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  • American Society of Clinical Oncology (ASCO)  (44)
  • Wang, Guoqiang  (44)
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  • American Society of Clinical Oncology (ASCO)  (44)
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  • 1
    Online Resource
    Online Resource
    A novel algorithm to redefine blood-based tumor mutational burden for optimized prediction of clinical benefits from immunotherapy.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e20514-e20514
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e20514-e20514
    Abstract: e20514 Background: The previous reported predictive biomarker, blood-based tumor mutational burden (bTMB) can only predict progression-free survival (PFS) while failed to predict overall survival (OS) from atezolizumab over docetaxel, or to predict PFS or OS in the atezolizumab arm. Here we aimed to explore the underlying mechanism and develop an algorithm to redefine bTMB as a predictor of both PFS and OS from immunotherapy. Methods: Data from POPLAR (N = 211) and OAK (N = 642) trials was used for algorithm development in bTMB redefinition. The derived algorithm was validated in two independent NSCLC cohorts (cohort 1 N = 64; cohort 2 N = 184). Results: In POPLAR and OAK cohorts, bTMB-H was not associated with favorable OS (P = 0.68, HR 1.06; 95% CI, 0.81-1.38) from immunotherapy at the reported cut-point of 16, which was validated in our independent cohort 1 (P = 0.86, HR 0.39; 95% CI, 0.39-1.89). Further analysis showed that blood TMB was associated with maximum somatic allele frequency (Pearson r = 0.47 in POPLAR and OAK cohorts, Pearson r = 0.36 in the independent cohort 2), which was a negative prognostic factor and may impede the predictive value of bTMB. The bTMB was thus redefined (referred to as bTMB*) with mutations with allele frequency 〉 5% filtered out, when the correlation between bTMB and MSAF became less correlated (Pearson r = 0.09 and 0.07, respectively). Both better PFS and OS benefits from atezolizumab over docetaxel was observed in the redefined bTMB-H group as tested in POPLAR (PFS HR = 0.41, 95% CI, 0.21-0.80; OS HR = 0.34, 95% CI, 0.16-0.71) and validated in OAK (PFS HR = 0.49, 95% CI, 0.33-0.71; OS HR = 0.47, 95% CI, 0.29-0.77) with the cut-point of 12, while there was no significant association in redefined bTMB-L group (P interaction = 0.01 and 0.04 for PFS and OS in POPALR, 〈 0.001 and 0.06 for OAK PFS and OS in OAK). The results was further validated in our independent cohort 1 treated with anti-PD-1/PD-L1, where the redefined bTMB-H was also associated with favorable PFS compared with bTMB-L (Logrank P = 0.005, HR = 0.34, 95% CI, 0.26-0.75) and OS (Logrank P = 0.08, HR 0.35, 95% CI, 0.11-1.18). Conclusions: The allele frequency needs to be taken into consideration in the algorithm of bTMB. The redefined bTMB may serve as a predictor of both PFS and OS of immunotherapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e20514
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Immunotherapy efficacy and safety of programmed cell death 1 (PD-1) versus programmed death ligand-1 (PD-L1) inhibitors in pan-cancer: A systematic review and meta-analysis.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14113-e14113
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14113-e14113
    Abstract: e14113 Background: Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) and its ligand (PD-L1) have led to a paradigm shift in cancer treatment, while whether PD-1 and PD-L1 inhibitors deliver different clinical outcomes remains obscure. Here we carried out a systematic review and meta-analysis to compare the efficacy and safety profile of PD-1 and PD-L1 inhibitors in pan-cancer patients. Methods: We systematically searched PubMed, Cochrane library, and Embase from January 2000 to December 2018 for randomized controlled trials that compared PD-1/PD-L1 inhibitors with standard treatment in patients with solid tumors. We also reviewed abstracts and presentations from all major conference proceedings. Retrospective studies and trials that compared anti-PD-1/PD-L1 with other immunotherapies were excluded. The primary outcome was the difference in overall survival (OS). Studies were stratified into comparison groups upon studies mirrored with trial design and patient characteristics. Effect size in each comparison group was pooled first, the difference in overall survival was estimated, and the overall effect sizes was pooled using a random-effects model. Results: A total of 3864 publications were retrieved through initial literature search, 17 randomized controlled trials involving 9549 patients with solid tumors were included for this meta-analysis. PD-1 inhibitors exhibited significantly improved OS over PD-L1 inhibitors either in overall population (HR 0.75, 95% CI 0.64-0.87), as monotherapy (HR 0.79, 95% CI 0.65-0.96), or combination with chemotherapy (HR 0.66, 95% CI 0.53-0.82). PD-1 inhibitors also showed improved progression free survival (PFS) over PD-L1 inhibitors in overall population (HR 0.70, 95% CI 0.53-0.94). No significant difference was observed for safety profile between PD-1 inhibitors and PD-L1 inhibitors as monotherapy. PD-1 inhibitors plus chemotherapy have less Grade 3-5 adverse events than PD-L1 inhibitors plus chemotherapy (overall RR 0.84, 95% CI 0.75-0.93). Sensitivity analysis presented a satisfactory consistency of the overall estimates across these analyses. Conclusions: PD-1 inhibitors exhibited better clinical performance for survival outcome and safety profile over PD-L1 inhibitors. Future studies and explorations of the underlying mechanisms are needed for the further optimization of treatment strategies in clinical practice.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14113
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    Identification of TGFBR2 mutation as a negative predictor of immunotherapy in NSCLC.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. e21002-e21002
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e21002-e21002
    Abstract: e21002 Abstract Background: Immune adaptive resistance is one of the reasons contributing to the resistance of immune checkpoint inhibitors (ICIs). Previous studies have demonstrated the role of TGFβ-SMAD signaling in the dysfunction of immune response. We hypothesized that transforming growth factor beta receptor 2 (TGFBR2) mutation in non-small cell lung cancer (NSCLC) might be a predictor of immunotherapeutic resistance. Methods: Genomic and transcriptomic data of NSCLC patients from The Cancer Genome Atlas (TCGA) were analyzed by the in silico Pathway Activation Network Decomposition Analysis (iPNADA) to study the association between TGFBR2 mutation and intracellular signaling pathway activation. Clinical and genomic data from public cohorts with patients treated with ICIs including POPLAR/OAK, MSKCC and Van Allen cohorts were obtained and analyzed. An independent China cohort was used to demonstrate the association between TGFBR2 mutation and immunotherapeutic efficacy and we further demonstrated a case with mutated TGFBR2 treated with ICI. Results: TGF-β signaling was decreased and JAK-STAT signaling was increased in patients with mutated TGFBR2 (P 〈 0.05). The immune checkpoints including CD274, LAG3, TIGHT, CTLA-4, PDCD1 and PDCD1LG2 were significantly increased in patients with mutated TGFRB2 (P 〈 0.05). The immune dysfunction score tended to be increased in patients with mutated TGFBR2 though no significant difference was observed (P = 0.23). In the POPLAR/OAK cohort, patients with mutated TGFBR2 had shorter progression-free survival (P = 0.004; HR, 2.83; 95% CI, 1.34-6.00) and overall survival (OS) (P = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than patients with wild-type TGFBR2 when treated with ICIs. While in patients treated with chemotherapy, there was no difference in PFS (P = 0.69; HR, 0.86; 95% CI, 0.41-1.82) and OS (P = 0.61; HR, 1.21; 95% CI, 0.57-2.57) between patients with mutated and wild-type TGFBR2. In the merged MSKCC and Van Allen cohorts, similar result was observed that the OS was shorter in patients with mutated TGFBR2 (P = 0.007; HR, 2.53; 95% CI, 1.25-5.12). At last, we demonstrated a 39-year-old case with TGFBR2 mutation who was treated with 3 mg/kg nivolumab as second-line treatment. The patient progressed after three cycles of nivolumab and the PFS was only 1.3 months. Conclusions: We identified TGFBR2 mutation as a negative predictor for ICIs in NSCLC and the clinical use of ICIs needs to be cautious in those patients, highlighting the importance of genomic profiling in the treatment of ICIs. Combination ICIs and TGF-β signaling inhibitors may overcome the resistance for those patients harboring TGFBR2 mutation and need to be developed in the future.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.e21002
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Immunotherapy efficacy and patients' age: A systematic review and meta-analysis.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e14168-e14168
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e14168-e14168
    Abstract: e14168 Background: Immunotherapy has revolutionized the treatment of cancer, however, little is known about the effect of patients’ age on the efficacy of immune checkpoint inhibitors. We did a systematic review and meta-analysis to assess the heterogeneity of immune checkpoint inhibitor efficacy between young and elder patients in pan cancer. Methods: We systematically searched PubMed, Cochrane library, and Embase from January 2000 to November 2018 for randomized controlled trials that had available hazard ratios (HRs) for death according to patients’ age. We also reviewed abstracts and presentations from all major conference proceedings. Retrospective studies and trials that compared anti-PD-1/PD-L1 with other immunotherapies were excluded. The primary outcome was the difference in overall survival (OS). We calculated the pooled overall survival HR and 95% CI in young and elder patients using a random-effects model. Results: A total of 3365 publications were retrieved through initial literature search, 19 randomized controlled trials involving 12276 patients with solid tumors were included for this meta-analysis. PD-1 inhibitors exhibited significantly improved OS over PD-L1 inhibitors in younger patient population (HR 0.67, 95% CI 0.53-0.85), while no differences have been observed in elder population (HR 0.89, 95% CI 0.70-1.13). Subgroup analysis showed that PD-L1 inhibitors plus chemotherapies led to significantly improved overall survival (OS) in elder population ( 〉 = 65 years old) over that in younger population ( 〈 65 years old) (HR 1.29, 95% CI 1.01-1.64). However, the opposite tendency was observed with PD-1 inhibitors plus chemotherapies, showing that the younger population obtained better OS benefit compared to the elder population (HR 0.69, 95% CI 0.47-1.01). Conclusions: In general, PD-1 inhibitors exhibited better clinical performance for survival outcome over PD-L1 inhibitors in younger patients. When combined with chemotherapies, PD-1 inhibitors and PD-L1 inhibitors showed distinct efficacy tendency across different age groups, indicating that age should be taken into account when making decisions about treatment strategies. Future studies and explorations of the underlying mechanisms are needed for the further optimization of treatment strategies in clinical practice.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e14168
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    Comparison between T1 with lymph node metastases and T3-4 without lymph node metastases in patients with non-small cell lung cancer.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. e21074-e21074
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e21074-e21074
    Abstract: e21074 Background: Patients with small tumor size but lymph node metastases (T1N1-N3, T1N1+) and patients with large tumor size but without lymph node metastases (T3-4N0, T3+N0) mainly belong to stage IIB to IIIA according to the 8 th version TNM staging. However, whether the contradictory between tumor size and lymph node may influence the survival and the underlying genomic differences have not been fully studied. Methods: Whole-exome sequencing and RNA sequencing data for 1001 patients with NSCLC including 514 lung adenocarcinoma (LUAD) and 487 lung squamous cell carcinoma (LUSC) were downloaded from TCGA. The prognosis between patients with T1N1+ and T3+N0 has been investigated. The DNA sequencing data and RNA sequencing data from TCGA were used to study the underlying mechanism. Results: Patients with T3N0+ consisted of 80.2% Stage IIB and 17.4% Stage IIIA and patients with T1N1+ consist of 66.7% Stage IIB and 25.9% Stage IIIA. There were no differences in race, age, staging or neoadjuvant history between T1N1+ and T3+N0 cases. T1N1+ patients were more frequent among females (P = 0.02) and were more likely to be adenocarcinomas (P = 0.01) compared to T3+N0. Patients with T1N1+ was associated with a prolonged disease-free survival (DFS) (HR, 0.47; 95% CI, 0.28-0.79; P 〈 0.05) and progression-free survival (PFS) (HR, 0.31; 95% CI, 0.17-0.56; P 〈 0.001) than patients with T3+N0. In the multivariable cox proportional hazards regression model including stage, patients with T1N1+ still had increased PFS (HR, 0.45; 95% CI, 0.26-0.82; P = 0.009) and DFS (HR, 0.38; 95% CI, 0.16-0.95; P = 0.04) compared to T3+N0 cases. Moreover, patients with T1N2, belong to Stage IIIA according to AJCC 8 th edition TNM staging, had a superior DFS (P = 0.01) and PFS (P = 0.04) compared with the patients with T3N0, who are in Stage IIB. Further investigation revealed that the tumor mutation burden was no significant difference between two groups (P 〉 0.05). There was no difference in genomic alterations between groups in LUSC and LUAD. GSEA analysis revealed that gene expression involved in DNA repair signaling was enriched in T1N1+ patients in LUSC and LUAD. Conclusions: Patients with T1N1+ shows a longer DFS and PFS compared with patients with T3+N0, especially T1N2 cases who belong to Stage IIIA show a better prognosis compared with T3N0 patients who are in Stage IIB, indicating the AJCC 8 th edition TNM staging need to be refined. Moreover, the better prognosis in T1N1+ patients may be related with DNA repair signaling genes enrichment.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.e21074
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Associations between mutations of DNA damage response and prognosis in microsatellite instability prevalent tumors.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. e24257-e24257
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. e24257-e24257
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.e24257
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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    Online Resource
  • 7
    Online Resource
    Online Resource
    Mutation in homologous recombination to predict a better prognosis in endometrial cancer.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 6082-6082
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 6082-6082
    Abstract: 6082 Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 515 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 48 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed.Gene set enrichment analysis (GSEA) were used to invesgate the gene signaling. Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.39; 95% CI, 0.22-0.71; P = 0.002), progression-free survival (PFS) (HR, 0.46; 95% CI, 0.31-0.68; P 〈 0.001) and overall survival (OS) (HR, 0.45; 95% CI, 0.28-0.72; P = 0.001) in endometrial cancers. HR mutation was related with clinical characteristics including histological types (P 〈 0.05). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, TP53 mutation, POLE mutation, the association between HR mutation and PFS was still significant (HR, 0.48; 95% CI, 0.27-0.86; P 〈 0.05), which indicating the HR mutation is an independent prognostic factor for PFS. HR mutations were associated with a higher tumor mutation burden. GSEA suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. In MSS endometrial cancers, HR mutation still showed a longer PFS (HR, 0.57; 95% CI, 0.34-0.98; P = 0.04), suggested HR mutation may help predict the effect of immunotherapy in MSS endometrial carcinoma. Conclusions: HR mutation was related with a favorable prognosis through increasing T cells signature. Identification of HR mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis independent of TCGA four subtype classifications and provides an inspiration for screening patients who may benefit from ICBs in endometrial cancer in the future.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.6082
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 8
    Online Resource
    Online Resource
    Co-mutations of DNA damage response system as predictive biomarker for immune checkpoint blockades.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 3024-3024
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 3024-3024
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.3024
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 9
    Online Resource
    Online Resource
    Comparative genomic profiling of paired tissue and blood samples from advanced non-small cell lung cancer patients.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e20521-e20521
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e20521-e20521
    Abstract: e20521 Background: While tissue-based next generation sequencing (NGS) ushered in a new era of precision medicine, profiling of circulating tumor DNA (ctDNA) has also emerged as a minimally invasive alternative to inform clinical decisions. In non-small cell lung cancer (NSCLC), data describing comparison between mutational profiles of paired tissue and blood samples remained scarce. Methods: Matched formalin-fixed paraffin-embedded tissue and peripheral blood samples (≤14 days apart) were collected from treatment naïve advanced NSCLC patients. Genomic profiling was performed using whole exome sequencing (WES) for tissues and a 150-gene panel for ctDNA, with a mean sequencing depth of 239× and 3417× respectively. Tumor- and blood-based tumor mutational burdens (tTMB and bTMB) were defined as the sum of missense, stop-loss, in-frame and frameshift mutations in protein coding regions and the number of somatic single nucleotide variations and indels in targeted coding regions respectively. Maximum somatic allele frequency (MSAF) was also determined for each case as a measure of ctDNA quantity. Results: Matched tissue and blood samples from 48 patients were included for sequencing. A total of 410 mutations were identified, where 84 (20.5%) were covered in both sample types. Sixty-three (15.4%) alterations were only detected in tissues while 263 (64.1%) were exclusively seen in ctDNA. The most frequently altered genes were SMARCA2 (62.5%), TP53 (54.2%), and AR (47.9%) in ctDNA and were TP53 (37.5%) and EGFR (22.9%) in tissues. Aberrations in all genes, except for FAT1 and KRAS, occurred at a higher frequency in ctDNA. The median tTMB and bTMB were 75 and 7, respectively. bTMB displayed a moderate linear relationship with tTMB as indicated by a Spearman correlation of 0.62 (P 〈 0.01). Patients with bTMB ≥ 7 had significantly higher MSAF (Mann-Whitney P 〈 0.001), suggesting a positive correlation between bTMB and ctDNA fraction in blood. Conclusions: Mutational profiles as well as TMB levels were in general consistent between blood and tissue samples, further corroborating a role for ctDNA testing as a complementary approach to tissue testing in advanced NSCLC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e20521
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 10
    Online Resource
    Online Resource
    Early detection and localization of multiple cancers using a blood-based methylation assay (ELSA-seq).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 3_suppl ( 2021-01-20), p. 459-459
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 3_suppl ( 2021-01-20), p. 459-459
    Abstract: 459 Background: Early detection of cancer can potentially offer clinical benefits, particularly for those without effective screening methods. The PREDICT study (pan-cancer early detection project, NCT 04383353) is a prospective, multi-center, longitudinal study that aims to identify multiple cancers non-invasively before symptoms become apparent. As a pilot project, the THUNDER (the unintrusive detection of early-stage cancer) study is designed for development and validation of ELSA-seq, a sensitive targeted methylation sequencing assay that interrogates epigenetic alterations from circulating cell-free DNA (cfDNA). Herein we report results from the second THUNDER sub study (THUNDER-II), which focused on malignancies developed in liver, colon/rectum, esophagus, pancreas, lung and ovary, of which four are gastrointestinal (GI) cancer types. Methods: THUNDER-II comprises four independent steps: marker discovery, model training, validation, and single-blind test. The marker discovery work was conducted by profiling 5.5 million CpG sites in 247 tissue samples (116 cancer, 131 normal/benign, 6 cancer types) using a SeqCap Epi CpGiant system (Roche). By combining data generated in-house and from public sources, a custom hybridization capture panel was designed to target 161,984 CpG sites. For cfDNA applications, 625 patients and 483 non-cancer controls were enrolled and divided into a training set (274 cancer and 195 non-cancer) and an independent validation set (351 cancer and 288 non-cancer). Results: The cancer patients and non-cancer controls were generally comparable with respect to age, gender, and smoking status. Various stages were represented in the cancer group, and 79.5% patients were diagnosed at early stages (I-III). At 99.5% training specificity (95%CI: 96.7-100%), the cross-validated sensitivity was 79.9% (95%CI: 74.6-84.4%). The results were consistent in the validation set, with 98.3% specificity (95%CI: 95.8-99.4%) and 80.6% (76.0-84.6%) sensitivity across stages and cancer types. In terms of tracking diseased organ(s), the classifier returned a tissue-of-origin (TOO) result in 98.6% cases, and 81.0% (95%CI: 77.2-84.3%) of these predictions were correct. Conclusions: Results from the THUNDER-II study demonstrated that early cancer signals could be identified by ELSA-seq with high specificity. This method also enabled accurate prediction of TOO, offering guidance for subsequent diagnostic work-up. Together these findings highlight the potential implementation of this sensitive and robust assay as a multi-cancer detection test.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.3_suppl.459
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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