, and Lim DW
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- Adult, Aged, Aged, 80 and over, Brain Neoplasms drug therapy, Brain Neoplasms secondary, Carcinoma, Non-Small-Cell Lung drug therapy, Dose-Response Relationship, Drug, ErbB Receptors genetics, Female, Humans, Lung Neoplasms drug therapy, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Afatinib administration & dosage, Antineoplastic Agents administration & dosage, Brain Neoplasms genetics, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics, Mutation genetics
- Abstract
Background: Afatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control., Methods: We performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models., Results: Out of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3-19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD (n = 17) vs. 30 mg OD (n = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15-0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34-1.80)., Conclusion: In patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.
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- 2018
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39. A Decade of Never-smokers Among Lung Cancer Patients-Increasing Trend and Improved Survival.
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Toh CK, Ong WS, Lim WT, Tan DS, Ng QS, Kanesvaran R, Seow WJ, Ang MK, and Tan EH
- Subjects
- Adenocarcinoma drug therapy, Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Cohort Studies, Female, Follow-Up Studies, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Male, Middle Aged, Prognosis, Risk Factors, Survival Rate, Adenocarcinoma mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinoma, Non-Small-Cell Lung mortality, Lung Neoplasms mortality, Smokers statistics & numerical data, Smoking mortality
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
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- 2018
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40. Correction: Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes.
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Walter V, Yin X, Wilkerson MD, Cabanski CR, Zhao N, Du Y, Ang MK, Hayward MC, Salazar AH, Hoadley KA, Fritchie K, Sailey CJ, Weissler MC, Shockley WW, Zanation AM, Hackman T, Thorne LB, Funkhouser WD, Muldrew KL, Olshan AF, Randell SH, Wright FA, Shores CG, and Hayes DN
- Abstract
[This corrects the article DOI: 10.1371/journal.pone.0056823.].
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- 2018
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41. Long noncoding RNA EGFR-AS1 mediates epidermal growth factor receptor addiction and modulates treatment response in squamous cell carcinoma.
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Tan DSW, Chong FT, Leong HS, Toh SY, Lau DP, Kwang XL, Zhang X, Sundaram GM, Tan GS, Chang MM, Chua BT, Lim WT, Tan EH, Ang MK, Lim TKH, Sampath P, Chowbay B, Skanderup AJ, DasGupta R, and Iyer NG
- Subjects
- Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell genetics, Cell Proliferation, Drug Resistance, Neoplasm genetics, Esophageal Neoplasms genetics, Esophageal Squamous Cell Carcinoma, Female, Gefitinib, Gene Knockdown Techniques, Head and Neck Neoplasms genetics, Humans, In Vitro Techniques, Male, Middle Aged, Molecular Targeted Therapy, Mouth Neoplasms genetics, RNA Isoforms, RNA Splicing, Squamous Cell Carcinoma of Head and Neck, Xenograft Model Antitumor Assays, Carcinoma, Squamous Cell drug therapy, ErbB Receptors genetics, Esophageal Neoplasms drug therapy, Head and Neck Neoplasms drug therapy, Mouth Neoplasms drug therapy, Protein Kinase Inhibitors therapeutic use, Quinazolines therapeutic use, RNA, Long Noncoding genetics
- 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.
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- 2017
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42. Improved Survival of Advanced Lung Cancer in Singapore Over the Past Decade.
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Toh CK, Ong WS, Tan DS, Ng QS, Kanesvaran R, Fong KW, Ang MK, Tan EH, and Lim WT
- Subjects
- Adenocarcinoma of Lung, Aged, Antineoplastic Agents therapeutic use, Female, Humans, Male, Neoplasm Staging, Prognosis, Retrospective Studies, Singapore epidemiology, Survival Analysis, Adenocarcinoma drug therapy, Adenocarcinoma mortality, Adenocarcinoma pathology, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung mortality, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell pathology, ErbB Receptors antagonists & inhibitors, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Lung Neoplasms pathology, Pemetrexed therapeutic use
- Abstract
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; P = 0.005) and adenocarcinoma (12.7 to 15.4 months; P = 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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- 2017
43. A three gene immunohistochemical panel serves as an adjunct to clinical staging of patients with head and neck cancer.
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Ong CJ, Shannon NB, Mueller S, Lek SM, Qiu X, Chong FT, Li K, Koh KKN, Tay GCA, Skanthakumar T, Hwang JSG, Hon Lim TK, Ang MK, Tan DSW, Tan NC, Tan HK, Soo KC, and Iyer NG
- Abstract
Background: Current management of head and neck squamous cell carcinoma (HNSCC) depends on tumor staging. Despite refinements in clinical staging algorithms, outcomes remain unchanged for the last two decades. In this study, we set out to identify a small, clinically applicable molecular panel to aid prognostication of patients with HNSCC., Materials and Methods: Data from The Cancer Genome Atlas (TCGA) was used to derive copy number aberrations and expression changes to identify putative prognostic genes. To account for cross entity relevance of the biomarkers, HNSCC ( n = 276), breast ( n = 808) and lung cancer ( n = 282) datasets were used to identify robust and reproducible markers with prognostic potential. Validation was performed using immunohistochemistry (IHC) on tissue microarrays of an independent cohort of HNSCC ( n = 333)., Findings: Using GISTIC algorithm together with gene expression analysis, we identified six putative prognostic genes in at least two out of three cancers analyzed, of which four were successfully optimized for automated IHC. Of these, three were successfully validated; each molecular target being significantly prognostic on univariate analysis. Patients were differentially segregated into four prognostic groups based on the number of genes dysregulated ( p < 0.001). The IHC panel remained an independent predictor of survival after adjusting for known survival covariates including clinical staging criteria in a multivariate Cox regression model ( p < 0.001). ., Interpretation: We have identified and validated a clinically applicable IHC biomarker panel that is independently associated with overall survival. This panel is readily applicable, serving as a useful adjunct to current staging systems and provides novel targets for future therapeutic strategies., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interests.
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- 2017
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44. EGFR Mutation Subtypes Influence Survival Outcomes following First-Line Gefitinib Therapy in Advanced Asian NSCLC Patients.
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Sutiman N, Tan SW, Tan EH, Lim WT, Kanesvaran R, Ng QS, Jain A, Ang MK, Tan WL, Toh CK, and Chowbay B
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma secondary, Adult, Aged, Aged, 80 and over, Asian People genetics, Biomarkers, Tumor genetics, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung secondary, Female, Follow-Up Studies, Gefitinib, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Staging, Prognosis, Protein Kinase Inhibitors therapeutic use, Retrospective Studies, Survival Rate, Adenocarcinoma mortality, Carcinoma, Non-Small-Cell Lung mortality, ErbB Receptors genetics, Lung Neoplasms mortality, Mutation, Quinazolines therapeutic use
- Abstract
Introduction: Activating mutations in the EGFR gene have been shown to confer sensitivity to EGFR tyrosine kinase inhibitors in patients with advanced NSCLC. However, wide interpatient variability in treatment outcomes in response to EGFR tyrosine kinase inhibitors in these patients remains unaccounted for. This study aimed to evaluate the influence of EGFR mutation types and subtypes on survival outcomes in advanced Asian patients with NSCLC receiving first-line gefitinib therapy., Methods: Patients with stage IIIB or IV NSCLC who were harboring EGFR mutations, receiving first-line gefitinib treatment, and of Asian descent (N = 383) were evaluated. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Log-rank tests and Cox proportional hazards models were implemented to evaluate the differences in PFS and OS., Results: Significant differences in PFS were observed between patients carrying EGFR mutations in exons 18, 19, 20, and 21, with patients carrying EGFR exon 19 mutations having the longest median PFS (overall p = 8.88 × 10
-15 ). Comparison of PFS among the five different exon 19 mutation subtypes and among the two exon 19 deletion start codons did not reveal any significant differences. No significant difference was observed in OS among patients carrying EGFR mutations on different exons (overall p = 0.054); however, OS was found to be significantly different among the various subtypes of exon 19 mutations, with the 15-nucleotide deletion "non-ELREA" group having the shortest OS of 11.3 months (overall p = 0.025)., Conclusions: EGFR mutation types and subtypes significantly influence survival outcomes in patients with advanced NSCLC who are receiving first-line gefitinib treatment., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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45. Influence of the KDM4A rs586339 polymorphism on overall survival in Asian non-small-cell lung cancer patients.
- Author
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Marvalim C, Wong JX, Sutiman N, Lim WT, Tan SW, Kanesvaran R, Ng QS, Jain A, Ang MK, Tan WL, Toh CK, Tan EH, and Chowbay B
- Subjects
- Adult, Aged, Aged, 80 and over, Asian People genetics, Carcinoma, Non-Small-Cell Lung ethnology, Female, Genetic Association Studies, Humans, Kaplan-Meier Estimate, Lung Neoplasms ethnology, Male, Middle Aged, Sequence Analysis, DNA, Survival Analysis, Asian People ethnology, Carcinoma, Non-Small-Cell Lung genetics, Jumonji Domain-Containing Histone Demethylases genetics, Lung Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
The critical role of lysine demethylase 4A (KDM4A), in regulating chromatin structure and consequently in driving cellular proliferation and oncogenesis has been the focus of recent studies. Non-small-cell lung cancer (NSCLC) patients with adenocarcinoma histology who were homozygous for KDM4A single nucleotide polymorphism (SNP)-A482 (rs586339) were recently shown to have significantly worse overall survival (OS) compared with patients with the wild-type or the heterozygous genotype at this locus (hazard ratio=1.68, P=0.042). In the current study, we investigated the association between the same polymorphism with OS in our Asian NSCLC-adenocarcinoma patients comprising Chinese (N=572), Malays (N=50), and Indians (N=22). KDM4A SNP-A482 genotype status was determined by Sanger sequencing. OS was calculated from the date of diagnosis to date of death or censored at the date of last follow-up. Kaplan-Meier analysis, log-rank test, and Cox regression methods were utilized to evaluate OS outcomes. KDM4A SNP-A482 had a minor allele (C) frequency of 18.8% and a major allele (A) frequency of 81.2% in our Asian NSCLC (adenocarcinoma) patients. However, the OS in our Asian NSCLC patients homozygous for KDM4A SNP-A482 was not significantly different from those who were wild type or heterozygous at this locus [CC vs. AA/AC: median OS (95% confidence interval): 40.2 (18.7-61.6) vs. 29.6 (26.9-32.3) months; P=0.858]. The results remained statistically nonsignificant even after adjustment for epidermal growth factor receptor mutational status, suggesting that KDM4A SNP-A482 does not significantly influence OS in Asian NSCLC patients.
- Published
- 2017
- Full Text
- View/download PDF
46. Metronomic chemotherapy: A relook at its basis and rationale.
- Author
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Rajasekaran T, Ng QS, Tan DS, Lim WT, Ang MK, Toh CK, Chowbay B, Kanesvaran R, and Tan EH
- Subjects
- Humans, Administration, Metronomic, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Neoplasms drug therapy
- Abstract
Metronomic administration of chemotherapy has long been recognized as having a different biological effect from maximal tolerated dose (MTD) administration. Preclinical studies have demonstrated these differences quite elegantly and many clinical trials have also demonstrated reproducible activity albeit small, in varied solid malignancies even in patients who were heavily pretreated. However, the concept of metronomic chemotherapy has been plagued by lack of a clear definition resulting in the published literature that is rather varied and confusing. There is a need for a definition that is mechanism(s)-based allowing metronomics to be distinguished from standard MTD concept. With significant advances made in understanding cancer biology and biotechnology, it is now possible to attain that goal. What is needed is both a concerted effort and adequate funding to work towards it. This is the only way for the oncology community to determine how metronomic chemotherapy fits in the overall cancer management schema., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
47. Germline hemizygous deletion of CDKN2A-CDKN2B locus in a patient presenting with Li-Fraumeni syndrome.
- Author
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Chan SH, Lim WK, Michalski ST, Lim JQ, Ishak NDB, Met-Domestici M, Young CNC, Vikstrom K, Esplin ED, Fulbright J, Ang MK, Wee J, Sittampalam K, Farid M, Lincoln SE, Itahana K, Abdullah S, Teh BT, and Ngeow J
- Abstract
Li-Fraumeni syndrome (LFS) is a rare cancer predisposition syndrome usually associated with TP53 germline alterations. Its genetic basis in TP53 wild-type pedigrees is less understood. Using whole-genome sequencing, we identified a germline hemizygous deletion ablating CDKN2A-CDKN2B in a TP53 wild-type patient presenting with high-grade sarcoma, laryngeal squamous cell carcinoma and a family history suggestive of LFS. Patient-derived cells demonstrated reduced basal gene and protein expression of the CDKN2A -encoded tumour suppressors p14
ARF and p16INK4A with concomitant decrease in p21 and faster cell proliferation, implying potential deregulation of p53-mediated cell cycle control. Review of 13 additional patients with pathogenic CDKN2A variants suggested associations of germline CDKN2A mutations with an expanded spectrum of non-melanoma familial cancers. To our knowledge, this is the first report of a germline gross deletion of the CDKN2A-CDKN2B locus in an LFS family. These findings highlight the potential contribution of germline CDKN2A deletions to cancer predisposition and the importance of interrogating the full extent of CDKN2A locus in clinical testing gene panels., Competing Interests: The authors declare no conflict of interest.- Published
- 2016
- Full Text
- View/download PDF
48. Imaging features of renal complications after crizotinib treatment for non-small-cell lung cancer: a case report.
- Author
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Chan WY, Ang MK, Tan DS, Koh WL, and Kwek JW
- Abstract
Crizotinib has been approved for the treatment of advanced ALK-positive non-small cell lung cancer. Its use is associated with the development of complex renal cysts. However, there is limited literature regarding imaging features of renal cystic disease during crizotinib therapy and its complications or progression. Here, we describe a case of a patient with ALK-positive advanced non-small cell lung cancer who developed complex renal cyst during crizotinib treatment. The renal cyst is complicated by infection and abscess formation. Subsequent renal biopsy, antibiotics treatment, and open drainage of loculated renal abscess showed no malignant cells and contributed to the diagnosis. The imaging features should be recognized as renal cystic disease of crizotinib treatment and not to be mistaken as new metastasis and disease progression.
- Published
- 2016
- Full Text
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49. Phase I Study of Oral Vinorelbine in Combination with Erlotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Using Two Different Schedules.
- Author
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Sutiman N, Zhang Z, Tan EH, Ang MK, Tan SW, Toh CK, Ng QS, Chowbay B, and Lim WT
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Drug Administration Schedule, Erlotinib Hydrochloride administration & dosage, Erlotinib Hydrochloride pharmacokinetics, Female, Humans, Male, Middle Aged, Quinazolines administration & dosage, Quinazolines pharmacokinetics, Quinazolines therapeutic use, Treatment Outcome, Vinblastine administration & dosage, Vinblastine pharmacokinetics, Vinblastine therapeutic use, Vinorelbine, Carcinoma, Non-Small-Cell Lung drug therapy, Erlotinib Hydrochloride therapeutic use, Vinblastine analogs & derivatives
- Abstract
Purpose: This study aimed to evaluate the safety, tolerability and pharmacokinetics of the combination of oral vinorelbine with erlotinib using the conventional (CSV) and metronomic (MSV) dosing schedules in patients with advanced non-small cell lung cancer (NSCLC)., Methods: This was an open-label, multiple dose-escalation phase I study. An alternating 3+3 phase I design was employed to allow each schedule to enroll three patients sequentially at each dose level. Thirty patients with Stage IIIB/IV NSCLC were treated with escalating doses of oral vinorelbine starting at 40 mg/m2 on day 1 and 8 in the CSV group (N = 16) and at 100 mg/week in the MSV group (N = 14). Erlotinib was administered orally daily., Results: The maximum tolerated dose was vinorelbine 80 mg/m2 with erlotinib 100 mg in the CSV group and vinorelbine 120 mg/week with erlotinib 100 mg in the MSV group. Grade 3/4 toxicities included neutropenia (N = 2; 13%) and hyponatremia (N = 1; 6%) in the CSV group, and neutropenia (N = 5; 36%) in the MSV group. Objective response was achieved in 38% and 29% in the CSV and MSV groups respectively. Vinorelbine co-administration did not significantly affect the pharmacokinetics of erlotinib and OSI-420 after initial dose. However, at steady-state, significantly higher Cmax, higher Cmin and lower CL/F of erlotinib were observed with increasing dose levels of vinorelbine in the CSV group. Significantly higher steady-state Cmin, Cavg and AUCss of erlotinib were observed with increasing dose levels of vinorelbine in the MSV group., Conclusions: Combination of oral vinorelbine with erlotinib is feasible and tolerable in both the CSV and MSV groups., Trial Registration: ClinicalTrials.gov NCT00702182.
- Published
- 2016
- Full Text
- View/download PDF
50. Outcomes and Prognostic Factors of Radiation-Induced and De Novo Head and Neck Squamous Cell Carcinomas.
- Author
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Tay GC, Iyer NG, Ong WS, Tai D, Ang MK, Ha TC, Soo KC, and Tan HK
- Subjects
- Aged, Aged, 80 and over, Carcinoma, Squamous Cell pathology, Case-Control Studies, Female, Head and Neck Neoplasms pathology, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasms, Radiation-Induced pathology, Prognosis, Retrospective Studies, Singapore, Smoking epidemiology, Survival Rate, Treatment Outcome, Carcinoma, Squamous Cell etiology, Carcinoma, Squamous Cell therapy, Head and Neck Neoplasms etiology, Head and Neck Neoplasms therapy, Neoplasms, Radiation-Induced etiology, Neoplasms, Radiation-Induced therapy
- Abstract
Objective: We sought to compare clinical outcomes, pathological features, treatment patterns, and survival outcomes between radiation-induced squamous cell carcinoma (RISCC) and de novo SCC (DNSCC) of the head and neck, as well as identify prognostic factors in these patients., Study Design: Case-control study., Setting: Tertiary medical center., Subjects and Methods: Retrospective case-control analysis of 34 RISCCs and 136 DNSCCs matched by age at diagnosis, sex, smoking status, and primary tumor site., Results: Median latency of RISCC development was 13 years. Radiation-induced squamous cell carcinomas were more likely to present with node-negative disease than DNSCCs (70.6% vs 42.9%; P = .024). A greater proportion of DNSCCs was treated with curative intent (92.6% vs 79.4%; P = .048) and achieved no residual disease posttreatment (82.2% vs 41.2%; P < .001) compared with RISCCs. Patients with RISCC had poorer overall survival (OS) (median, 1.67 vs 5.03 years; P = .018) and disease-specific survival (DSS) (median, 1.67 vs 8.65 years; P = .001) than those with DNSCC. Among patients who underwent curative treatment with no residual disease after treatment, there were, however, no survival differences between RISCC and DNSCC., Conclusion: In our cohort, RISCCs have a poorer prognosis than DNSCCs. However, those able to undergo curative treatment and have no residual disease after treatment have comparable survival outcomes. Locoregional control of these tumors appears paramount in achieving the best outcomes for patients with RISCC., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)
- Published
- 2016
- Full Text
- View/download PDF
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