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  • 1
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    Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant
    Springer Science and Business Media LLC ; 2023
    In:  International Journal of Clinical Oncology Vol. 28, No. 5 ( 2023-05), p. 654-663
    Details
    In: International Journal of Clinical Oncology, Springer Science and Business Media LLC, Vol. 28, No. 5 ( 2023-05), p. 654-663
    Abstract: Oncogenic mutations in BRAF genes are found in approximately 5–10% of colorectal cancers. The majority of BRAF mutations are located within exons 11–15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. Methods HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. Results The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. Conclusions We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.
    Type of Medium: Online Resource
    ISSN: 1341-9625 , 1437-7772
    URL: Article
    DOI: 10.1007/s10147-023-02318-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1481773-1
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  • 2
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    Artificial intelligence (AI)-powered HER2 quantification continuous score (QCS) and tumor microenvironment (TME) analysis in HER2-amplified metastatic colorectal cancer (mCRC) treated with pertuzumab plus trastuzumab.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  JCO Global Oncology Vol. 9, No. Supplement_1 ( 2023-08), p. 34-34
    Details
    In: JCO Global Oncology, American Society of Clinical Oncology (ASCO), Vol. 9, No. Supplement_1 ( 2023-08), p. 34-34
    Abstract: 34 Background: Pertuzumab plus trastuzumab (per-/tra-) has shown clinical benefits in patients (pts) with HER2-amplified mCRC, but still there is an unmet need of biomarkers to optimize treatment decisions. In this study, we applied AI-powered whole-slide image (WSI) analyzers, to investigate the association of HER2 QCS and TME with clinical outcomes of per-/tra- in pts with HER2-amplified mCRC enrolled in TRIUMPH, a phase II study. Methods: TRIUMPH is a multicenter phase II study to evaluate the efficacy of per-/tra- in pts with mCRC with HER2 amplification confirmed by tumor tissue or circulating tumor DNA (ctDNA) analysis. HER2 immunohistochemistry (IHC) and H & E-stained WSIs from 30 pts enrolled in TRIUMPH were included in the analysis. AI-powered WSI analyzers, Lunit SCOPE HER2 and Lunit SCOPE IO (Lunit, Republic of Korea) detects tumor cells (TC) by HER2 staining intensity (negative, 1+, 2+, or 3+) in HER2-WSI, and detects various class of cells including tumor-infiltrating lymphocytes (TIL), macrophages and fibroblasts in H & E-WSI, respectively. Immune-excluded score (IES) was defined as the proportion of high stromal TIL but low intratumoral TIL area in all analyzable TME. Tumor response was measured by RECIST v1.1, and the primary endpoint was progression-free survival (PFS) assessed by the investigators. Results: All 30 tumor samples had proven HER2-amplification by either HER FISH or ctDNA analysis. The concordance rate between pathologists and AI to examine HER2 IHC was 86.7% (26/30), AI-powered HER2 QCS showed the proportion of HER2 3+ TC was widely distributed (median 73.9%; min-max 11.9%-98.9%) in the samples with HER2 3+ assessed by pathologists. Objective response rates (ORR) of per-/tra- in the whole set and a subgroup of HER2 IHC 3+ assessed by pathologists were 26.7% (8/30) and 34.8% (8/23), respectively. AI-powered HER2 QCS enabled enrichment of responders, as a subgroup of HER2 3+ QCS ≥ 50%, which is a higher cutoff than ASCO/CAP guideline (10%), had 42.1% (8/19) ORR, since all 8 responders harbored HER2 3+ QCS ≥ 50%. PFS and overall survival (OS) were significantly favorable in HER2 3+ QCS ≥ 50% group compared to 〈 50% group (median PFS [mPFS] 4.4 vs 1.4 m, hazard ratio [HR] 0.12 [95% CI, 0.04-0.38], p = 0.0000994; median OS [mOS] 16.5 vs 4.1 m, HR 0.13 [95% CI, 0.05-0.38], p = 0.000117, respectively). Interestingly, IES and the densities of macrophages and fibroblasts within cancer stroma were correlated with poor response to per-/tra-. Among HER2 3+ QCS ≥ 50% group, 5 pts with high IES (≥ 54%), macrophage density (≥ 26.3/mm 2 ), and fibroblast density (≥ 1790/mm 2 ) had ORR 0%, mPFS 1.3 m, and mOS 4.5 m. Conclusions: AI-powered HER2 QCS and TME analysis may provide additional information to precisely predict per-/tra- response in HER2-positive mCRC.
    Type of Medium: Online Resource
    ISSN: 2687-8941
    URL: Article
    DOI: 10.1200/GO.2023.9.Supplement_1.34
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 3
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    FMS‐like tyrosine kinase 3 ( FLT3 ) amplification in patients with metastatic colorectal cancer
    Wiley ; 2021
    In:  Cancer Science Vol. 112, No. 1 ( 2021-01), p. 314-322
    Details
    In: Cancer Science, Wiley, Vol. 112, No. 1 ( 2021-01), p. 314-322
    Abstract: FMS‐like tyrosine kinase 3 (FLT3) plays a key role in hematopoiesis. However, the oncogenic role of FLT3 amplification in patients with metastatic colorectal cancer (mCRC) remains unclear. Here, we aimed to evaluate the characteristics, prognosis, and treatment efficacy of an FLT3 inhibitor (regorafenib) in patients with mCRC with FLT3 amplifications. Tumor tissue samples from 2329 patients were sequenced using NGS in the Nationwide Cancer Genome Screening Project in Japan. The effects of clinicopathological features, co‐altered genes, prognosis, and efficacy of regorafenib were investigated. Between April 2015 and June 2018, 85 patients with mCRC with FLT3 amplification were observed. There were no differences in baseline characteristics between patients with or without FLT3 amplification. The frequency of RAS or other gene co‐alterations was inversely correlated with the copy number status. Median survival time in patients with FLT3 amplification was significantly shorter compared with those with non‐ FLT3 amplification. Further investigations of FLT3 amplification as a potential treatment target in mCRC are warranted.
    Type of Medium: Online Resource
    ISSN: 1347-9032 , 1349-7006
    URL: Issue
    URL: Article
    DOI: 10.1111/cas.v112.1
    DOI: 10.1111/cas.14693
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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  • 4
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    Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial
    Springer Science and Business Media LLC ; 2021
    In:  Nature Medicine Vol. 27, No. 11 ( 2021-11), p. 1899-1903
    Details
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 27, No. 11 ( 2021-11), p. 1899-1903
    Abstract: The applicability of circulating tumor DNA (ctDNA) genotyping to inform enrollment of patients with cancer in clinical trials has not been established. We conducted a phase 2 trial to evaluate the efficacy of pertuzumab plus trastuzumab for metastatic colorectal cancer (mCRC), with human epidermal growth factor receptor 2 ( HER2 ) amplification prospectively confirmed by tumor tissue or ctDNA analysis ( UMIN000027887 ). HER2 amplification was confirmed in tissue and/or ctDNA in 30 patients with mCRC. The study met the primary endpoint with a confirmed objective response rate of 30% in 27 tissue-positive patients and 28% in 25 ctDNA-positive patients, as compared to an objective response rate of 0% in a matched real-world reference population treated with standard-of-care salvage therapy. Post hoc exploratory analyses revealed that baseline ctDNA genotyping of HER2 copy number and concurrent oncogenic alterations adjusted for tumor fraction stratified patients according to efficacy with similar accuracy to tissue genotyping. Decreased ctDNA fraction 3 weeks after treatment initiation associated with therapeutic response. Pertuzumab plus trastuzumab showed similar efficacy in patients with mCRC with HER2 amplification in tissue or ctDNA, showing that ctDNA genotyping can identify patients who benefit from dual-HER2 blockade as well as monitor treatment response. These findings warrant further use of ctDNA genotyping in clinical trials for HER2- amplified mCRC, which might especially benefit patients in first-line treatment.
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    URL: Article
    DOI: 10.1038/s41591-021-01553-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1484517-9
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  • 5
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    Expression of PD-L1 and PD-L2 in colorectal cancer (CRC): A post-hoc integrated analysis of SCRUM-Japan GI-SCREEN CRC.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 3_suppl ( 2021-01-20), p. 120-120
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 3_suppl ( 2021-01-20), p. 120-120
    Abstract: 120 Background: PD-1, PD-L1/L2 axis is responsible for cancer immune escape which facilitate disease progression. However, expression of these proteins in CRC and its significance in clinical prognosis are yet to be fully clarified. Methods: This was a post-hoc analysis using FFPE tumor samples from the Nationwide Cancer Genome Screening Project, SCRUM-Japan GI-SCREEN for metastatic CRC. Patients (Pts) with MSI-H or BRAF V600E mutant tumors were prioritized to be included. PD-L1 (22C3) and PD-L2 expressions were centrally assessed using immunohistochemical assays at QualTek and NeoGenomics, respectively. Tumor infiltrating lymphocytes (TILs) were morphologically evaluated by H & E staining. Clinical information including biomarker status and overall survival (OS) were extracted from SCRUM-Japan GI-SCREEN database. Results: In total, 200 pts were included in this study with a median age of 65 (range, 29–88) years; male/female (116/84); MSI status MSI-H/non-MSI-H/unknown (8/189/3); RAS wild-type/mutant (113/87); and BRAF V600E wild-type/mutant (173/27). Positivity rate of PD-L1 in tumor cells (TC), immune cells (IC), PD-L2 on TC and IC were 10.8%, 46.9%, 0% and 20.3%, respectively. Expression of PD-L1 on TC or IC and PD-L2 on IC were associated with TIL (p = 0.023, p = 0.009, respectively). PD-L1 on TC was highly seen in BRAF V600E-mutated tumors (p = 0.043), but not related to other factors including RAS and MSI status. The pts with PD-L1+ tumors on TC or IC had longer OS than those with PD-L1- (Median, 31.9 vs 23.5 months; HR = 0.67, 95% CI, 0.46–0.99; p = 0.040), while OS in pts with PD-L2+ tumors was similar to that with PD-L2- (Median, 21.4 vs 27.3 months; HR = 0.87, 95% CI, 0.53–1.44; p = 0.60). The PD-L1 expression was also associated with the longer OS in pts with BRAF wild-type or non-MSI-H tumors. Conclusions: Our study suggested different prognostic impact of PD-L1 and PD-L2 expression in CRC pts, which require further evaluations as potential therapeutic targets for CRC. Clinical trial information: UMIN000016343.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.3_suppl.120
    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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  • 6
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    Efficacy and safety of futibatinib for refractory advanced solid malignancies with FGFR alterations identified in circulating tumor DNA: TiFFANY, A GOZILA-affiliated Trial.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3102-3102
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3102-3102
    Abstract: 3102 Background: FGFR alterations are observed in approximately 7% of advanced solid malignancies and are associated with poor prognosis and resistance to traditional anti-cancer therapy. Despite this, optimal therapeutic strategies with FGFR inhibitors for most of FGFR-altered solid malignancies are yet to be defined. Circulating tumor DNA (ctDNA) analysis has the potential to accurately detect FGFR alterations by assessing spatial and temporal intratumoral heterogeneity. Methods: We conducted a multicenter, investigator-initiated, phase II basket-type trial, TiFFANY, to evaluate the efficacy and safety of futibatinib, a highly selective covalent pan-FGFR inhibitor, in patients (pts) with advanced solid malignancies with FGFR alterations identified by ctDNA analysis who were refractory or intolerant to standard-of-care treatment. ctDNA analysis was performed in the GOZILA study. Enrolled pts received futibatinib at a dose of 20 mg once daily in a 21 day-cycle. The primary endpoint was investigator-assessed objective response rate (ORR). We set the threshold ORR of 5% and expected one of 25%. Planned sample size was 26 with one-sided alpha of 2.5% and power of 80%. Blood and tissue samples collected before treatment (baseline), at week 3, and after disease progression were analyzed for biomarkers and resistance mechanisms. Results: Twenty-six pts with FGFR alterations (mutation, 9; amplification, 13; fusion, 4) in ctDNA were enrolled between August 2019 and March 2021. The primary endpoint was met with five (19.2%; 95% CI, 6.6–39.4%) achieving a confirmed partial response (PR) in various cancer types (biliary tract, gastric, urothelial, and urachal cancer). Median progression-free survival and overall survival were 2.6 and 8.9 months. The most common treatment-associated adverse events were hyperphosphatemia (100%), eye toxicity (46.2%) and diarrhea (42.3%), all of which were manageable. The median proportional change in ctDNA fraction from baseline to 3 weeks after treatment initiation in pts who achieved PR was significantly less than in pts with stable or progressive disease (0.11 vs. 1.0 vs. 1.6, respectively). Pts with no concurrent RTK/RAS/PI3K and cell cycle alterations in ctDNA were significantly more likely to respond to futibatinib than those with at least one of these alterations (ORR 50% vs. 0%; P=0.0038). Acquired gene alterations in ctDNA after progression tended to be more common in pts with FGFR amplification (83.3%) than in those with FGFR mutation or fusion (60% or 66.7%). Conclusions: Futibatinib demonstrated promising efficacy in refractory advanced solid malignancies with FGFR alterations in ctDNA with an acceptable toxicity profile. Oncogenic co-alterations detected by ctDNA genotyping may predict primary resistance. Clinical trial information: JapicCTI-194624 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3102
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 7
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    Profiling plasma angiogenesis factors after use of biologics in metastatic colorectal cancer (mCRC): Update results from GI-SCREEN CRC Ukit study.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3529-3529
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3529-3529
    Abstract: 3529 Background: No predictive biomarkers have been validated to determine which patients (pts) with metastatic colorectal cancer (mCRC) benefit the most from angiogenesis inhibitors. Recent studies suggest that plasma angiogenesis factors and their dynamics may have some prognostic or predictive value. Methods: In this prospective longitudinal study, serial plasma sample collections were done at the time points of pre- and post-treatments in mCRC pts receiving biologics in either first- or second-line chemotherapy (chemo). Comprehensive measurements of 17 factors were performed by the multiplex assay with Luminex technology. Statistical analyses were conducted by using the Brunner-Munzel and Jonckheere-Terpstra test. Results: From Sep 2017 to Dec 2020, 789 plasma samples were collected from 498 enrolled pts [first-line chemo plus bevacizumab (BEV, n=102), first-line chemo plus anti-EGFR antibody (aEGFR, n=100), second-line chemo plus BEV (n=100), second-line FOLFIRI plus ramucirumab (RAM, n=99), second-line FOLFIRI plus aflibercept (AFL, n=85) and other treatment (n=7)]. 789 samples were evaluable for this analysis. In the analysis of first-line, level of VEGF-D was significantly higher in both post-BEV and post-aEGFR comparing with pre-first-line [pre-first-line; 264 pg/ml, post-first-line BEV; 354 pg/ml (p 〈 0.001), post-first-line aEGFR; 380.5 pg/ml (p 〈 0.001)], while PlGF was significantly higher only in post-BEV [pre-first-line; 6.7 pg/ml, post-first-line BEV; 23.4 pg/ml (p 〈 0.001), post-first-line EGFR; 7.4 pg/ml (p=0.650)]. These dynamics were also observed in pts with paired samples (Table). In pts with paired samples who received second-line treatment, level of VEGF-A was significantly decreased in post-BEV, while it significantly increased in post-RAM and AFL. A significant elevation of VEGF-D level was observed in only post-RAM. PlGF level significantly increased in post all second-line angiogenesis inhibitors. In the distribution analysis of angiogenesis factors, there were no or weak correlations between VEGF-D and PlGF at the time points of all post-treatments (r = 0.09-0.26). Conclusions: Plasma levels of VEGF-D, VEGF-A and PlGF were independently changed by angiogenesis inhibitors as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting better biologics by measuring baseline angiogenesis-related factors in first- and second-line chemo. Clinical trial information: UMIN000028616. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3529
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 8
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    Mutational spectrum of TP53 gene correlates with nivolumab treatment efficacy in advanced gastric cancer (TP53MUT study)
    Springer Science and Business Media LLC ; 2023
    In:  British Journal of Cancer Vol. 129, No. 6 ( 2023-10-05), p. 1032-1039
    Details
    In: British Journal of Cancer, Springer Science and Business Media LLC, Vol. 129, No. 6 ( 2023-10-05), p. 1032-1039
    Type of Medium: Online Resource
    ISSN: 0007-0920 , 1532-1827
    URL: Article
    DOI: 10.1038/s41416-023-02378-9
    RVK:
    XA 33500
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2002452-6
    detail.hit.zdb_id: 80075-2
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  • 9
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    Analysis of plasma angiogenesis factors on the efficacy of first-line (1L) chemotherapy (chemo) combined with biologics in RAS wild-type metastatic colorectal cancer (mCRC): Results from GI-SCREEN CRC Ukit study.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3530-3530
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3530-3530
    Abstract: 3530 Background: Angiogenesis factors have been reported as prognostic and predictive biomarkers of angiogenesis inhibitors for mCRC (Weickhardt AJ. Br J Cancer 2015. Tabernero J. Ann Oncol 2018). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemo in 1L treatment in patients (pts) with RAS wild-type mCRC. Methods: Serial plasma samples were prospectively collected at the time points of pre- and post-treatments in mCRC pts receiving biologics in either 1L or 2nd-line (2L) chemo. From Sep 2017 to Dec 2020, 497 pts were enrolled [1L chemo plus bevacizumab (1L BEV, n=102), 1L chemo plus anti-EGFR antibody (1L aEGFR, n=100), 2L chemo plus bevacizumab (n=100), 2L FOLFIRI plus RAM (n=99), 2L FOLFIRI plus aflibercept (n=85) and other treatment (n=11)]. Total of 17 plasma angiogenesis factors (HGF, PlGF, VEGF-A, VEGF-D, Angiopoietin-2, IFN-γ, IL-6, IL-8, sNeuropilin-1, TSP-2, OPN, sVEGFR1, sVEGFR2, sVEGFR3, sICAM-1, sVCAM-1, and TIMP-1) were analyzed by the multiplex assay with Luminex ® technology. Interactions of their pre-treatment measurements with treatment groups on PFS and OS were assessed via Cox proportional hazards model. The strength of interactions was estimated using a propensity score weighting analysis, and the continuous plasma angiogenesis variables were categorized according to the median. The significance level in the interaction was defined as p≤0.1. Results: 133 pts were included in adjusted RAS wild-type 1L cohort (1L BEV: n=33, 1L aEGFR [reference]: n=100). Baseline characteristics of adjusted RAS wild-type 1L cohort were as follows; median age 64 years; male 62.4%; left-sided tumor 88.7%; triplet chemo 15.0%. Propensity-score weighted Cox model for OS showed significant interactions in IL-8 (median 8.03 pg/mL, high: HR 1.738, p=0.0838, Low: HR 0.479, p=0.2624, interaction p=0.0283), sVEGFR-1 (median 1,350 pg/mL, high: HR 0.333, p=0.1770, Low: HR 1.311, p=0.3004, interaction p=0.0777), and sVCAM-1 (median 1,020,000 pg/mL, high: HR 0.100, p=0.0558, Low: HR 1.616, p=0.1765, interaction p=0.0011). In terms of PFS, there were significant interactions in IL-8 (high: HR 1.322, p=0.0418, Low: HR 0.517, p=0.0528, interaction p=0.0752) and sVCAM-1 (high: HR 0.285, p=0.0414, Low: HR 1.200, p=0.7725, interaction p=0.0156). Conclusions: Pre-treatment plasma IL-8 and sVCAM-1 could be predictive biomarkers for efficacy of biologics combined with chemo in 1L treatment of RAS wild-type mCRC. Clinical trial information: UMIN000028616. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3530
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 10
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    Impact of a metastatic site on circulating tumor DNA (ctDNA) analysis in patients (pts) with metastatic colorectal cancer (mCRC).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3554-3554
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3554-3554
    Abstract: 3554 Background: ctDNA genotyping has been used as an alternative to tissue genotyping for precision oncology. In mCRC, although low plasma RAS variant allelic frequencies (VAFs) and low concordance with tissue RAS tests have been reported in pts with lung-only metastasis (mets) (Kagawa Y. et al., Clin Cancer Res 2021), the association of ctDNA identified using the next-generation sequencing method with metastatic sites is still unknown. Methods: We investigated the association between metastatic site and ctDNA detection by using the Guardant360 (G360), a ctDNA assay which detects 74 gene alterations including mutations with the 95% of limit of detection of 0.2%, in mCRC pts with single organ mets in pts who had not received anti-EGFR therapy in the SCRUM-Japan GOZILA study. We also evaluated the correlations between the size/number of mets by CT and detected VAFs. Results: Of 1187 mCRC pts enrolled in GOZILA, 138 pts (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only mets) were eligible for this study. The concordance of RAS/ BRAF status between G360 and tissue in-vitro diagnostic tests were 93.9% in liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only mets. The median maximum VAF (maxVAF) corresponding to the highest ctDNA fraction and the median numbers of detected variants were 23.1% and 5 in liver-only, 6.0% and 5 in lymph node-only, 0.4% and 3 in peritoneum-only, and 0.4% and 3 in lung-only (all P 〈 0.001, Kruskal-Wallis test). A few pts with liver-only (2.0%) and lymph node-only mets (13.3%) had a maxVAF of 〈 0.2%, but maxVAF was more frequently 〈 0.2% in pts with lung-only (27.7%) or peritoneum-only mets (29.6%), especially in those with lung-only mets 〈 20 mm as the longest diameter and 〈 20 lesions (69.2%) or with peritoneum-only mets 〈 20 mm as the longest diameter (87.5%). Conclusions: Lung-only and peritoneum-only mets had significantly lower maxVAF and lower numbers of detected variants, suggesting lower detections of subclonal variants. To ensure the sufficient clinical performance in G360 assay, inclusion of pts with lung-only mets ≥20 mm of longest diameter and/or ≥20 lesions, and ≥20 mm of the longest diameter in pts with peritoneum-only mets may be required.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3554
    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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