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  • 1
    Online Resource
    Online Resource
    Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer
    BMJ ; 2022
    In:  Gut Vol. 71, No. 12 ( 2022-12), p. 2502-2517
    Details
    In: Gut, BMJ, Vol. 71, No. 12 ( 2022-12), p. 2502-2517
    Abstract: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy. Design To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours. Results By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p 〈 0.05) and reduced liver metastases (p 〈 0.0002). Conclusion This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2021-326183
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1492637-4
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  • 2
    Online Resource
    Online Resource
    Image-based consensus molecular subtype (imCMS) classification of colorectal cancer using deep learning
    BMJ ; 2021
    In:  Gut Vol. 70, No. 3 ( 2021-03), p. 544-554
    Details
    In: Gut, BMJ, Vol. 70, No. 3 ( 2021-03), p. 544-554
    Abstract: Complex phenotypes captured on histological slides represent the biological processes at play in individual cancers, but the link to underlying molecular classification has not been clarified or systematised. In colorectal cancer (CRC), histological grading is a poor predictor of disease progression, and consensus molecular subtypes (CMSs) cannot be distinguished without gene expression profiling. We hypothesise that image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data and to resolve unclassifiable or heterogeneous cases. In this study, we present an image-based approach to predict CRC CMS from standard H & E sections using deep learning. Design Training and evaluation of a neural network were performed using a total of n=1206 tissue sections with comprehensive multi-omic data from three independent datasets (training on FOCUS trial, n=278 patients; test on rectal cancer biopsies, GRAMPIAN cohort, n=144 patients; and The Cancer Genome Atlas (TCGA), n=430 patients). Ground truth CMS calls were ascertained by matching random forest and single sample predictions from CMS classifier. Results Image-based CMS (imCMS) accurately classified slides in unseen datasets from TCGA (n=431 slides, AUC)=0.84) and rectal cancer biopsies (n=265 slides, AUC=0.85). imCMS spatially resolved intratumoural heterogeneity and provided secondary calls correlating with bioinformatic prediction from molecular data. imCMS classified samples previously unclassifiable by RNA expression profiling, reproduced the expected correlations with genomic and epigenetic alterations and showed similar prognostic associations as transcriptomic CMS. Conclusion This study shows that a prediction of RNA expression classifiers can be made from H & E images, opening the door to simple, cheap and reliable biological stratification within routine workflows.
    Type of Medium: Online Resource
    ISSN: 0017-5749 , 1468-3288
    URL: Article
    DOI: 10.1136/gutjnl-2019-319866
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 1492637-4
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  • 3
    Online Resource
    Online Resource
    In-depth Clinical and Biological Exploration of DNA Damage Immune Response as a Biomarker for Oxaliplatin Use in Colorectal Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 1 ( 2021-01-01), p. 288-300
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 1 ( 2021-01-01), p. 288-300
    Abstract: The DNA damage immune response (DDIR) assay was developed in breast cancer based on biology associated with deficiencies in homologous recombination and Fanconi anemia pathways. A positive DDIR call identifies patients likely to respond to platinum-based chemotherapies in breast and esophageal cancers. In colorectal cancer, there is currently no biomarker to predict response to oxaliplatin. We tested the ability of the DDIR assay to predict response to oxaliplatin-based chemotherapy in colorectal cancer and characterized the biology in DDIR-positive colorectal cancer. Experimental Design: Samples and clinical data were assessed according to DDIR status from patients who received either 5-fluorouracil (5-FU) or 5FUFA (bolus and infusion 5-FU with folinic acid) plus oxaliplatin (FOLFOX) within the FOCUS trial (n = 361, stage IV), or neoadjuvant FOLFOX in the FOxTROT trial (n = 97, stage II/III). Whole transcriptome, mutation, and IHC data of these samples were used to interrogate the biology of DDIR in colorectal cancer. Results: Contrary to our hypothesis, DDIR-negative patients displayed a trend toward improved outcome for oxaliplatin-based chemotherapy compared with DDIR-positive patients. DDIR positivity was associated with microsatellite instability (MSI) and colorectal molecular subtype 1. Refinement of the DDIR signature, based on overlapping IFN-related chemokine signaling associated with DDIR positivity across colorectal cancer and breast cancer cohorts, further confirmed that the DDIR assay did not have predictive value for oxaliplatin-based chemotherapy in colorectal cancer. Conclusions: DDIR positivity does not predict improved response following oxaliplatin treatment in colorectal cancer. However, data presented here suggest the potential of the DDIR assay in identifying immune-rich tumors that may benefit from immune checkpoint blockade, beyond current use of MSI status.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-3237
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    Transformer-based biomarker prediction from colorectal cancer histology: A large-scale multicentric study
    Elsevier BV ; 2023
    In:  Cancer Cell Vol. 41, No. 9 ( 2023-09), p. 1650-1661.e4
    Details
    In: Cancer Cell, Elsevier BV, Vol. 41, No. 9 ( 2023-09), p. 1650-1661.e4
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/j.ccell.2023.08.002
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2074034-7
    detail.hit.zdb_id: 2078448-X
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial
    BMJ ; 2016
    In:  Journal of Clinical Pathology Vol. 69, No. 1 ( 2016-01), p. 35-41
    Details
    In: Journal of Clinical Pathology, BMJ, Vol. 69, No. 1 ( 2016-01), p. 35-41
    Type of Medium: Online Resource
    ISSN: 0021-9746 , 1472-4146
    URL: Article
    DOI: 10.1136/jclinpath-2015-203097
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2016
    detail.hit.zdb_id: 2028928-5
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  • 6
    Online Resource
    Online Resource
    Mismatch Repair Status and BRAF Mutation Status in Metastatic Colorectal Cancer Patients: A Pooled Analysis of the CAIRO, CAIRO2, COIN, and FOCUS Studies
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 20 ( 2014-10-15), p. 5322-5330
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 20 ( 2014-10-15), p. 5322-5330
    Abstract: Purpose: To determine the prevalence and prognostic value of mismatch repair (MMR) status and its relation to BRAF mutation (BRAFMT) status in metastatic colorectal cancer (mCRC). Experimental Design: A pooled analysis of four phase III studies in first-line treatment of mCRC (CAIRO, CAIRO2, COIN, and FOCUS) was performed. Primary outcome parameter was the hazard ratio (HR) for median progression-free survival (PFS) and overall survival (OS) in relation to MMR and BRAF. For the pooled analysis, Cox regression analysis was performed on individual patient data. Results: The primary tumors of 3,063 patients were analyzed, of which 153 (5.0%) exhibited deficient MMR (dMMR) and 250 (8.2%) a BRAFMT. BRAFMT was observed in 53 (34.6%) of patients with dMMR tumors compared with 197 (6.8%) of patients with proficient MMR (pMMR) tumors (P & lt; 0.001). In the pooled dataset, median PFS and OS were significantly worse for patients with dMMR compared with pMMR tumors [HR, 1.33; 95% confidence interval (CI), 1.12–1.57 and HR, 1.35; 95% CI, 1.13–1.61, respectively), and for patients with BRAFMT compared with BRAF wild-type (BRAFWT) tumors (HR, 1.34; 95% CI, 1.17–1.54 and HR, 1.91; 95% CI, 1.66–2.19, respectively). PFS and OS were significantly decreased for patients with BRAFMT within the group of patients with pMMR, but not for BRAF status within dMMR, or MMR status within BRAFWT or BRAFMT. Conclusions: Prevalence of dMMR and BRAFMT in patients with mCRC is low and both biomarkers confer an inferior prognosis. Our data suggest that the poor prognosis of dMMR is driven by the BRAFMT status. Clin Cancer Res; 20(20); 5322–30. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-0332
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
    Online Resource
    Online Resource
    Abstract 5365: Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5365-5365
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 5365-5365
    Abstract: Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMS) and colorectal cancer intrinsic subtypes (CRIS) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, in pre-treatment biopsies from multiple regions or at different time points remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n=543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n=10), (iv) multi-regional biopsies from colon tumours (n=29 biopsies, n=7 tumours) and (v) pre-treatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n=44). Compared to previous results obtained using CRC resection material, we now demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p=0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p= 0.003 and p=0.02, respectively). These findings may have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials. Citation Format: Matthew Alderdice, Susan D. Richman, Simon Gollins, Peter Stewart, Chris Hurt, Richard Adams, Amy M. McCorry, Aideen Roddy, Dale Vimalachandran, Claudio Isella, Enzo Medico, Tim Maughan, Darrgh G. McArt, Mark Lawler, Philip D. Dunne. Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5365.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-5365
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    Online Resource
    Online Resource
    Prospective patient stratification into robust cancer‐cell intrinsic subtypes from colorectal cancer biopsies
    Wiley ; 2018
    In:  The Journal of Pathology Vol. 245, No. 1 ( 2018-05), p. 19-28
    Details
    In: The Journal of Pathology, Wiley, Vol. 245, No. 1 ( 2018-05), p. 19-28
    Abstract: Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly‐guided clinical trials. The consensus molecular subtypes (CMSs) and colorectal cancer intrinsic subtypes (CRISs) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, particularly in pretreatment biopsies from multiple regions or at different time points, remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser‐capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets ( n =  543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n =  10), (iv) multi‐regional biopsies from colon tumours ( n =  29 biopsies, n =  7 tumours), and (v) pretreatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n =  44). Compared to previous results obtained using CRC resection material, we demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p =  0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially‐ and temporally‐ robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS ( p =  0.003 and p =  0.02, respectively). These findings have potential to inform ongoing biopsy‐based patient stratification in CRC, enabling robust and stable assignment of patients into clinically‐informative arms of prospective multi‐arm, multi‐stage clinical trials. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
    Type of Medium: Online Resource
    ISSN: 0022-3417 , 1096-9896
    URL: Issue
    URL: Article
    DOI: 10.1002/path.2018.245.issue-1
    DOI: 10.1002/path.5051
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1475280-3
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  • 9
    Online Resource
    Online Resource
    Confirmation that somatic mutations of beta‐2 microglobulin correlate with a lack of recurrence in a subset of stage II mismatch repair deficient colorectal cancers from the QUASAR trial
    Wiley ; 2019
    In:  Histopathology Vol. 75, No. 2 ( 2019-08), p. 236-246
    Details
    In: Histopathology, Wiley, Vol. 75, No. 2 ( 2019-08), p. 236-246
    Abstract: Beta2‐microglobulin (B2M) forms part of the HLA class I complex and plays a role in metastatic biology. B2M mutations occur frequently in mismatch repair‐deficient colorectal cancer (dMMR CRC), with limited data suggesting they may protect against recurrence. Our experimental study tested this hypothesis by investigating B2M mutation status and B2M protein expression and recurrence in patients in the stage II QUASAR clinical trial. Methods and results Sanger sequencing was performed for the three coding exons of B2M on 121 dMMR and a subsample of 108 pMMR tumours; 52 with recurrence and 56 without. B2M protein expression was assessed by immunohistochemistry. Mutation status and protein expression were correlated with recurrence and compared to proficient mismatch repair (pMMR) CRCs. Deleterious B2M mutations were detected in 39 of 121 (32%) dMMR tumours. Five contained missense B2M ‐variants of unknown significance, so were excluded from further analyses. With median follow‐up of 7.4 years, none of the 39 B2M ‐mutant tumours recurred, compared with 14 of 77 (18%) B2M‐ wild‐type tumours ( P  = 0.005); six at local and eight at distant sites. Sensitivity and specificity of IHC in detecting B2M mutations was 87 and 71%, respectively. Significantly ( P   〈  0.0001) fewer (three of 104, 2.9%) of the 108 pMMR CRCs demonstrated deleterious B2M mutations. One pMMR tumour, containing a frameshift mutation, later recurred. Conclusion B2M mutations were detected in nearly one‐third of dMMR cancers, none of which recurred. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC. The mechanism of protection against recurrence and whether this protection extends to stage III disease remains unclear.
    Type of Medium: Online Resource
    ISSN: 0309-0167 , 1365-2559
    URL: Issue
    URL: Article
    DOI: 10.1111/his.2019.75.issue-2
    DOI: 10.1111/his.13895
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2019
    detail.hit.zdb_id: 2006447-0
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  • 10
    Online Resource
    Online Resource
    Analysis of primary and acquired resistance to cetuximab from multiomic data in the New EPOC trial.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3577-3577
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3577-3577
    Abstract: 3577 Background: The use of cetuximab (cetux) with chemotherapy (chemo) in patients with operable liver metastases from colorectal cancer (CRC) conferred a survival disadvantage in New EPOC. Whilst genetic alterations such as emergent sub-clonal mutations in RAS/ BRAF, ERBB2 and MET are recognized as mechanisms of resistance to EGFR inhibition (EGFRi), divergent mechanisms such as transcriptomic changes may also be responsible. Of the CRC intrinsic subtypes (CRIS), CRIS-C has elevated EGFR signalling and is thought to have greater sensitivity to EGFRi. Methods: Resected primary tumors (n = 205; pre neoadjuvant treatment) and/or liver metastases (n = 144; post neoadjuvant treatment) from 223 patients, wild type for KRAS (codons 12/13/61) at trial entry, randomized to chemo +/- cetux underwent targeted NGS and/or transcriptome profiling. Primary clinical endpoints were progression free (PFS) and overall survival (OS). Results: Repeat NGS identified additional RAS/BRAF mutations in primary tumors from 49 patients (25 KRAS, 15 NRAS, 9 BRAF V6000E). Of the 148 patients with confirmed RAS/BRAF wild type primary tumors , 46% were classified as CRIS-C with the remainder being CRIS-A (9.5%), CRIS-B (11%), CRIS-D (8.8%) or CRIS-E (8.1%). CRIS-C patients had a similar PFS with ChemoCetux vs Chemo (HR 0.84 95% CI 0.47-1.5 p = 0.55) whereas non-CRIS-C had a shorter PFS (HR 2.12 95%CI 1.24-3.63 p = 0.006; p interaction 0.021). OS results were similar (p interaction 0.067). In liver metastases, genetic changes were comparable (Chemo vs ChemoCetux): KRAS (4.1% v 2.1%), NRAS (4.1% v 0%), BRAF V600E (0% v 0%), ERBB2 gain/amplification (20% v 21%) and MET gain/amplification (25% v 18%). However, gain/amplification of MET resulted in shorter OS with ChemoCetux vs Chemo (HR 5.13 95%CI 1.38-19.15 p = 0.015) whereas those without MET gain/amplification had a similar OS (HR 1.32 95%CI 0.76-2.28 p = 0.32; p interaction 0.029). The same association was found after excluding liver metastases with RAS/BRAF mutations (n = 101, p interaction 0.030). Differential expression/mutation analyses did not identify other stratifiers after false discovery correction. Conclusions: The shorter survival with ChemoCetux was restricted to patients with a non CRIS-C subtype before treatment supporting the use of this transcriptomic classifier to stratify for EGFRi. After neoadjuvant treatment, gain/amplification of MET was associated with a shorter survival with ChemoCetux. By contrast MAPK pathway mutations were largely unchanged supporting earlier findings that alternative resistance mechanisms predominate when EGFRi is combined with chemotherapy. In summary these results highlight the heterogeneity and differential responses to EGFRi that exist within RAS/RAF wild type CRC and provide insights into the substantial survival detriment observed in the New EPOC trial. Clinical trial information: ISRCTN22944367 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3577
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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