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  • 1
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    Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia
    Springer Science and Business Media LLC ; 2020
    In:  British Journal of Cancer Vol. 123, No. 8 ( 2020-10-13), p. 1280-1288
    Details
    In: British Journal of Cancer, Springer Science and Business Media LLC, Vol. 123, No. 8 ( 2020-10-13), p. 1280-1288
    Abstract: Immunohistochemical quantification of the immune response is prognostic for colorectal cancer (CRC). Here, we evaluate the suitability of alternative immune classifiers on prognosis and assess whether they relate to biological features amenable to targeted therapy. Methods Overall survival by immune (CD3, CD4, CD8, CD20 and FOXP3) and immune-checkpoint (ICOS, IDO-1 and PD-L1) biomarkers in independent CRC cohorts was evaluated. Matched mutational and transcriptomic data were interrogated to identify associated biology. Results Determination of immune-cold tumours by combined low-density cell counts of CD3, CD4 and CD8 immunohistochemistry constituted the best prognosticator across stage II–IV CRC, particularly in patients with stage IV disease (HR 1.98 [95% CI: 1.47–2.67]). These immune-cold CRCs were associated with tumour hypoxia, confirmed using CAIX immunohistochemistry ( P  = 0.0009), which may mediate disease progression through common biology ( KRAS mutations, CRIS-B subtype and SPP1 mRNA overexpression). Conclusions Given the significantly poorer survival of immune-cold CRC patients, these data illustrate that assessment of CD4-expressing cells complements low CD3 and CD8 immunohistochemical quantification in the tumour bulk, potentially facilitating immunophenotyping of patient biopsies to predict prognosis. In addition, we found immune-cold CRCs to associate with a difficult-to-treat, poor prognosis hypoxia signature, indicating that these patients may benefit from hypoxia-targeting clinical trials.
    Type of Medium: Online Resource
    ISSN: 0007-0920 , 1532-1827
    URL: Article
    DOI: 10.1038/s41416-020-0985-5
    RVK:
    XA 33500
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2002452-6
    detail.hit.zdb_id: 80075-2
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  • 2
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    Recruitment of cancer patients to National Institute for Health research cancer research network portfolio studies between 2001 and 2011.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 6091-6091
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 6091-6091
    Abstract: 6091 Background: The National Institute for Health Research Cancer Research Network (NCRN) was established in 2001 in England, United Kingdom to improve cancer patient outcomes by improving the coordination, integration and speed of cancer research. Methods: Baseline recruitment of cancer patients in England to clinical studies was around 4% of incident population. Research Networks were established initially in England (NCRN) and then across the UK, co-terminus with clinical cancer service networks, and a per capita based funding model used to provide a research infrastructure to support recruitment to a nationally defined research portfolio. Results: Within 3 years, as the networks were established, recruitment of patients to studies doubled from 10,000 to 20,000 cancer patients per year. Recruitment has continued to increase year on year, supported initially by underspend that had accrued from earlier years in the life of NCRN, and more recently from additional resources invested via the NIHR comprehensive networks. Data for 2010/11 show that over 45,000 cancer patients are now recruited into portfolio studies in England each year, with over 50,000 across the whole of the UK. Conclusions: Dedicated, targeted, clinician-led National Health Service investment into supporting national portfolio studies, has delivered an unprecedented five-fold increase in recruitment of cancer patients into clinical trials across the United Kingdom. This required coordinated research infrastructure, close cooperation with research funders, particularly Cancer Research UK and the National Cancer Research Institute, and the enthusiasm and hard work of many clinicians, patients and others working to deliver clinical cancer care in the National Health Service in the United Kingdom.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.6091
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Growth in head and neck cancer clinical research in the NCRN and NCRI: Expanding opportunities for patients across the United Kingdom.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. e16007-e16007
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e16007-e16007
    Abstract: e16007 Background: The National Institute for Health Research Cancer Research Network (NCRN) was established in 2001 to benefit patients by improving the coordination, integration and speed of cancer research. Networks were established in England (NCRN), Scotland, Wales and Northern Ireland, supporting recruitment to a national portfolio across the NHS. In a decade recruitment to cancer studies has increased five fold in England to 20% of new incident cases. Head and Neck cancers affect basic functions including breathing and eating; particularly devastating for patients. The NCRI Head and Neck Cancer Clinical Studies Group is one of 23 Groups funded by NCRI members with a UK wide remit to develop a national portfolio of clinical studies. All CSGs include patients and carers as members resulting in active patient involvement in trial design, patient information and strategic direction of the portfolio. Methods: The last decade has seen unprecedented growth in the Head and Neck portfolio, which now includes 43 studies from only three studies in 2003/4. By 2010/11, 95% of UK Cancer Local Research Networks (37 networks) were recruiting to Head and Neck studies from only 2 networks in 2001/2, expanding trial access for patients and developing Head and Neck research expertise in new sites and with new investigators. Results: Numbers of patients participating in Head and Neck studies has grown exponentially. Since 2006/7 UK patient recruitment has risen 15-fold from 126 to 1890, representing almost 25% new incident cases of Head and Neck cancer. Conclusions: Rapid portfolio growth and associated network activity has expanded opportunities for patients with Head and Neck cancer; providing access to new therapeutic agents and treatment modalities, including NIHR CRN-adopted commercial trials and studies in a surgical setting. Participation in studies demonstrating the effectiveness of Intensity Modulated Radiotherapy in reducing xerostomia (including PARSPORT), has supported integration of this technique into cancer service.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.e16007
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 4
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    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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  • 5
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    FOCUS 3: A study to determine the feasibility of molecular selection of therapy using K -RAS , B -RAF , and topo-1 in patients with advanced colorectal cancer (ACRC).
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 4_suppl ( 2012-02-01), p. 563-563
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 4_suppl ( 2012-02-01), p. 563-563
    Abstract: 563 Background: Molecular characteristics of cancer vary between individuals. In future increasing numbers of trials will require assessment of biomarkers in order to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The FOCUS 3 trial is a feasibility study to assess whether tumour samples could be collected from referring hospitals’ pathology departments, sent to designated reference laboratories for biomarker evaluation, and results provided to oncologists within 10 working days. Methods: Patients with ACRC, fit for chemotherapy, were registered from 24 centres between 02.10 and 04.11. Following consent, paraffin embedded tumour samples were sent to Cardiff or Leeds for analysis of topoisomerase 1 (topo-1) by immunohistochemistry and of KRAS and BRAF mutation status, and results were forwarded to the MRC CTU. Patients were classified into 1 of 4 molecular strata, which determined the set of 2 hypothesis driven experimental therapies they could be randomised to in addition to control chemotherapy (irinotecan + 5FU). At this stage eligibility was reconfirmed and consent for randomisation obtained. Results: 332 patients were registered to participate in FOCUS 3. Biomarker results were provided to oncologists within 10 working days (wd) in 71%, within 15 wd in 91% and within 20 wd in 99% patients. A 4 stage suite of patient information sheets (PIS) was designed and implemented to avoid patient overload; separate information sheets were provided to patients at stages during the consent process and patient understanding was assessed. 93% of eligible patients gave consent to randomisation. KRAS mutation was detected in 88 (36%), BRAF in 15 (6%), 2 patients had both mutations and 133 were double wildtype. 77% of patients were high (2-3), 19% low (0-1) and 4% inconclusive for topo-1. Tumour response and toxicity results for the 244 randomised patients will be presented. Conclusions: Patient samples can be collected and analysed at designated reference laboratories within acceptable timeframes. Multi-arm designs can be made acceptable to patients through good PIS, ensured by patient and carer input into their design.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.4_suppl.563
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 6
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    A biomarker enrichment trial of anti-EGFR agents in right primary tumor location (rPTL), RAS wild-type ( RAS -wt) advanced colorectal cancer (aCRC): ARIEL (ISRCTN11061442).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS3633-TPS3633
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS3633-TPS3633
    Abstract: TPS3633 Background: Meta-analysis of 6 RCTs indicates that anti-EGFR agents are ineffective in rPTL RAS-wt aCRC (Arnold D, et al. Ann Oncol. 2017;28:1713-1729). However, data from the phase III PICCOLO and COIN trials suggest high tumor expression of the EGFR ligands, EREG and AREG, confers sensitivity to anti-EGFR agents in a subset of this population (Adams RA, et al. J Clin Oncol. 2012;30(30_suppl):32-32; Seligmann JF, et al. Ann Oncol. 2020;31:1021-1029). More data is needed before ligand assessment can be integrated into routine care: to date, EREG/AREG mRNA has only been assessed retrospectively, and feasibility of timely delivery of results must be demonstrated. The ARIEL trial aims to determine whether first-line chemotherapy plus cetuximab or panitumumab is more effective than chemotherapy alone in achieving early tumor shrinkage (ETS) after 8 weeks of treatment in patients (pts) with EREG/AREG-high rPTL RAS-wt aCRC. Methods: ARIEL is a multicentre, phase IV, open label, biomarker enrichment RCT. Pts with previously untreated rPTL RAS-wt (or RAS-unknown) aCRC are eligible for registration and EREG/AREG assessment using archival FFPE tumor tissue. Those confirmed as RAS-wt EREG/AREG-high (expression above 30th centile based on PICCOLO) 3 are eligible for randomization to chemotherapy alone (fluoropyrimidine backbone plus irinotecan or oxaliplatin) vs chemotherapy (FOLFOX or FOLFIRI) plus anti-EGFR therapy (panitumumab or cetuximab) (options at physician’s discretion). Pts with EREG/AREG-low tumors are not eligible for randomization but may consent to translational research and follow-up. The primary endpoint is ETS at 8 weeks (≥30%, yes vs no). Secondary endpoints are depth of response at 16 weeks, overall survival, overall treatment utility, pt-reported quality of life, cost per QALY, pt acceptability of trial procedures, and safety. Pre-trial work-up included cross-validation of the EREG/AREG RT-qPCR assay at trial laboratories in Leeds and Birmingham, UK demonstrating reproducibility of biomarker results. Recruitment to an internal pilot phase is currently ongoing to demonstrate feasibility of timely delivery of biomarker results to sites (lower limit of 90% CI of mean result delivery time for first 20 pts must include 3 weeks). Mean monthly recruitment rate will be assessed at 18 months to determine likelihood of completion of the trial within the 3 year recruitment period. ARIEL is funded by the UK National Institute for Health Research (NIHR) and opened the first of 40 sites in February 2022. 440 pts will be registered for biomarker assessment in order to randomize 162 pts. All pts will be followed-up to 1 year post-randomisation, with a final assessment in all pts when the last pt has completed a year of follow-up (median 3.5 years). ARIEL is participating in the NIHR Associate PI scheme. Clinical trial information: 11061442.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS3633
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Severe Sequence-Specific Toxicity When Capecitabine Is Given After Fluorouracil and Leucovorin
    American Society of Clinical Oncology (ASCO) ; 2008
    In:  Journal of Clinical Oncology Vol. 26, No. 20 ( 2008-07-10), p. 3411-3417
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 26, No. 20 ( 2008-07-10), p. 3411-3417
    Abstract: Options for single-agent fluoropyrimidine adjuvant therapy after bowel cancer resection include intravenous fluorouracil with leucovorin (FU/LV) or oral capecitabine. These treatments have similar efficacy but differ in convenience and toxicity. We therefore wished to compare their overall acceptability to patients. Patients and Methods Patients scheduled for adjuvant single-agent fluoropyrimidine therapy were randomly assigned to receive once-weekly FU/LV (425 mg/m 2 FU, 45 mg LV) for 6 weeks, followed by two 3-week cycles of capecitabine (1,250 mg/m 2 twice daily, days 1 through 14), or the same treatments but in reverse order. After 12 weeks, the patients were asked which treatment they preferred, and received the preferred treatment for an additional 12 weeks. The primary end point was patient preference. Results After 40 of the planned 74 patients had been randomly assigned, real-time adverse event monitoring led to early trial closure because of excess sequence-specific toxicity. Eleven of 14 patients (79%) receiving capecitabine as their second treatment experienced grade ≥ 3 toxicity. This compared with five of 18 patients (28%) receiving capecitabine as the first treatment, and no patients receiving FU/LV as the first treatment (zero of 16) or the second treatment (zero of 12). Similar imbalances were seen in the proportion of patients requiring interruption of treatment. Conclusion In chemotherapy-naïve patients, capecitabine produced more toxicity than FU/LV, but at levels in line with previously reported data. However, treatment with capecitabine after FU/LV caused markedly increased toxicity, indicating a sequence-specific interaction. The mechanism has not been determined, but interaction with intracellularly retained folate after FU/LV therapy is a possibility. Oncologists need to be aware of this risk if considering crossing patients over from FU/LV to capecitabine-based regimens.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2007.15.9426
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2008
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Optimizing chemotherapy for frail and elderly patients (pts) with advanced gastroesophageal cancer (aGOAC): The GO2 phase III trial.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 4006-4006
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 4006-4006
    Abstract: 4006 Background: Many pts with aGOAC are elderly and/or frail. We previously compared epirubin/ oxaliplatin/ capecitabine (EOCap) vs OCap vs Cap in a pick-the-winner study and found OCap best. GO2 was designed to find the optimum dose of OCap and to explore the use of an objective baseline geriatric assessment to individualize doses for maximum Overall Treatment Utility (OTU), a composite of clinical benefit, tolerability, QL and patient value. Methods: Pts with aGOAC were eligible if unsuitable for full-dose EOCap due to age or frailty, but fit for OCap; GFR ≥ 30, bili 〈 2x ULN. Baseline assessment included global QL; symptoms; functional scales; comorbidity; frailty. Randomization was 1:1:1 to dose Level A (Ox 130 mg/m 2 d1, Cap 625 mg/m 2 bd d1-21, q21d), B (80% Level A doses) or C (60% Level A doses). Pts with GFR 30-50 ml/min or bili 1.5-2.0 xULN received 75% of the allocated dose of Cap. At 9 wks, pts were scored for OTU. Continuation thereafter was based on clinical judgement. Non-inferiority (vs A) was assessed using PFS censored at 12 months, with boundary HR 1.34 (based on discussion with pts and clinicians), needing 284 PFS events per 2-way comparison. Baseline fitness was assessed as predictive of OTU, overall and by interaction with dose level. Results: 514 pts were randomised, 2014-17, at 61 UK centres. Clinical trial information: 44687907. Non-inferiority of PFS is confirmed for Level B vs A (HR 1.09, CI 0.89-1.32) and for Level C vs A (HR 1.10, CI 0.90-1.33). Level C pts had less toxicity and better OTU outcomes than A or B. When analysed by baseline age, frailty and PS, Level C produced the best OTU even in younger, less frail and better PS patients; no group was identified who benefit more from the higher dose levels. Conclusions: This is the largest RCT to date specifically investigating frail and/or elderly aGOAC pts, and should guide future treatment. The lowest dose tested was non-inferior in terms of PFS and produced less toxicity and better overall treatment utility.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.4006
    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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  • 9
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    Chemotherapy to reverse diminished immune responses (IRs) associated with a raised neutrophil lymphocyte ratio (NLR) in patients with advanced colorectal cancer (aCRC).
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. e15635-e15635
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. e15635-e15635
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.e15635
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 10
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    Exploring the poor outcomes of BRAF mutant ( BRAF mut) advanced colorectal cancer (aCRC): Analysis from 2,530 patients (pts) in randomized clinical trials (RCTs).
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 3509-3509
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 3509-3509
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.3509
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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