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  • American Association for Cancer Research (AACR)  (6)
  • Tan, Eng-Huat  (6)
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  • American Association for Cancer Research (AACR)  (6)
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  • 1
    Online Resource
    Online Resource
    Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 21 ( 2021-11-01), p. 5939-5950
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 21 ( 2021-11-01), p. 5939-5950
    Abstract: Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFRT790M-negative resistance. 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.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-4607
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    Abstract CT203: A phase II trial of ipilimumab in combination with nivolumab in EBV-associated advanced nasopharyngeal carcinoma (NCT03097939)
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT203-CT203
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT203-CT203
    Abstract: Background: Single agent PD-1/PD-L1 studies in previously treated EBV-associated nasopharyngeal carcinoma (NPC) demonstrate clinical outcomes inferior to salvage combination chemotherapy. Dual blockade of PD-1/CTLA4 is a viable treatment strategy in other solid tumors. We hypothesized that this strategy would also be feasible and efficacious in NPC. Materials and Methods: A single arm phase 2 study using a Simon 2-stage design was used. Nivolumab was dosed at 3 mg/kg q2 weeks, and Ipilimumab was dosed at 1 mg/kg q6 weeks. Eligible pts had EBER-ISH positive NPC, measurable plasma EBV DNA, no more than 1 prior line of chemotherapy, ECOG 0-1, and adequate organ function. All pts who met the eligibility criteria and received at least one dose of the combination were included in the safety and efficacy analysis. The primary efficacy endpoint was best overall response (BOR) by RECIST 1.1. Toxicity was assessed using CTCAE criteria. Pretreatment EBV DNA load was used to discriminate EBVhi from EBVlo at a threshold of 30,000 copies/ml, and sub-group analyses were carried out for BOR, time to progression, progression-free survival and overall survival based on this cutoff. Paired tumor and blood sampling were done at baseline and on-treatment and results are presented separately. Results: A total of 28 patients were enrolled and 26 were evaluable. Two patients were excluded from analysis for eligibility reason and consent withdrawal. Median age of pts was 56 years (range 23-73). Most patients (85%) were of Chinese ethnicity and 19 patients (73%) were male. The median number of cycles received was 4. Three patients remain on treatment. Twenty-one patients (81%) experienced any grade treatment-related adverse events (trAE). Common trAEs were maculopapular rash (n=8; 31%) and hypothyroidism (n=8; 31%). Three pts (11%) required treatment discontinuation due to grade 3/4 AE, including pneumonitis and myasthenia gravis. In stage one, of 15 pts recruited, 7 reported BOR of PR (47%) and another 11 patients were recruited into stage two. In total, 8 out of 26 patients achieved PR (BOR 31%; 95% CI 14.3% to 51.8%). Median duration of response (DOR) was 5.9 mths (95% CI 3.9 to 9.0). With a median follow up of 10.6 mths, median PFS was 5.3 mths (95% CI 2.8 to 6.4). Of EBVlo pts, 8 experienced a PR (53%; 95% CI 26.6% to 78.7%). No responses were observed in EBVhi pts. EBVlo pts had a median PFS of 6.8 mths (95% CI 2.8 to 10.4) compared to EBVhi 2.7 mths (95% CI 1.7 to 5.2). Conclusions: Dual PD-1/CTLA4 blockade is safe and feasible in NPC, achieving durable responses in pts with lower plasma EBV DNA. Efficacy was comparable to that seen in other solid tumors using this combination. The trial has been expanded to further study efficacy of this combination in NPC. Citation Format: Darren Wan-Teck Lim, Quan Sing Ng, Ruey-Long Hong, Daniel S. Tan, Eng-Huat Tan, Boon-Cher Goh, Wan Ling Tan, Stella Li-Li Chan, Sze-Huey Tan, Hsiang-Fong Kao, Gopalakishna N. Iyer, Mei-Kim Ang. A phase II trial of ipilimumab in combination with nivolumab in EBV-associated advanced nasopharyngeal carcinoma (NCT03097939) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT203.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-CT203
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 3
    Online Resource
    Online Resource
    Abstract 5114: Ultra-sensitive detection of minimal residual disease (MRD) through whole genome sequencing (WGS) using an AI-based error suppression model in resected early-stage non-small cell lung cancer (NSCLC)
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5114-5114
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5114-5114
    Abstract: Background: Early detection of recurrence and monitoring of MRD post-surgery is critical for clinical decision-making to tailor adjuvant therapy. In early-stage NSCLC, circulating tumor DNA (ctDNA) detection is especially challenging, requiring highly sensitive and specific assays. Therefore, we used a WGS approach (MRDetect) for ultra-sensitive ctDNA detection in NSCLC patients (pts) undergoing curative surgery. Methods: We conducted a pilot study to evaluate the MRDetect approach in serial plasma samples (including pre-surgery, post-surgery and follow-up [f/u] timepoints) from resected stage IB-IIIA NSCLC pts. Pts underwent routine surveillance by computed tomography scans. ctDNA was extracted from ~1mL plasma. MRDetect uses WGS by a tumor-informed approach (sequencing coverage 40x for tumor, 20x for plasma DNA) combined with AI-based error suppression models (trained and calibrated with a non-cancer cohort, n=17) to increase the signal to noise ratio for precise ctDNA detection, and improve the accuracy of readouts especially for low tumor burden scenarios. The assay reports the detection and quantification of ctDNA burden in blood with a prognostic value for risk of recurrence. The ability of the assay to predict recurrence from a single sample, taken at the clinical landmark point (median 1.6 mths post-surgery, range 0.1-6.5) was evaluated. Results: Overall, 52 NSCLC pts were enrolled (n=88 plasma samples) with median clinical f/u of 32.6 mths (range 3.1-98.6). There were 43 pts with post-surgery landmark samples, with median age 62 years, 70% were male, 79% were adenocarcinoma and 49% were EGFR mutated. 26% were stage IB and 37% each were stage II and III. There were 15/18 (sensitivity 83%) pts with confirmed radiological recurrence in which MRDetect was positive, including 6/7 (86%) EGFR mutated pts. The median RFS in MRDetect positive pts was 15.2 mths (range 3.7-33.4). Among 25 pts with no recurrence (median f/u 25.6 mths), MRDetect reported 4 pts to be MRD positive (specificity 84%). These results were consistent between EGFR mutated (sensitivity 86%, specificity 86%) and wildtype pts (sensitivity 82%, specificity 82%). For longitudinal samples (n=17 pts), negative ctDNA was associated with absence of recurrence in 14/15 pts (specificity 93%). At the AACR meeting, results from a planned larger validation study will be presented. Conclusion: Using a robust WGS implemented AI-based computational platform (MRDetect), we demonstrate high sensitivity and specificity detection of MRD in both EGFR mutated and wildtype NSCLC. With an increasing number of therapeutic options in the adjuvant setting for NSCLC, an ultra-sensitive MRD assay has the potential to facilitate personalized clinical decision-making for tailoring both the need and choice of adjuvant therapies. Citation Format: Aaron C. Tan, Stephanie P. Saw, Gillianne G. Lai, Kevin L. Chua, Angela Takano, Boon-Hean Ong, Tina P. Koh, Amit Jain, Wan Ling Tan, Quan Sing Ng, Ravindran Kanesvaran, Tanujaa Rajasekaran, Sunil Deochand, Dillon Maloney, Danielle Afterman, Tomer Lauterman, Noah Friedman, Imane Bourzgui, Nidhi Ramaraj, Zohar Donenhirsh, Ronel Veksler, Jonathan Rosenfeld, Ravi Kandasamy, Iman Tavassoly, Boris Oklander, Asaf Zviran, Wan-Teck Lim, Eng-Huat Tan, Anders J. Skanderup, Mei-Kim Ang, Daniel S. Tan. Ultra-sensitive detection of minimal residual disease (MRD) through whole genome sequencing (WGS) using an AI-based error suppression model in resected early-stage non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5114.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5114
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
    Online Resource
    Online Resource
    Abstract A1-25: Intratumor heterogeneity in never-smoker Asian EGFR mutant lung adenocarcinoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 22_Supplement_1 ( 2015-11-15), p. A1-25-A1-25
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22_Supplement_1 ( 2015-11-15), p. A1-25-A1-25
    Abstract: Lung cancer has the highest cancer associated mortality rate in many countries across the world. In contrast to western populations, approximately half of lung adenocarcinoma cases in Singapore harbour activating epidermal growth factor receptor (EGFR) mutations, with preponderance for never smokers and female gender. Although EGFR tyrosine kinase inhibitors (TKIs) confer high response rates of up to 70%, drug resistance invariably ensues - most commonly through the “acquisition” of EGFR T790M mutation. While the extent and pattern of intratumoral heterogeneity (ITH) in non-small cell lung cancer (NSCLC) were recently described, these studies examined histologically and molecularly diverse cohort of patients, majority being current or ex-smokers. Here we report ITH in eight never-smoker EGFR mutant lung adenocarcinoma cases of Asian ethnicity. All eight patients had no prior treatment history and harboured an activating EGFR mutation (5 L858R, 2 exon 19 deletion, 1 exon 20 insertion). They underwent lobectomy for Stage IA, IB NSCLC. Tumors were harvested using a systematic sectoring protocol according to standard operation procedures, with tissue banked for exome sequencing, RNA-sequencing and SNP array. A total of 46 tumor sectors (at least 4 regions from each of the 8 tumors) were subject to whole exome sequencing, with matched normal samples. With an average sequencing depth of 100x, we identified 860 somatic exonic SNVs (601 being non-synonymous) and 49 indels across all samples. The median number of SNVs per patient was 112 and per sector was 49. Notably, activating EGFR mutations were identified across all tumor sectors of all but two patients (for whom it was identified in 3 of 5 and 5 of 7 sectors respectively). In addition, we did not identify the EGFR T790M mutation in any of the sequenced tumor sectors, suggesting that, this resistance mutation is not present at detectable frequencies even as a branch or subclonal event in a treatment naïve scenario. Of 20 genes that were significantly mutated across 46 individual tumor sectors, only two overlapped with published recurrently mutated genes in NSCLC. In conclusion, we show that activating EGFR mutations are ubiquitous truncal events in 6 of 8 Asian never-smoker lung adenocarcinoma – consistent with its role as a therapeutically tractable driver gene. The T790M mutation commonly associated with TKI resistance was not detected as a subclonal event in treatment naïve patients. Further, our study reveals the unique mutation spectra of Asian EGFR mutant lung adenocarcinoma, highlighting the value of multi-region sequencing in characterising the genomic architecture of defined molecular subsets of NSCLC from different ethnic backgrounds. Citation Format: Rahul Nahar, Weiwei Zhai, Angela Takano, Alexis Jiaying Khng, Xingliang Liu, Chong Hee Lim, Audrey S.M. Teo, Cheryl Xueli Chan, Apoorva Gogna, Kiat-Hon Lim, Tina Koh, Huay Mei Poh, Yin Yeng Lee, Liang He Chen, Tong Zhang, Vidhya Gomathi Krishnan, N Gopalakrishna Iyer, Pauline Ng, Wan Teck Lim, Bing Lim, Eng-Huat Tan, Daniel S.W. Tan, Axel M. Hillmer. Intratumor heterogeneity in never-smoker Asian EGFR mutant lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-25.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TRANSCAGEN-A1-25
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
    Online Resource
    Online Resource
    A Phase II Study of Pazopanib in Asian Patients with Recurrent/Metastatic Nasopharyngeal Carcinoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Clinical Cancer Research Vol. 17, No. 16 ( 2011-08-15), p. 5481-5489
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 16 ( 2011-08-15), p. 5481-5489
    Abstract: Purpose: Nasopharyngeal carcinoma is endemic in Asia and angiogenesis is important for growth and progression. We hypothesized that pazopanib would have antiangiogenic activity in nasopharyngeal carcinoma. Experimental Design: A single arm monotherapy study of pazopanib in patients with WHO type II/III nasopharyngeal carcinoma who had metastatic/recurrent disease and failed at least one line of chemotherapy. A Simon's optimal 2-stage design was used. Patients with Eastern Cooperative Oncology Group (ECOG) 0-2 and adequate organ function were treated with pazopanib 800 mg daily on a 21-day cycle. The primary endpoint was clinical benefit rate (CR/PR/SD) achieved after 12 weeks of treatment. Secondary endpoints included toxicity and progression-free survival. Exploratory studies of dynamic-contrast enhanced computed tomography (DCE-CT) paired with pharmacokinetics (PK) of pazopanib was done. Results: Thirty-three patients were accrued. Patients were ECOG 0-1 with median age of 50 years (range 36–68). There were 2 (6.1%) partial responses, 16 (48.5%) stable disease, 11 (33.3%) progressive disease, 4 (12.1%) were not evaluable for response. The clinical benefit rate was 54.5% (95% CI: 38.0–70.2). Ten patients (30.3%) received more than 6 cycles (4 months) of treatment and 7 (21.2%) had PR/SD that lasted at least 6 months. One patient each died from epistaxis and myocardial infarction. Common grade 3/4 toxicities included fatigue (15.2%), hand-foot syndrome (15.2%), anorexia (9.1%), diarrhea (6.1%), and vomiting (6.1%). Serial DCE-CT scans show significant reductions in tumor blood flow, permeability surface area product, and fractional intravascular blood volume. Conclusion: Pazopanib showed encouraging activity in heavily pretreated nasopharyngeal carcinoma with an acceptable toxicity profile. Clin Cancer Res; 17(16); 5481–9. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-10-3409
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 6
    Online Resource
    Online Resource
    Abstract B2-54: Intratumor heterogeneity in never-smoker Asian EGFR mutant lung adenocarcinoma
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 22_Supplement_2 ( 2015-11-15), p. B2-54-B2-54
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 22_Supplement_2 ( 2015-11-15), p. B2-54-B2-54
    Abstract: Lung cancer has the highest cancer associated mortality rate in many countries across the world. In contrast to western populations, approximately half of lung adenocarcinoma cases in Singapore harbour activating epidermal growth factor receptor (EGFR) mutations, with preponderance for never smokers and female gender. Although EGFR tyrosine kinase inhibitors (TKIs) confer high response rates of up to 70%, drug resistance invariably ensues - most commonly through the “acquisition” of EGFR T790M mutation. While the extent and pattern of intratumoral heterogeneity (ITH) in non-small cell lung cancer (NSCLC) were recently described, these studies examined histologically and molecularly diverse cohort of patients, majority being current or ex-smokers. Here we report ITH in eight never-smoker EGFR mutant lung adenocarcinoma cases of Asian ethnicity. All eight patients had no prior treatment history and harboured an activating EGFR mutation (5 L858R , 2 exon 19 deletion, 1 exon 20 insertion). They underwent lobectomy for Stage IA, IB NSCLC. Tumors were harvested using a systematic sectoring protocol according to standard operation procedures, with tissue banked for exome sequencing, RNA-sequencing and SNP array. A total of 46 tumor sectors (at least 4 regions from each of the 8 tumors) were subject to whole exome sequencing, with matched normal samples. With an average sequencing depth of 100x, we identified 860 somatic exonic SNVs (601 being non-synonymous) and 49 indels across all samples. The median number of SNVs per patient was 112 and per sector was 49. Notably, activating EGFR mutations were identified across all tumor sectors of all but two patients (for whom it was identified in 3 of 5 and 5 of 7 sectors respectively). In addition, we did not identify the EGFR T790M mutation in any of the sequenced tumor sectors, suggesting that, this resistance mutation is not present at detectable frequencies even as a branch or subclonal event in a treatment naïve scenario. Of 20 genes that were significantly mutated across 46 individual tumor sectors, only two overlapped with published recurrently mutated genes in NSCLC. In conclusion, we show that activating EGFR mutations are ubiquitous truncal events in 6 of 8 Asian never-smoker lung adenocarcinoma – consistent with its role as a therapeutically tractable driver gene. The T790M mutation commonly associated with TKI resistance was not detected as a subclonal event in treatment naïve patients. Further, our study reveals the unique mutation spectra of Asian EGFR mutant lung adenocarcinoma, highlighting the value of multi-region sequencing in characterising the genomic architecture of defined molecular subsets of NSCLC from different ethnic backgrounds. Citation Format: Rahul Nahar, Weiwei Zhai, Angela Takano, Alexis Jiaying Khng, Xingliang Liu, Chong Hee Lim, Audrey S.M. Teo, Cheryl Xueli Chan, Apoorva Gogna, Kiat-Hon Lim, Tina Koh, Huay Mei Poh, Yin Yeng Lee, Liang He Chen, Tong Zhang, Vidhya Gomathi Krishnan, N Gopalakrishna Iyer, Pauline Ng, Wan Teck Lim, Bing Lim, Eng-Huat Tan, Daniel S.W. Tan, Axel M. Hillmer. Intratumor heterogeneity in never-smoker Asian EGFR mutant lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B2-54.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.COMPSYSBIO-B2-54
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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