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  • Denda, Tadamichi  (12)
  • Nishina, Tomohiro  (12)
  • 1
    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
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2115647-5
    detail.hit.zdb_id: 2111204-6
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  • 2
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-05)
    Abstract: Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing–based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction–based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti–programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 3
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-05)
    Abstract: Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology. MATERIALS AND METHODS We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315). RESULTS Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS/ BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P 〈 .001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF 〈 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently 〈 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%). CONCLUSION Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 4
    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
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 5
    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
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 6
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 7 ( 2023-03)
    Abstract: Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery. PATIENTS AND METHODS Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results. RESULTS A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies. CONCLUSION Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 8
    In: Cancer Medicine, Wiley, Vol. 12, No. 18 ( 2023-09), p. 18702-18716
    Abstract: Several biomarkers have been established for metastatic colorectal cancer (mCRC). We investigated whether plasma angiogenesis factors could predict the efficacy of biologics combined with chemotherapy in first‐line (1L) treatment in patients with RAS wild‐type mCRC and the dynamics of plasma angiogenesis factors at progression during 1L treatment. Methods In this multicenter prospective observational study, serial plasma samples were prospectively collected at pretreatment and progression stages; 17 plasma angiogenesis factors were analyzed using the multiplex assay with Luminex® technology. Interactions between the pretreatment measurements and treatment groups on progression‐free survival (PFS) and overall survival (OS) in patients with RAS wild‐type were assessed using the propensity‐score weighted Cox proportional hazards model. Results From February 2018 to September 2020, 202 patients were enrolled in the 1L cohort; 133 patients had RAS wild‐type (chemotherapy plus bevacizumab [BEV group, n = 33] and plus anti‐epidermal growth factor receptor monoclonal antibodies [aEGFR group, n = 100]). A trend of strong interaction on PFS was observed for interleukin‐8 (IL‐8) ( p = 0.0752) and soluble vascular cell adhesion molecule‐1 (sVCAM‐1) ( p = 0.0156). Regarding OS, IL‐8 ( p = 0.0283), soluble vascular endothelial growth factor‐receptor‐1 (sVEGFR‐1) ( p = 0.0777) and sVCAM‐1 ( p = 0.0011) tended to differentiate the treatment effect. In 112 patients, plasma samples were evaluable for dynamic analysis (57 and 55 from the BEV and aEGFR groups, respectively). In the BEV group, six factors significantly increased during progression, whereas two decreased. In the aEGFR group, three factors significantly increased, and six decreased. Conclusion Pretreatment plasma IL‐8 and sVCAM‐1 levels could be predictive biomarkers to distinguish BEV and anti‐EGFR mAbs when combined with chemotherapy in the 1L treatment of RAS wild‐type mCRC. Several plasma angiogenesis factors showed significant change at progression in 1L chemotherapy plus biologics for RAS wild‐type mCRC, which are potential biomarkers for selecting an optimal angiogenesis inhibitor in second‐line treatment.
    Type of Medium: Online Resource
    ISSN: 2045-7634 , 2045-7634
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2659751-2
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  • 9
    In: Journal of Cancer Research and Clinical Oncology, Springer Science and Business Media LLC, Vol. 148, No. 10 ( 2022-10), p. 2841-2854
    Type of Medium: Online Resource
    ISSN: 0171-5216 , 1432-1335
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1459285-X
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 4_suppl ( 2020-02-01), p. 178-178
    Abstract: 178 Background: Plasma vascular endothelial growth factor-D (VEGF-D) level is a potential predictor for ramucirumab efficacy in patients (pts) with metastatic colorectal cancer (mCRC), while a high VEGF-A and placental growth factor (PlGF) level in bevacizumab naïve pts receiving 2nd-line FOLFIRI plus aflibercept may suggest relatively higher activity. However, there are a few data associating 1st-line antiangiogenic treatments as well as anti-EGFR with angiogenic factors. Methods: This prospective longitudinal study aims to investigate an association between plasma angiogenesis-related mediators and clinical outcomes in mCRC. Serial plasma collections were done at time points of pre- and post-treatments of either 1st- or 2nd-line. Comprehensive measurements of 17 mediators were analyzed by the multiplex assay with Luminex technology. Here we report an association between levels of VEGF-D, PlGF and patient backgrounds. Results: From Sep 2017 to Aug 2019, 375 samples from 317 pts were enrolled in this analysis. Baseline characteristics were follows; 169 samples at pre-1st-line (pre-1L), 151 with prior bevacizumab treatment (post-bev) and 55 with prior anti-EGFR antibody (post-EGFR); median age, 66 years; male gender, 58%; RAS mutant, 46%; left-sided primary, 76%. In pre-1L, the median values of VEGF-D/ PlGF were 264/ 7.21 pg/mL without a clear association between the two in each patient (r = 0.094) and any baseline characteristics. Compared to pre-1L, the values of VEGF-D/ PlGF showed significantly higher in post-bev (median VEGF-D/ PlGF; 346/ 23.5 pg/mL, respectively). Moreover, there was no clear relationship between the two cytokines in each patient (r = 0.190). In 37 pts with serial blood collection, VEGF-D/ PlGF levels showed similar trends. In addition, VEGF-D/ PlGF levels in post-EGFR tended to be higher than those in pre-1L (median VEGF-D/ PlGF; 395/ 9.11 pg/mL, respectively). Conclusions: The VEGF-D/ PlGF may be separately induced by bev treatment as well as anti-EGFR therapy, suggesting the possibility of usefulness for selecting a better antiangiogenic inhibitor by measuring baseline VEGF-D/ PlGF. Clinical trial information: UMIN000028616.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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