Publications by authors named "Tim Maughan"

54 Publications

Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis.

Ther Adv Med Oncol 2021 30;13:17588359211020547. Epub 2021 Jun 30.

Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France.

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs).

Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions.

Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( = 0.0034 and  < 0.001, respectively), with median difference of 3-4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( < 0.001).

Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.
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http://dx.doi.org/10.1177/17588359211020547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252342PMC
June 2021

Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone.

Br J Cancer 2021 Jul 12. Epub 2021 Jul 12.

Amsterdam UMC, University of Amsterdam, LEXOR, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Background: Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location.

Methods: Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively.

Results: When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26-0.75, P = 0.003 and HR 0.12, 95% CI 0.04-0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04-0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36-0.96, P = 0.034).

Conclusions: The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.
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http://dx.doi.org/10.1038/s41416-021-01477-9DOI Listing
July 2021

Stromal composition predicts recurrence of early rectal cancer after local excision.

Histopathology 2021 Jun 26. Epub 2021 Jun 26.

Department of Pathology and Molecular Pathology, University and University Hospital Zürich, Zürich, Switzerland.

Aims: After local excision of early rectal cancer, definitive lymph node status is not available. An alternative means for accurate assessment of recurrence risk is required to determine the most appropriate subsequent management. Currently used measures are suboptimal. We assess three measures of tumour stromal content to determine their predictive value after local excision in a well-characterized cohort of rectal cancer patients without prior radiotherapy.

Methods And Results: 143 patients were included. H&E sections were scanned for 1) deep neural network (DNN, a machine learning algorithm) tumour segmentation into compartments including desmoplastic stroma and inflamed stroma; and 2) digital assessment of tumour stromal fraction (TSR) and optical DNA ploidy analysis. 3' mRNA sequencing was performed to obtain gene expression data, from which stromal and immune scores were calculated using the ESTIMATE method. Full results were available for 139 samples and compared with disease-free survival. All three methods were prognostic. Most strongly predictive was a DNN-determined ratio of desmoplastic to inflamed stroma >5.41 (p<0.0001). A ratio of ESTIMATE stromal to immune score <1.19 was also predictive of disease-free survival (p=0.00051), as was stromal fraction >36.5% (p=0.037).

Conclusions: The DNN-determined ratio of desmoplastic to inflamed ratio is a novel and powerful predictor of disease recurrence in locally excised early rectal cancer. It can be assessed on a single H&E section so could be applied in routine clinical practice to improve the prognostic information available to patients and clinicians to inform the decision about further management.
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http://dx.doi.org/10.1111/his.14438DOI Listing
June 2021

Incorporating oxygenation levels in analytical DNA-damage models-quantifying the oxygen fixation mechanism.

Phys Med Biol 2021 Jul 9;66(14). Epub 2021 Jul 9.

University of Oxford, Department of Oncology, Oxford, United Kingdom.

To develop a framework to include oxygenation effects in radiation therapy treatment planning which is valid for all modalities, energy spectra and oxygen levels. The framework is based on predicting the difference in DNA-damage resulting from ionising radiation at variable oxygenation levels.Oxygen fixation is treated as a statistical process in a simplified model of complex and simple damage. We show that a linear transformation of the microscopic oxygen fixation process allows to extend this to all energies and modalities, resulting in a relatively simple rational polynomial expression. The model is expanded such that it can be applied for polyenergetic beams. The methodology is validated using Microdosimetric Monte Carlo Damage Simulation code (MCDS). This serves as a bootstrap to determine relevant parameters in the analytical expression, as MCDS is shown to be extensively verified with published empirical data. Double-strand break induction as calculated by this methodology is compared to published proton experiments. Finally, an example is worked out where the oxygen enhancement ratio (OER) is calculated at different positions in a clinically relevant spread out Bragg peak (SOBP) dose deposition in water. This dose deposition is obtained using a general Monte Carlo code (FLUKA) to determine dose deposition and locate fluence spectra.For all modalities (electrons, protons), the damage categorised as complex could be parameterised to within 0.3% of the value calculated using microdosimetric Monte Carlo. The proton beam implementation showed some variation in OERs which differed slightly depending on where the assessment was made; before the SOBP, mid-SOBP or at the distal edge. Environment oxygenation was seen to be the more important variable.An analytic expression calculating complex damage depending on modality, energy spectrum, and oxygenation levels was shown to be effective and can be readily incorporated in treatment planning software, to take into account the impact of variable oxygenation, forming a first step to an optimised treatment based on biological factors.
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http://dx.doi.org/10.1088/1361-6560/ac0b80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273901PMC
July 2021

Treatment breaks in first line treatment of advanced colorectal cancer: An individual patient data meta-analysis.

Cancer Treat Rev 2021 May 19;99:102226. Epub 2021 May 19.

MRC Clinical Trials Unit at UCL, United Kingdom. Electronic address:

Background: Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break.

Patients And Methods: An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken.

Results: All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy).

Conclusion: The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy.
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http://dx.doi.org/10.1016/j.ctrv.2021.102226DOI Listing
May 2021

Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer: a Mendelian randomisation analysis.

Br J Cancer 2021 Mar 7;124(6):1169-1174. Epub 2021 Jan 7.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

Background: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR).

Methods: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (OR) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions.

Results: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (OR = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown.

Conclusions: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.
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http://dx.doi.org/10.1038/s41416-020-01211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961009PMC
March 2021

The Challenge of Combining Chemo- and Radiotherapy with Checkpoint Kinase Inhibitors.

Clin Cancer Res 2021 Feb 30;27(4):937-962. Epub 2020 Nov 30.

MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.

Preclinical models of cancer have demonstrated enhanced efficacy of cell-cycle checkpoint kinase inhibitors when used in combination with genotoxic agents. This combination therapy is predicted to be exquisitely toxic to cells with a deficient G-S checkpoint or cells with a genetic predisposition leading to intrinsic DNA replication stress, as these cancer cells become fully dependent on the intra-S and G-M checkpoints for DNA repair and cellular survival. Therefore, abolishing remaining cell-cycle checkpoints after damage leads to increased cell death in a tumor cell-specific fashion. However, the preclinical success of these drug combinations is not consistently replicated in clinical trials. Here, we provide a perspective on the translation of preclinical studies into rationally designed clinical studies. We will discuss successes and failures of current treatment combinations and drug regimens and provide a detailed overview of all clinical trials using ATR, CHK1, or WEE1 inhibitors in combination with genotoxic agents. This highlights the need for revised patient stratification and the use of appropriate pharmacodynamic biomarkers to improve the success rate of clinical trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3358DOI Listing
February 2021

Circulating biomarkers and outcomes from a randomised phase 2 trial of gemcitabine versus capecitabine-based chemoradiotherapy for pancreatic cancer.

Br J Cancer 2021 02 26;124(3):581-586. Epub 2020 Oct 26.

Department of Oncology, University of Oxford, Oxford, UK.

Background: The Phase 2 SCALOP trial compared gemcitabine with capecitabine-based consolidation chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC).

Methods: Thirty-five systematically identified circulating biomarkers were analysed in plasma samples from 60 patients enroled in SCALOP. Each was measured in triplicate at baseline (prior to three cycles of gemcitabine-capecitabine induction chemotherapy) and, for a subset, prior to CRT. Association with overall survival (OS) was determined using univariable Cox regression and optimal thresholds delineating low to high values identified using time-dependent ROC curves. Independence from known prognostic factors was assessed using Spearman correlation and the Wilcoxon rank sum test prior to multivariable Cox regression modelling including independent biomarkers and known prognostic factors.

Results: Baseline circulating levels of C-C motif chemokine ligand 5 (CCL5) were significantly associated with OS, independent of other clinicopathological characteristics. Patients with low circulating CCL5 (CCL5) had a median OS of 18.5 (95% CI 11.76-21.32) months compared to 11.3 (95% CI 9.86-15.51) months in CCL5; hazard ratio 1.95 (95% CI 1.04-8.65; p = 0.037).

Conclusions: CCL5 is an independent prognostic biomarker in LAPC. Given the known role of CCL5 in tumour invasion, metastasis and the induction of an immunosuppressive micro-environment, targeting of CCL5-mediated pathways may offer therapeutic potential in pancreatic cancer.

Clinical Trial Registration: The SCALOP trial was registered with ISRCTN, number 96169987 (registered 29 May 2008).
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http://dx.doi.org/10.1038/s41416-020-01120-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851394PMC
February 2021

NRF2 metagene signature is a novel prognostic biomarker in colorectal cancer.

Cancer Genet 2020 10 21;248-249:1-10. Epub 2020 Aug 21.

Oxford Institute of Radiation Oncology, University of Oxford, United Kingdom.

We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer.

Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights.

Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms.

Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2-2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086-1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06-1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04-1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4.

Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study.
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http://dx.doi.org/10.1016/j.cancergen.2020.08.006DOI Listing
October 2020

Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia.

Br J Cancer 2020 10 20;123(8):1280-1288. Epub 2020 Jul 20.

Precision Medicine Centre of Excellence, Centre for Cell Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland.

Background: 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.
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http://dx.doi.org/10.1038/s41416-020-0985-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555485PMC
October 2020

A phase 1 trial of the safety, tolerability and biological effects of intravenous Enadenotucirev, a novel oncolytic virus, in combination with chemoradiotherapy in locally advanced rectal cancer (CEDAR).

Radiat Oncol 2020 Jun 12;15(1):151. Epub 2020 Jun 12.

Department of Physics and Biomedical Engineering, University College London, Oxford, UK.

Background: Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation.

Methods: Eligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for 'proof-of-concept' and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years.

Discussion: Chemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies.

Trial Registration: ClinicalTrial.gov, NCT03916510. Registered 16th April 2019.
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http://dx.doi.org/10.1186/s13014-020-01593-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291514PMC
June 2020

A phase II open label, randomised study of ipilimumab with temozolomide versus temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: the Ipi-Glio trial protocol.

BMC Cancer 2020 Mar 12;20(1):198. Epub 2020 Mar 12.

Department of Oncology, University College London Hospitals, 250 Euston Road, London, NW1 2PQ, UK.

Background: Median survival for patients with glioblastoma is less than a year. Standard treatment consists of surgical debulking if feasible followed by temozolomide chemo-radiotherapy. The immune checkpoint inhibitor ipilimumab targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and has shown clinical efficacy in preclinical models of glioblastoma. The aim of this study is to explore the addition of ipilimumab to standard therapy in patients with glioblastoma.

Methods/design: Ipi-Glio is a phase II, open label, randomised study of ipilimumab with temozolomide (Arm A) versus temozolomide alone (Arm B) after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma. Planned accrual is 120 patients (Arm A: 80, Arm B: 40). Endpoints include overall survival, 18-month survival, 5-year survival, and adverse events. The trial is currently recruiting in seven centres in the United Kingdom.

Trial Registration: ISRCTN84434175. Registered 12 November 2018.
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http://dx.doi.org/10.1186/s12885-020-6624-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068928PMC
March 2020

A systematic review of health economic evaluations of proton beam therapy for adult cancer: Appraising methodology and quality.

Clin Transl Radiat Oncol 2020 Jan 31;20:19-26. Epub 2019 Oct 31.

Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, UK.

Background And Purpose: With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area.

Materials And Methods: We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively.

Results: Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient.

Conclusion: In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence.
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http://dx.doi.org/10.1016/j.ctro.2019.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854069PMC
January 2020

Modifiable pathways for colorectal cancer: a mendelian randomisation analysis.

Lancet Gastroenterol Hepatol 2020 01 24;5(1):55-62. Epub 2019 Oct 24.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Background: Epidemiological studies have linked lifestyle, cardiometabolic, reproductive, developmental, and inflammatory factors to the risk of colorectal cancer. However, which specific factors affect risk and the strength of these effects are unknown. We aimed to examine the relationship between potentially modifiable risk factors and colorectal cancer.

Methods: We used a random-effects model to examine the relationship between 39 potentially modifiable risk factors and colorectal cancer in 26 397 patients with colorectal cancer and 41 481 controls (ie, people without colorectal cancer). These population data came from a genome-wide association study of people of European ancestry, which was amended to exclude UK BioBank data. In the model, we used genetic variants as instruments via two-sample mendelian randomisation to limit bias from confounding and reverse causation. We calculated odds ratios per genetically predicted SD unit increase in each putative risk factor (OR) for colorectal cancer risk. We did mendelian randomisation Egger regressions to identify evidence of potential violations of mendelian randomisation assumptions. A Bonferroni-corrected threshold of p=1·3 × 10 was considered significant, and p values less than 0·05 were considered to be suggestive of an association.

Findings: No putative risk factors were significantly associated with colorectal cancer risk after correction for multiple testing. However, suggestive associations with increased risk were noted for genetically predicted body fat percentage (OR 1·14 [95% CI 1·03-1·25]; p=0·0086), body-mass index (1·09 [1·01-1·17]; p=0·023), waist circumference (1·13 [1·02-1·26]; p=0·018), basal metabolic rate (1·10 [1·03-1·18]; p=0·0079), and concentrations of LDL cholesterol (1·14 [1·04-1·25]; p=0·0056), total cholesterol (1·09 [1·01-1·18]; p=0·025), circulating serum iron (1·17 [1·00-1·36]; p=0·049), and serum vitamin B12 (1·21 [1·04-1·42]; p=0·016), although potential pleiotropy among genetic variants used as instruments for vitamin B12 constrains the finding. A suggestive association was also noted between adult height and increased risk of colorectal cancer (OR 1·04 [95% CI 1·00-1·08]; p=0·032). Low blood selenium concentration had a suggestive association with decreased risk of colorectal cancer (OR 0·85 [95% CI 0·75-0·96]; p=0·0078) based on a single variant, as did plasma concentrations of interleukin-6 receptor subunit α (also based on a single variant; 0·98 [0·96-1·00]; p=0·035). Risk of colorectal cancer was not associated with any sex hormone or reproductive factor, serum calcium, or circulating 25-hydroxyvitamin D concentrations.

Interpretation: This analysis identified several modifiable targets for primary prevention of colorectal cancer, including lifestyle, obesity, and cardiometabolic factors, that should inform public health policy.

Funding: Cancer Research UK, UK Medical Research Council Human Genetics Unit Centre, DJ Fielding Medical Research Trust, EU COST Action, and the US National Cancer Institute.
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http://dx.doi.org/10.1016/S2468-1253(19)30294-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026696PMC
January 2020

Molecular biomarkers and precision medicine in colorectal cancer: a systematic review of health economic analyses.

Oncotarget 2019 May 21;10(36):3408-3423. Epub 2019 May 21.

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom.

An increased understanding of the biology of colorectal cancer (CRC) has fuelled identification of biomarkers with potential to drive a stratified precision medicine care approach in this common malignancy. We conducted a systematic review of health economic assessments of molecular biomarkers (MBMs) and their employment in patient stratification in CRC. Our analysis revealed scenarios where health economic analyses have been applied to evaluate the cost effectiveness of MBM-guided clinical interventions: (i) evaluation of Dihydropyrimidine dehydrogenase gene (DPYD) status to identify patients susceptible to 5-Fluouracil toxicity; (ii) determination of Uridine 5'-diphospho- glucuronosyltransferase family 1 member A1 gene (UGT1A1) polymorphism status to help guide irinotecan treatment; (iii) assessment of RAS/RAF mutational status to stratify patients for chemotherapy or Epidermal Growth Factor Receptor (EGFR) therapy and (iv) multigene expression analysis (Oncotype Dx) to identify and spare non-responders the debilitating effects of particular chemotherapy interventions. Our findings indicate that Oncotype Dx is cost-effective in high income settings within specific price points, by limiting treatment toxicity in CRC patients. DPYD status testing may also be cost effective in certain settings to avoid specific 5-FU toxicities post treatment. In contrast, current research does not support UGT1A1 polymorphism status as a cost-effective guide to irinotecan dosing, while the health economic evidence to support testing of KRAS/NRAS mutational status and chemo/EGFR therapy choice was inconclusive, despite its widespread adoption in CRC treatment management. However, we also show that there is a paucity of high-quality cost-effectiveness studies to support clinical application of precision medicine approaches in CRC.
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http://dx.doi.org/10.18632/oncotarget.26909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534362PMC
May 2019

This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols.

Trials 2019 May 29;20(1):264. Epub 2019 May 29.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, UCL, 90 High Holborn, London, WC1V 6LJ, UK.

Background: There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results. We share here our experiences from a trial management perspective, highlighting the challenges and successes.

Methods: We evaluated the operational aspects of making changes to these adaptive platform trials and identified both common and trial-specific challenges. The operational steps and challenges linked to both the addition of new research comparisons and stopping recruitment following pre-planned interim analysis were considered in our evaluation.

Results: Specific operational challenges in these adaptive platform protocols, additional to those in traditional two-arm trials, were identified. Key lessons are presented describing some of the solutions and considerations over conducting these trials. Careful consideration on the practicality of the protocol structure (modular versus single protocol), the longevity and continuity of trial oversight committees, and having clear clinical and scientific criteria for the addition of new research comparisons were identified as some of the most common challenges.

Conclusions: Understanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective.

Trial Registration: FOCUS4: ISRCTN Registry, ISRCTN90061546 . Registered on 16 October 2013.

Stampede: ISRCTN Registry, ISRCTN78818544 . Registered on 2 February 2004.
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http://dx.doi.org/10.1186/s13063-019-3216-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540525PMC
May 2019

Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons.

Trials 2019 May 29;20(1):294. Epub 2019 May 29.

MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK.

Background: There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management.

Methods: We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began.

Discussion: We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time.

Conclusions: Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks.
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http://dx.doi.org/10.1186/s13063-019-3322-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540437PMC
May 2019

Association analyses identify 31 new risk loci for colorectal cancer susceptibility.

Nat Commun 2019 05 14;10(1):2154. Epub 2019 May 14.

Wellcome Centre for Human Genetics, McCarthy Group, Roosevelt Drive, Oxford, OX3 7BN, UK.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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http://dx.doi.org/10.1038/s41467-019-09775-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517433PMC
May 2019

Guidelines for using sigQC for systematic evaluation of gene signatures.

Nat Protoc 2019 05 10;14(5):1377-1400. Epub 2019 Apr 10.

Computational Biology and Integrative Genomics Lab, MRC/CRUK Oxford Institute and Department of Oncology, University of Oxford, Oxford, UK.

With the increased use of next-generation sequencing generating large amounts of genomic data, gene expression signatures are becoming critically important tools for the interpretation of these data, and are poised to have a substantial effect on diagnosis, management, and prognosis for a number of diseases. It is becoming crucial to establish whether the expression patterns and statistical properties of sets of genes, or gene signatures, are conserved across independent datasets. Conversely, it is necessary to compare established signatures on the same dataset to better understand how they capture different clinical or biological characteristics. Here we describe how to use sigQC, a tool that enables a streamlined, systematic approach for the evaluation of previously obtained gene signatures across multiple gene expression datasets. We implemented sigQC in an R package, making it accessible to users who have knowledge of file input/output and matrix manipulation in R and a moderate grasp of core statistical principles. SigQC has been adopted in basic biology and translational studies, including, but not limited to, the evaluation of multiple gene signatures for potential clinical use as cancer biomarkers. This protocol uses a previously obtained signature for breast cancer metastasis as an example to illustrate the critical quality control steps involved in evaluating its expression, variability, and structure in breast tumor RNA-sequencing data, a different dataset from that in which the signature was originally derived. We demonstrate how the outputs created from sigQC can be used for the evaluation of gene signatures on large-scale gene expression datasets.
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http://dx.doi.org/10.1038/s41596-019-0136-8DOI Listing
May 2019

The evolutionary landscape of colorectal tumorigenesis.

Nat Ecol Evol 2018 10 31;2(10):1661-1672. Epub 2018 Aug 31.

Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations-considered to be functionally important in the carcinogenic process-that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a 'punctuated' fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.
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http://dx.doi.org/10.1038/s41559-018-0642-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152905PMC
October 2018

A prospective phase II study of pre-operative chemotherapy then short-course radiotherapy for high risk rectal cancer: COPERNICUS.

Br J Cancer 2018 09 17;119(6):697-706. Epub 2018 Aug 17.

Centre for Trials Research, Cardiff University, Room 409, Neuadd Meirionnydd, Heath Park, Cardiff, CF14 4YS, UK.

Background: Neoadjuvant chemotherapy (NAC) allows earlier treatment of rectal cancer micro-metastases but is not standard of care. There are currently no biomarkers predicting long-term progression-free survival (PFS) benefit from NAC.

Patients And Methods: In this single arm phase II trial, patients with non-metastatic magnetic resonance imaging (MRI)-defined operable rectal adenocarcinoma at high risk of post-operative metastatic recurrence, received 8 weeks of oxaliplatin/fluorouracil NAC then short-course preoperative radiotherapy (SCPRT) before immediate surgery. Sixteen weeks of post-operative adjuvant chemotherapy (AC) was planned. A pelvic MRI was performed at week 9 immediately post-NAC, before SCPRT. The primary end point was feasibility assessed by completion of protocol treatment up to and including surgery. Secondary endpoints included compliance, toxicity, downstaging efficacy, and PFS.

Results: In total 60 patients were recruited May 2012-June 2014. In total 57 patients completed protocol treatment, meeting the primary endpoint. Compliance with NAC was much better than AC: Comparing NAC vs. AC, the median percentage dose intensity for fluoropyrimidine was 100% vs. 63% and for oxaliplatin 100% vs. 45%. Treatment-related toxicity was acceptable with no treatment-related deaths. Post-NAC MRI showed 44 tumours (73%) were T-downstaged and 22 (37%) had excellent MRI tumour regression grade (mrTRG 1-2). Median follow-up was 27 months with 2-year PFS of 86.2% (10 events). On exploratory analysis, post-NAC mrTRG predicted PFS with no event among those with excellent regression.

Conclusion: The regimen was well tolerated with effective downstaging and encouraging PFS. mrTRG response to NAC may be a new prognostic factor for long-term PFS, but needs validation in larger studies.
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http://dx.doi.org/10.1038/s41416-018-0209-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6173784PMC
September 2018

Functional Parameters Derived from Magnetic Resonance Imaging Reflect Vascular Morphology in Preclinical Tumors and in Human Liver Metastases.

Clin Cancer Res 2018 10 29;24(19):4694-4704. Epub 2018 Jun 29.

CRUK and MRC Oxford Institute for Radiation Oncology Department of Oncology, University of Oxford, Oxford, United Kingdom.

Tumor vessels influence the growth and response of tumors to therapy. Imaging vascular changes using dynamic contrast-enhanced MRI (DCE-MRI) has shown potential to guide clinical decision making for treatment. However, quantitative MR imaging biomarkers of vascular function have not been widely adopted, partly because their relationship to structural changes in vessels remains unclear. We aimed to elucidate the relationships between vessel function and morphology Untreated preclinical tumors with different levels of vascularization were imaged sequentially using DCE-MRI and CT. Relationships between functional parameters from MR (AUC, , and BAT) and structural parameters from CT (vessel volume, radius, and tortuosity) were assessed using linear models. Tumors treated with anti-VEGFR2 antibody were then imaged to determine whether antiangiogenic therapy altered these relationships. Finally, functional-structural relationships were measured in 10 patients with liver metastases from colorectal cancer. Functional parameters AUC and primarily reflected vessel volume in untreated preclinical tumors. The relationships varied spatially and with tumor vascularity, and were altered by antiangiogenic treatment. In human liver metastases, all three structural parameters were linearly correlated with AUC and For AUC, structural parameters also modified each other's effect. Our findings suggest that MR imaging biomarkers of vascular function are linked to structural changes in tumor vessels and that antiangiogenic therapy can affect this link. Our work also demonstrates the feasibility of three-dimensional functional-structural validation of MR biomarkers to improve their biological interpretation and clinical utility. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171743PMC
October 2018

Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies.

J Pathol 2018 05 25;245(1):19-28. Epub 2018 Mar 25.

Centre for Cancer Research and Cell Biology, Queens's University Belfast, Belfast, UK.

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.
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http://dx.doi.org/10.1002/path.5051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947827PMC
May 2018

Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2-3 randomised trial.

Lancet Gastroenterol Hepatol 2018 03 16;3(3):162-171. Epub 2017 Dec 16.

Cancer Research UK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.

Background: A substantial change in trial methodology for solid tumours has taken place, in response to increased understanding of cancer biology. FOCUS4 is a phase 2-3 trial programme testing targeted agents in patients with advanced colorectal cancer in molecularly stratified cohorts. Here, we aimed to test the hypothesis that combined inhibition of EGFR, HER2, and HER3 signalling with the tyrosine kinase inhibitor AZD8931 will control growth of all wild-type tumours.

Methods: In FOCUS4-D, we included patients from 18 hospitals in the UK with newly diagnosed advanced or metastatic colorectal cancer whose tumour was wild-type for BRAF, PIK3CA, KRAS, and NRAS. After 16 weeks of first-line therapy, patients with stable or responding tumours were randomised to oral AZD8931 (40 mg twice a day) or placebo. Randomisation was done by minimisation with a random element of 20%, minimisation by hospital site, site of primary tumour, WHO performance status, 16-week CT scan result, number of metastatic sites, and first-line chemotherapy regimen. The primary outcome was progression-free-survival. CT scans were assessed by local radiologists according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Preplanned interim analyses were assessed per protocol and were agreed using multiarm multistage (MAMS) trial design methodology triggered by occurrence of progression-free survival events in the placebo group. The final analysis was assessed by intention to treat. This trial is registered at controlled-trials.com, ISRCTN 90061546.

Findings: Between July 7, 2014, and March 7, 2016, 32 patients were randomised to study treatment, 16 to AZD8931 and 16 to placebo. At the first preplanned interim analysis (March, 2016), the independent data monitoring committee (IDMC) recommended closure of FOCUS4-D because of a lack of activity. At the final analysis (Aug 1, 2016), 31 patients had had a progression-free survival event (15 with AZD8931 and 16 with placebo). Median progression-free survival was 3·48 months (95% CI 1·51-5·09) in the placebo group and 2·96 months (1·94-5·62) in the AZD8931 group. No progression-free survival benefit of AZD8931 compared with placebo was noted (hazard ratio [HR] 1·10, 95% CI 0·47-3·57; p=0·95). The most common grade 3 adverse event in the AZD8931 group was skin rash (three [20%] of 15 patients with available data vs none of 16 patients in the placebo group), and in the placebo group it was diarrhoea (one [7%] vs one [6%]). No grade 4 adverse events were recorded and no treatment-related deaths were reported.

Interpretation: The MAMS trial design for FOCUS4 has shown efficiency and effectiveness in trial outcome delivery, informing the decision to proceed or stop clinical evaluation of a targeted treatment within a molecularly defined cohort of patients. The overarching FOCUS4 trial is now aiming to open a replacement arm in the cohort with all wild-type tumours.

Funding: Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme, Cancer Research UK, NIHR Clinical Trials Research Network, Health and Care Research Wales, and AstraZeneca.
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http://dx.doi.org/10.1016/S2468-1253(17)30394-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125825PMC
March 2018

Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci.

Int J Cancer 2018 02 12;142(3):540-546. Epub 2017 Oct 12.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.
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http://dx.doi.org/10.1002/ijc.31076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383773PMC
February 2018

[F]Fluoromisonidazole PET in rectal cancer.

EJNMMI Res 2017 Sep 20;7(1):78. Epub 2017 Sep 20.

CRUK/MRC Oxford Institute of Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ, UK.

Background: There is an increasing interest in developing predictive biomarkers of tissue hypoxia using functional imaging for personalised radiotherapy in patients with rectal cancer that are considered for neoadjuvant chemoradiotherapy (CRT). The study explores [F]fluoromisonidazole ([F]FMISO) positron emission tomography (PET) scans for predicting clinical response in rectal cancer patients receiving neoadjuvant CRT.

Methods: Patients with biopsy-proven rectal adenocarcinoma were imaged at 0-45 min, 2 and 4 h, at baseline and after 8-10 fractions of CRT (week 2). The first 6 patients did not receive an enema (the non-enema group) and the last 4 patients received an enema before PET-CT scan (the enema group). [F]FMISO production failed on 2 occasions. Static PET images at 4 h were analysed using tumour-to-muscle (T:M) SUVmax and tumour-to-blood (T:B) SUVmax. The 0-45 min dynamic PET scans were analysed using Casciari model to report hypoxia and perfusion. Akaike information criteria (AIC) were used to compare data fittings for different pharmacokinetic models. Pathological tumour regression grade was scored using American Joint Committee on Cancer (AJCC) 7.0. Shapiro-Wilk test was used to evaluate the normality of the data.

Results: Five out of eleven (5/11) patients were classed as good responders (AJCC 0/1 or good clinical response) and 6/11 as poor responders (AJCC 2/3 or poor clinical response). The median T:M SUVmax was 2.14 (IQR 0.58) at baseline and 1.30 (IQR 0.19) at week 2, and the corresponding median tumour hypoxia volume was 1.08 (IQR 1.31) cm and 0 (IQR 0.15) cm, respectively. The median T:B SUVmax was 2.46 (IQR 1.50) at baseline and 1.61 (IQR 0.14) at week 2, and the corresponding median tumour hypoxia volume was 5.68 (IQR 5.86) cm and 0.76 (IQR 0.78) cm, respectively. For 0-45 min tumour modelling, the median hypoxia was 0.92 (IQR 0.41) min at baseline and 0.70 (IQR 0.10) min at week 2. The median perfusion was 4.10 (IQR 1.71) ml g min at baseline and 2.48 (IQR 3.62) ml g min at week 2. In 9/11 patients with both PET scans, tumour perfusion decreased in non-responders and increased in responders except in one patient. None of the changes in other PET parameters showed any clear trend with clinical outcome.

Conclusions: This pilot study with small number of datasets revealed significant challenges in delivery and interpretation of [F]FMISO PET scans of rectal cancer. There are two principal problems namely spill-in from non-tumour tracer activity from rectal and bladder contents. Emphasis should be made on reducing spill-in effects from the bladder to improve data quality. This preliminary study has shown fundamental difficulties in the interpretation of [F]FMISO PET scans for rectal cancer, limiting its clinical applicability.
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http://dx.doi.org/10.1186/s13550-017-0324-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607050PMC
September 2017

Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification.

Nat Commun 2017 05 31;8:15657. Epub 2017 May 31.

Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT9 7AE, UK.

Stromal-derived intratumoural heterogeneity (ITH) has been shown to undermine molecular stratification of patients into appropriate prognostic/predictive subgroups. Here, using several clinically relevant colorectal cancer (CRC) gene expression signatures, we assessed the susceptibility of these signatures to the confounding effects of ITH using gene expression microarray data obtained from multiple tumour regions of a cohort of 24 patients, including central tumour, the tumour invasive front and lymph node metastasis. Sample clustering alongside correlative assessment revealed variation in the ability of each signature to cluster samples according to patient-of-origin rather than region-of-origin within the multi-region dataset. Signatures focused on cancer-cell intrinsic gene expression were found to produce more clinically useful, patient-centred classifiers, as exemplified by the CRC intrinsic signature (CRIS), which robustly clustered samples by patient-of-origin rather than region-of-origin. These findings highlight the potential of cancer-cell intrinsic signatures to reliably stratify CRC patients by minimising the confounding effects of stromal-derived ITH.
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http://dx.doi.org/10.1038/ncomms15657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460026PMC
May 2017

Standardising RNA profiling based biomarker application in cancer-The need for robust control of technical variables.

Biochim Biophys Acta Rev Cancer 2017 Aug 23;1868(1):258-272. Epub 2017 May 23.

Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK; Northern Ireland Molecular Pathology Laboratory, Queen's University Belfast, UK. Electronic address:

Histopathology-based staging of colorectal cancer (CRC) has utility in assessing the prognosis of patient subtypes, but as yet cannot accurately predict individual patient's treatment response. Transcriptomics approaches, using array based or next generation sequencing (NGS) platforms, of formalin fixed paraffin embedded tissue can be harnessed to develop multi-gene biomarkers for predicting both prognosis and treatment response, leading to stratification of treatment. While transcriptomics can shape future biomarker development, currently <1% of published biomarkers become clinically validated tests, often due to poor study design or lack of independent validation. In this review of a large number of CRC transcriptional studies, we identify recurrent sources of technical variability that encompass collection, preservation and storage of malignant tissue, nucleic acid extraction, methods to quantitate RNA transcripts and data analysis pipelines. We propose a series of defined steps for removal of these confounding issues, to ultimately aid in the development of more robust clinical biomarkers.
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http://dx.doi.org/10.1016/j.bbcan.2017.05.005DOI Listing
August 2017

The Promise and the Hype of 'Personalised Medicine'.

Authors:
Tim Maughan

New Bioeth 2017 Apr;23(1):13-20

a CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford , Oxford , UK.

Personalised medicine is widely considered as the way of the future for medicine. However, progress in cancer, with a few outstanding exceptions, has fallen below expectations because of the challenges of tumour heterogeneity and clonal evolution. In both benign and malignant disease, diseases caused by single genetic alterations are more amenable to precision medicine approaches. However, most common diseases are caused by a complex interplay of multiple genetic and environmental factors making personalised medicine far more challenging. The current optimism for personalised medicine is distorting clinical consultations, resource allocation and research funding prioritisation. A research active clinician must act both as an agent of change and development, and as a communicator of realism. Thus personalised medicine that includes a sober appreciation of what genomics can achieve, together with continued focus on the individual as a person not just as a genome, will contribute to further improvements in health and healthcare.
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http://dx.doi.org/10.1080/20502877.2017.1314886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448398PMC
April 2017

From Rosalind Franklin to Barack Obama: Data Sharing Challenges and Solutions in Genomics and Personalised Medicine.

New Bioeth 2017 Apr;23(1):64-73

c CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford , Oxford , UK.

The collection, storage and use of genomic and clinical data from patients and healthy individuals is a key component of personalised medicine enterprises such as the Precision Medicine Initiative, the Cancer Moonshot and the 100,000 Genomes Project. In order to maximise the value of this data, it is important to embed a culture within the scientific, medical and patient communities that supports the appropriate sharing of genomic and clinical information. However, this aspiration raises a number of ethical, legal and regulatory challenges that need to be addressed. The Global Alliance for Genomics and Health, a worldwide coalition of researchers, healthcare professionals, patients and industry partners, is developing innovative solutions to support the responsible and effective sharing of genomic and clinical data. This article identifies the challenges that a data sharing culture poses and highlights a series of practical solutions that will benefit patients, researchers and society.
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http://dx.doi.org/10.1080/20502877.2017.1314883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448399PMC
April 2017
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