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1. Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer

Author: Brown, LC, Graham, J, Fisher, D, Adams, R, Seligmann, J, Seymour, M, Kaplan, R, Yates, E, Parmar, M, Richman, SD, Quirke, P, Butler, R, Shiu, K, Middleton, G, Samuel, L, Wilson, RH, Maughan, TS, and On Behalf of the FOCUS4 Trial Investigators
Abstract: Background: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. Methods: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. Results: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014–March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016–July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017–October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. Conclusion: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.
Published: 2022

2. Inhibition of WEE1 Is Effective in TP53- and RAS-Mutant Metastatic Colorectal Cancer: A Randomized Trial (FOCUS4-C) Comparing Adavosertib (AZD1775) With Active Monitoring

Author: Seligmann, JF, Fisher, DJ, Brown, LC, Adams, RA, Graham, J, Quirke, P, Richman, SD, Butler, R, Domingo, E, Blake, A, Yates, E, Braun, M, Collinson, F, Jones, R, Brown, E, de Winton, E, Humphrey, TC, Parmar, M, Kaplan, R, Wilson, RH, Seymour, M, and Maughan, TS
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), biology, Colorectal cancer, business.industry, Kinase, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Active monitoring, Mutant, medicine.disease, law.invention, Wee1, Randomized controlled trial, law, Internal medicine, medicine, biology.protein, business
Abstract: PURPOSEOutcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small-molecule inhibitor of WEE1 kinase. We hypothesized that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitize tumors to WEE1 inhibition.METHODSPatients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomly assigned 2:1 between adavosertib and active monitoring (AM). Adavosertib (250 mg or 300 mg) was taken orally once on days 1-5 and days 8-12 of a 3-week cycle. The primary outcome was progression-free survival (PFS), with a target hazard ratio (HR) of 0.5 and 80% power with a one-sided 0.025 significance level.RESULTSFOCUS4-C was conducted between April 2017 and Mar 2020 during which time 718 patients were registered; 247 (34%) were RAS/TP53-mutant. Sixty-nine patients were randomly assigned from 25 UK hospitals (adavosertib = 44; AM = 25). Adavosertib was associated with a PFS improvement over AM (median 3.61 v 1.87 months; HR = 0.35; 95% CI, 0.18 to 0.68; P = .0022). Overall survival (OS) was not improved with adavosertib versus AM (median 14.0 v 12.8 months; HR = 0.92; 95% CI, 0.44 to 1.94; P = .93). In prespecified subgroup analysis, adavosertib activity was greater in left-sided tumors (HR = 0.24; 95% CI, 0.11 to 0.51), versus right-sided (HR = 1.02; 95% CI, 0.41 to 2.56; interaction P = .043). Adavosertib was well-tolerated; grade 3 toxicities were diarrhea (9%), nausea (5%), and neutropenia (7%).CONCLUSIONIn this phase II randomized trial, adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Further testing is required in this sizable population of unmet need.
Published: 2021

3. Capecitabine Versus Active Monitoring in Stable or Responding Metastatic Colorectal Cancer After 16 Weeks of First-Line Therapy: Results of the Randomized FOCUS4-N Trial

Author: Adams, RA, Fisher, DJ, Graham, J, Seligmann, JF, Seymour, M, Kaplan, R, Yates, E, Parmar, M, Richman, SD, Quirke, P, Butler, R, Brown, E, Collinson, F, Falk, S, Wasan, H, Shiu, K-K, Middleton, G, Samuel, L, Wilson, RH, Brown, LC, Maughan, TS, and on behalf of the FOCUS4 Trial Investigators
Abstract: PURPOSE Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.
Published: 2021

4. In-depth clinical and biological exploration of DNA Damage Immune Response (DDIR) as a biomarker for oxaliplatin use in colorectal cancer

Author: Malla, SB, Fisher, DJ, Domingo, E, Blake, A, Hassanieh, S, Redmond, KL, Richman, SD, Youdell, M, Walker, SM, Logan, GE, Chatzipli, A, Amirkhah, R, Humphries, MP, Craig, SG, McDermott, U, Seymour, M, Morton, D, Quirke, P, West, N, Salto-Tellez, M, Kennedy, R, Johnston, PG, Tomlinson, I, Koelzer, VH, Campo, L, Kaplan, R, Longley, D, Lawler, M, Maughan, TS, Brown, LC, Dunne, PD, and on behalf of the S:CORT consortium.
Subjects: digestive system diseases
Abstract: Purpose: 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.
Published: 2020

5. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial

Author: Maughan, TS, James, RD, Kerr, DJ, Ledermann, JA, Seymour, MT, Topham, C., McArdle, C., Cain, D., and Stephens, RJ
Published: 2003

6. Comparison of survival, palliation, and quality of life with three chemotherapy regimens in metastatic colorectal cancer: a multicentre randomised trial

Author: Maughan, TS, James, RD, Kerr, DJ, Ledermann, JA, McArdle, C., Seymour, MT, Cohen, D., Hopwood, P., Johnston, C., and Stephens, RJ
Published: 2002

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

Author: Tanskanen, T, van den Berg, L, Valimaki, N, Aavikko, M, Ness-Jensen, E, Hveem, K, Wettergren, Y, Lindskog, EB, Tonisson, N, Metspalu, A, Silander, K, Orlando, G, Law, PJ, Tuupanen, S, Gylfe, AE, Hanninen, UA, Cajuso, T, Kondelin, J, Sarin, A-P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, MA, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, FR, Casey, G, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Palin, K, Aaltonen, LA, Tanskanen, T, van den Berg, L, Valimaki, N, Aavikko, M, Ness-Jensen, E, Hveem, K, Wettergren, Y, Lindskog, EB, Tonisson, N, Metspalu, A, Silander, K, Orlando, G, Law, PJ, Tuupanen, S, Gylfe, AE, Hanninen, UA, Cajuso, T, Kondelin, J, Sarin, A-P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, MA, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, FR, Casey, G, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Palin, K, and Aaltonen, LA
Abstract: 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 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; 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.
Published: 2018

8. Combining oncolytic adenovirus with radiation – a paradigm for the future of radiosensitization

Author: O'Cathail, S, Pokrovska, TD, Maughan, TS, Fisher, KD, Seymour, LW, and Hawkins, MA
Abstract: Oncolytic viruses and radiotherapy represent two diverse areas of cancer therapy, utilising quite different treatment modalities and with non-overlapping cytotoxicity profile. It is therefore an intriguing possibiltiy to consider that oncolytic ('cancer-killing') viruses may act as cancer-selective radiosensitisers, enhancing the therapeutic consequences of radiation treatment on tumours whilst exerting minimal effects on normal tissue. There is a solid mechanistic basis for this potential synergy, with many viruses having developed strategies to inhibit cellular DNA repair pathways in order to protect themselves, during genome replication, from unwanted interference by cell processes that are normally triggered by DNA damage. Exploiting these abilities to inhibit cellular DNA repair following damage by therapeutic irradiation may well augment the anticancer potency of the approach. In this review we focus on oncolytic adenovirus, the most widely developed and best understood oncolytic virus, and explore its various mechanisms for modulating cellular DNA repair pathways. The most obvious effects of the various adenovirus serotypes are to interfere with activity of the MRN complex, temporally one of the first sensors of double stranded DNA damage, and inhibition of DNA ligase IV, a central repair enzyme for healing double stranded breaks by non-homologous end-joining (NHEJ). There have been several preclinical and clinical studies of this approach and we assess the current state of progress. In addition, oncolytic viruses provide the option to promote a localised proinflammatory response, both by mediating immunogenic death of cancer cells by oncosis and also by encoding and expressing proinflammatory biologics within the tumour microenvironment. Both of these approaches provide exciting potential to augment the known immunological consequences of radiotherapy, aiming to develop systems capable of creating a systemic anticancer immune response following localised tumour treatment.
Published: 2017

9. Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Author: Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, Houlston, RS, Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, and Houlston, RS
Abstract: While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20-1.79, p = 1.68 × 10-4 ). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92-1.18, p = 0.49), 0.94 (95% CI: 0.84-1.05, p = 0.27), and 0.98 (95% CI: 0.85-1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49-0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.
Published: 2017

10. Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis

Author: May-Wilson, S, Sud, A, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Fisher, D, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, Houlston, RS, May-Wilson, S, Sud, A, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Fisher, D, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG, and Houlston, RS
Abstract: BACKGROUND: While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. METHODS: We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. RESULTS: Risk reduction was observed for oleic and palmitoleic MUFAs (OROA = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10-3; ORPOA = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (ORLA = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10-4; ORAA = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10-4). The SFA stearic acid was associated with increased CRC risk (ORSA = 1.17, 95% CI: 1.01-1.35, P = 0.041). CONCLUSION: Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk.
Published: 2017

11. The clinical impact of expert pathological review on lymphoma management: a regional experience

Author: Lester, JF, Dojcinov, SD, Attanoos, RL, O'Brien, CJ, Maughan, TS, Toy, ET, and Poynton, CH
Abstract: The All Wales Lymphoma Panel (AWLP) was established in January 1998 to provide a central expert pathological review service for district general hospital pathologists. A discordance rate of 20% between the submitted and reviewed diagnosis has previously been identified. It has not been known whether this change in diagnosis affects clinical management. Ninety-nine patients whose diagnosis was changed as a result of central pathological review are presented. Between January 1998 and August 2000, 125 of 745 (17%) specimens submitted for AWLP review had a consequent change in pathological diagnosis. Of these 125 specimens, 99 (79%) complete case notes were recovered. In all 99 cases, a hypothetical management plan was generated using collected data, clinical protocols and the submitted pathological diagnosis. These plans were compared with the actual management patients received based on the reviewed diagnosis proffered by the AWLP. Forty-six of 99 (46%) cases had a change in management as a result of central pathological review. Overall, management was changed in 8% of cases referred for central pathological review. In conclusion, expert central pathological review has a direct effect on patient management.
Published: 2016

12. Chemotherapy for older patients with colorectal cancer Reply

Author: Seymour, MT, Thompson, LC, O'Mahony, S, Brewster, AE, Wasan, HS, Maughan, TS, and Investigators, FA
Published: 2016

13. Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer--a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer

Author: Anderson, H, Hopwood, P, Stephens, RJ, Thatcher, N, Cottier, B, Nicholson, M, Milroy, R, Maughan, TS, Falk, SJ, Bond, MG, Burt, PA, Connolly, CK, McIllmurray, MB, and Carmichael, J
Subjects: urogenital system, viruses, biochemical phenomena, metabolism, and nutrition
Abstract: Three hundred patients with symptomatic, locally advanced or metastatic NSCLC not requiring immediate radiotherapy were enrolled into this randomized multicentre trial comparing gemcitabine + BSC vs BSC alone. Patients allocated gemcitabine received 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, for a maximum of six cycles. The main aim of this trial was to compare patient assessment of a predefined subset of commonly reported symptoms (SS14) from the EORTC QLQ-C30 and LC13 scales. The primary end-points were defined as (1) the percentage change in mean SS14 score between baseline and 2 months and (2) the proportion of patients with a marked (> or = 25%) improvement in SS14 score between baseline and 2 months sustained for > or =4 weeks. The secondary objectives were to compare treatments with respect to overall survival, and multidimensional QL parameters. The treatment groups were balanced with regard to age, gender, Karnofsky performance status (KPS) and disease stage (40% had metastatic disease). The percentage change in mean SS14 score from baseline to 2 months was a 10% decrease (i.e. improvement) for gemcitabine plus BSC and a 1% increase (i.e. deterioration) for BSC alone (P = 0.113, two-sample t-test). A sustained (> or = 4 weeks) improvement (> or =25%) on SS14 was recorded in a significantly higher proportion of gemcitabine + BSC patients (22%) than in BSC alone patients (9%) (P = 0.0014, Pearson's chi-squared test). The QLQ-C30 and L13 subscales showed greater improvement in the gemcitabine plus BSC arm (in 11 domains) than in the BSC arm (one symptom item). There was greater deterioration in the BSC alone arm (six domains/items) than in the gemcitabine + BSC arm (three QL domains). Tumour response occurred in 19% (95% CI 13-27) of gemcitabine patients. There was no difference in overall survival: median 5.7 months (95% CI 4.6-7.6) for gemcitabine + BSC patients and 5.9 months (95% CI 5.0-7.9) (log-rank, P = 0.84) for BSC patients, and 1 -year survival was 25% for gemcitabine + BSC and 22% for BSC. Overall, 74 (49%) gemcitabine + BSC patients and 119 (79%) BSC patients received palliative radiotherapy. The median time to radiotherapy was 29 weeks for gemcitabine + BSC patients and 3.8 weeks for BSC. Patients treated with gemcitabine + BSC reported better QL and reduced disease-related symptoms compared with those receiving BSC alone. These improvements in patient-assessed QL were significant in magnitude and were sustained.
Published: 2016

14. Intermittent versus continuous oxaliplatin-based combination chemotherapy in patients with advanced colorectal cancer: a randomised non-inferiority trial (MRC COIN)

Author: Adams, R, Wilson, R, Seymour, MT, Meade, AM, Madi, A, Cassidy, J, Fisher, D, Kenny, S, Kaplan, R, and Maughan, TS
Published: 2016

15. Intravenous glutamine dipeptide is able to restore plasma glutamine levels and protect against liver injury during high dose chemotherapy

Author: Povnton, CH, Maughan, TS, Goringe, AP, Brown, SA, Jebb, S, and Elia, M
Published: 2016

16. Glycyl-glutamine supplementation and high dose therapy

Author: Maughan, TS, Poynton, CH, Hanson, J, Shelley, M, Jebb, S, and Eiya, M
Published: 2016

17. A pilot study of the use of Oxaliplatin in metastatic colorectal cancer at Velindre

Author: Mitra, SS, Brewster, AE, Crosby, T, and Maughan, TS
Published: 2016

18. Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease

Author: Orlando, G, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, S, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Aaltonen, LA, Houlston, RS, Orlando, G, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Tenesa, A, Farrington, S, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Aaltonen, LA, and Houlston, RS
Abstract: To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.
Published: 2016

19. Mendelian randomisation analysis strongly implicates adiposity with risk of developing colorectal cancer

Author: Jarvis, D, Mitchell, JS, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Aaltonen, LA, Cheadle, JP, Dunlop, MG, Tomlinson, IP, Houlston, RS, Jarvis, D, Mitchell, JS, Law, PJ, Palin, K, Tuupanen, S, Gylfe, A, Hanninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Kaprio, J, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Ripatti, S, Palotie, A, Jarvinen, H, Renkonen-Sinisalo, L, Lepisto, A, Bohm, J, Mecklin, J-P, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Taipale, J, Aaltonen, LA, Cheadle, JP, Dunlop, MG, Tomlinson, IP, and Houlston, RS
Abstract: BACKGROUND: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. METHODS: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. RESULTS: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02-1.49, P=0.033), 1.59 (95% CI: 1.08-2.34, P=0.019) and 1.07 (95% CI: 1.03-1.13, P=0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89-1.67, P=0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10-1.44, P=7.7 × 10(-4)) and 1.40 (95% CI: 1.14-1.72, P=1.2 × 10(-3)), respectively. CONCLUSIONS: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.
Published: 2016

20. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer

Author: Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchannan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, Houlston, RS, Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchannan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, and Houlston, RS
Abstract: Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
Published: 2015

21. A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer (vol 5, 10442, 2015)

Author: Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, Houlston, RS, Al-Tassan, NA, Whiffin, N, Hosking, FJ, Palles, C, Farrington, SM, Dobbins, SE, Harris, R, Gorman, M, Tenesa, A, Meyer, BF, Wakil, SM, Kinnersley, B, Campbell, H, Martin, L, Smith, CG, Idziaszczyk, S, Barclay, E, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Dunlop, MG, Tomlinson, IP, Cheadle, JP, and Houlston, RS
Published: 2015

22. Oxaliplatin/capecitabine vs oxaliplatin/infusional 5-FU in advanced colorectal cancer: the MRC COIN trial

Author: Madi, A, Fisher, D, Wilson, RH, Adams, RA, Meade, AM, Kenny, SL, Nichols, LL, Seymour, MT, Wasan, H, Kaplan, R, Maughan, TS, and COIN trial research group
Subjects: neoplasms, digestive system diseases
Abstract: BACKGROUND: COIN compared first-line continuous chemotherapy with the same chemotherapy given intermittently or with cetuximab in advanced colorectal cancer (aCRC). METHODS: Choice between oxaliplatin/capecitabine (OxCap) and oxaliplatin/leucovorin (LV)/infusional 5-FU (OxFU) was by physician and patient choice and switching regimen was allowed. We compared OxCap with OxFU and OxCap+cetuximab with OxFU+cetuximab retrospectively in patients and examined efficacy, toxicity profiles and the effect of mild renal impairment. RESULTS: In total, 64% of 2397 patients received OxCap(± cetuximab). Overall survival, progression free survival and overall response rate were similar between OxCap and OxFU but rate of radical surgeries was higher for OxFU. Progression free survival was longer for OxFU+cetuximab compared with OxCap+cetuximab but other efficacy measures were similar. Oxaliplatin/LV/infusional 5-FU (± cetuximab) was associated with more mucositis and infection whereas OxCap(± cetuximab) caused more gastrointestinal toxicities and palmar-plantar erythema. In total, 118 patients switched regimen, mainly due to toxicity; only 16% came off their second regimen due to intolerance. Patients with creatinine clearance (CrCl) 50-80 ml min(-1) on OxCap(± cetuximab) or OxFU+cetuximab had more dose modifications than those with better renal function. CONCLUSIONS: Overall, OxFU and OxCap are equally effective in treating aCRC. However, the toxicity profiles differ and switching from one regimen to the other for poor tolerance is a reasonable option. Patients with CrCl 50-80 ml min(-1) on both regimens require close toxicity monitoring.
Published: 2012

23. A feasibility study testing four hypotheses with phase II outcomes in advanced colorectal cancer (MRC FOCUS3): a model for randomised controlled trials in the era of personalised medicine?

Author: Maughan, TS, Meade, AM, Adams, RA, Richman, SD, Butler, R, Fisher, D, Wilson, RH, Jasani, B, Taylor, GR, Williams, GT, Sampson, JR, Seymour, MT, Nichols, LL, Kenny, SL, Nelson, A, Sampson, CM, Hodgkinson, E, Bridgewater, JA, Furniss, DL, Roy, R, Pope, MJ, Pope, JK, Parmar, M, Quirke, P, Kaplan, R, Maughan, TS, Meade, AM, Adams, RA, Richman, SD, Butler, R, Fisher, D, Wilson, RH, Jasani, B, Taylor, GR, Williams, GT, Sampson, JR, Seymour, MT, Nichols, LL, Kenny, SL, Nelson, A, Sampson, CM, Hodgkinson, E, Bridgewater, JA, Furniss, DL, Roy, R, Pope, MJ, Pope, JK, Parmar, M, Quirke, P, and Kaplan, R
Abstract: BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.
Published: 2014

24. The Assisted Dying for the Terminally Ill Bill 2004

Author: Kenwright, Simon, primary, Maughan, TS, additional, and Lewis, Myles, additional
Published: 2005
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25. Epirubicin, cisplatin and continuous infusion 5-fluorouracil (ECF) as neoadjuvant chemotherapy in gastro-oesophageal cancer

Author: Melcher, AA, primary, Mort, D, additional, and Maughan, TS, additional
Published: 1996
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26. High-dose folinic acid and 5-fluorouracil bolus and continuous infusion in advanced colorectal cancer: poor response rate in unselected patients

Author: Hanna, CL, primary, McKinna, FE, additional, Williams, LB, additional, Morrey, D, additional, Adams, M, additional, Mason, MD, additional, and Maughan, TS, additional
Published: 1995
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27. 5-fluorouracil and folinic acid-induced mucositis: no effect of oral glutamine supplementation

Author: Jebb, SA, primary, Osborne, RJ, additional, Maughan, TS, additional, Mohideen, N, additional, Mack, P, additional, Mort, D, additional, Shelley, MD, additional, and Elia, M, additional
Published: 1994
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28. Combined Radiotherapy and Chemotherapy in Clinical Oncology

Author: Maughan, TS, primary
Published: 1993
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29. Tumour concentrations of flavone acetic acid (FAA) in human melanoma: comparison with mouse data

Author: Maughan, TS, primary, Ward, R, additional, Dennis, I, additional, Honess, DJ, additional, Workman, P, additional, and Bleehen, NM, additional
Published: 1992
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30. Irinotecan/fluorouracil combination in first-line therapy of older and younger patients with metastatic colorectal cancer: combined analysis of 2,691 patients in randomized controlled trials.

Author: Folprecht G, Seymour MT, Saltz L, Douillard JY, Hecker H, Stephens RJ, Maughan TS, Van Cutsem E, Rougier P, Mitry E, Schubert U, Köhne CH, Folprecht, Gunnar, Seymour, Matthew T, Saltz, Leonard, Douillard, Jean-Yves, Hecker, Hartmut, Stephens, Richard J, Maughan, Timothy S, and Van Cutsem, Eric
Published: 2008
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31. Bone marrow scintigraphy in small cell carcinoma of the lung

Author: D. J. Li, Maughan Ts, Miles Ka, and Wraight Ep
Subjects: Adult, Male, medicine.medical_specialty, Pathology, Lung Neoplasms, Biopsy, medicine.medical_treatment, Scintigraphy, Sensitivity and Specificity, Small-cell carcinoma, Metastasis, Bone Marrow, medicine, Humans, Radiology, Nuclear Medicine and imaging, Anaplastic carcinoma, Carcinoma, Small Cell, Radionuclide Imaging, Technetium Tc 99m Aggregated Albumin, Aged, Chemotherapy, medicine.diagnostic_test, business.industry, General Medicine, Middle Aged, medicine.disease, medicine.anatomical_structure, Bone scintigraphy, Female, Bone marrow, Radiology, business
Abstract: A comparative study of bone marrow scintigraphy using 99Tcm-nanocolloid, conventional bone scintigraphy and bone marrow biopsy were performed in 35 patients with histologically proven small cell carcinoma of the lung to determine whether bone marrow scintigraphy has a role in the early detection of bone marrow metastases. The sensitivity, specificity and accuracy for detection of metastases were 100, 92 and 94%, respectively, in bone marrow scintigraphy, 91, 88 and 89%, respectively, in bone scintigraphy, and 50, 100 and 86%, respectively in bone marrow biopsy. This study confirmed that bone marrow scintigraphy is a useful technique for the detection of early metastases. Bone marrow scintigraphy is also suggested as the first choice examination in clinical practice for diagnosis of metastases in small cell carcinoma of the lung.
Published: 1994

32. CA125 in ovarian tumour tissue at second laparotomy

Author: Maughan, TS, primary, Fish, RG, additional, Shelley, MD, additional, Jasani, B, additional, Williams, GT, additional, and Adams, M, additional
Published: 1989
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33. Ethics of PCT decision making on funding cancer treatments.

Author: Maughan TS and Rule J
Published: 2008
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34. FRAGMATIC: a randomised phase III clinical trial investigating the effect of fragmin added to standard therapy in patients with lung cancer.

Author: Griffiths GO, Burns S, Noble SI, Macbeth FR, Cohen D, Maughan TS, Griffiths, Gareth O, Burns, Sarah, Noble, Simon I, Macbeth, Fergus R, Cohen, David, and Maughan, Timothy S
Abstract: Background: Venous thromboembolism (VTE) occurs when blood clots in the leg, pelvic or other deep vein (deep vein thrombosis) with or without transport of the thrombus into the pulmonary arterial circulation (pulmonary embolus). VTE is common in patients with cancer and is increased by surgery, chemotherapy, radiotherapy and disease progression. Low molecular weight heparin (LMWH) is routinely used to treat VTE and some evidence suggests that LMWH may also have an anticancer effect, by reduction in the incidence of metastases. The FRAGMATIC trial will assess the effect of adding dalteparin (FRAGMIN), a type of LMWH, to standard treatment for patients with lung cancer.Methods/design: The study design is a randomised multicentre phase III trial comparing standard treatment and standard treatment plus daily LMWH for 24 weeks in patients with lung cancer. Patients eligible for this study must have histopathological or cytological diagnosis of primary bronchial carcinoma (small cell or non-small cell) within 6 weeks of randomisation, be 18 or older, and must be willing and able to self-administer 5000 IU dalteparin by daily subcutaneous injection or have it administered to themselves or by a carer for 24 weeks. A total of 2200 patients will be recruited from all over the UK over a 3 year period and followed up for a minimum of 1 year after randomisation. Patients will be randomised to one of the two treatment groups in a 1:1 ratio, standard treatment or standard treatment plus dalteparin. The primary outcome measure of the trial is overall survival. The secondary outcome measures include venous thrombotic event (VTE) free survival, serious adverse events (SAEs), metastasis-free survival, toxicity, quality of life (QoL), levels of breathlessness, anxiety and depression, cost effectiveness and cost utility.Trial Registration: Current Controlled Trials ISRCTN80812769. [ABSTRACT FROM AUTHOR]
Published: 2009
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35. Attitudes of the general public and professional health care staff in Wales towards cancer treatment: the influence of age, quality of life, survival and side effects.

Author: Brewster AE, Morrison V, Branston L, Hackett P, White-Gwenin C, Price P, Robbe IJ, O'Mahony S, and Maughan TS
Published: 2006

36. Standard or high dose chemoradiotherapy, with or without the protease inhibitor nelfinavir, in patients with locally advanced pancreatic cancer: The phase 1/randomised phase 2 SCALOP-2 trial.

Author: Mukherjee S, Qi C, Shaw R, Jones CM, Bridgewater JA, Radhakrishna G, Patel N, Holmes J, Virdee PS, Tranter B, Parsons P, Falk S, Wasan HS, Ajithkumar TV, Holyoake D, Roy R, Scott-Brown M, Hurt CN, O'Neill E, Sebag-Montefiore D, Maughan TS, Hawkins MA, and Corrie P
Subjects: Humans, Male, Female, Middle Aged, Aged, Adult, Paclitaxel administration & dosage, Paclitaxel adverse effects, Maximum Tolerated Dose, Deoxycytidine analogs & derivatives, Deoxycytidine administration & dosage, Deoxycytidine adverse effects, Deoxycytidine therapeutic use, Gemcitabine, Aged, 80 and over, Quality of Life, Albumins administration & dosage, Albumins therapeutic use, Albumins adverse effects, Progression-Free Survival, Protease Inhibitors adverse effects, Protease Inhibitors therapeutic use, Protease Inhibitors administration & dosage, Nelfinavir therapeutic use, Nelfinavir administration & dosage, Nelfinavir adverse effects, Pancreatic Neoplasms therapy, Pancreatic Neoplasms pathology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms mortality, Chemoradiotherapy adverse effects, Chemoradiotherapy methods, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects
Abstract: Background: The multi-centre two-stage SCALOP-2 trial (ISRCTN50083238) assessed whether dose escalation of consolidative chemoradiotherapy (CRT) or concurrent sensitization using the protease inhibitor nelfinavir improve outcomes in locally advanced pancreatic cancer (LAPC) following four cycles of gemcitabine/nab-paclitaxel., Methods: In stage 1, the maximum tolerated dose (MTD) of nelfinavir concurrent with standard-dose CRT (50.4 Gy in 28 fractions) was identified from a cohort of 27 patients. In stage 2, 159 patients were enrolled in an open-label randomized controlled comparison of standard versus high dose (60 Gy in 30 fractions) CRT, with or without nelfinavir at MTD. Primary outcomes following dose escalation and nelfinavir use were respectively overall survival (OS) and progression free survival (PFS). Secondary endpoints included health-related quality of life (HRQoL)., Results: High dose CRT did not improve OS (16.9 (60 % confidence interval, CI 16.2-17.7) vs. 15.6 (60 %CI 14.3-18.2) months; adjusted hazard ratio, HR 1.13 (60 %CI 0.91-1.40; p = 0.68)). Similarly, median PFS was not improved by nelfinavir (10.0 (60 %CI 9.9-10.2) vs. 11.1 (60 %CI 10.3-12.8) months; adjusted HR 1.71 (60 %CI 1.38-2.12; p = 0.98)). Local progression at 12 months was numerically lower with high-dose CRT than with standard dose CRT (n = 11/46 (23.9 %) vs. n = 15/45 (33.3 %)). Neither nelfinavir nor radiotherapy dose escalation impacted on treatment compliance or grade 3/4 adverse event rate. There were no sustained differences in HRQoL scores between treatment groups over 28 weeks post-treatment., Conclusions: Dose-escalated CRT may improve local tumour control and is well tolerated when used as consolidative treatment in LAPC but does not impact OS. Nelfinavir use does not improve PFS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2024
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37. Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis.

Author: Cohen R, Raeisi M, Chibaudel B, Shi Q, Yoshino T, Zalcberg JR, Adams R, Cremolini C, Van Cutsem E, Heinemann V, Tabernero J, Punt CJA, Arnold D, Hurwitz HI, Douillard JY, Venook AP, Saltz LB, Maughan TS, Kabbinavar F, Bokemeyer C, Grothey A, Mayer RJ, Kaplan R, Tebbutt NC, Randolph Hecht J, Giantonio BJ, Díaz-Rubio E, Sobrero AF, Peeters M, Koopman M, Goldberg RM, Andre T, and de Gramont A
Subjects: Humans, Male, Female, Middle Aged, Prognosis, Aged, Progression-Free Survival, Pyridines therapeutic use, Adult, Trifluridine therapeutic use, Phenylurea Compounds therapeutic use, Thymine therapeutic use, Drug Combinations, Pyrrolidines, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Colorectal Neoplasms mortality, Liver Neoplasms secondary, Liver Neoplasms drug therapy, Liver Neoplasms mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use
Abstract: Background: The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment., Methods: A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR)., Results: Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L., Conclusion: LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC., Competing Interests: Declaration of Competing Interest Benoist Chibaudel reports consulting and advisory role from Amgen, Bayer, Beigine, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Revolution Medicines, Roche, SeqOne, Sanofi, Servier, Takeda. Josep Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc and Tolremo Therapeutics. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). Qian Shi reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Kronos Bio, and Mirati Therapeutics Inc; Honorarium/speaker role from Chugai Pharmaceutical Co., Ltd (to myself), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution). Thierry Andre reports attending advisory board meetings and receiving consulting fees from Abbvie, Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Seagen, Servier, Takeda and Transgène and honoraria from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Merck Serono, Pierre Fabre, Roche, Sanofi, Seagen and Servier; and support for meetings from Merck & Co. Inc. and Servier. John Zalcberg reports leadership from ICON Group, Lipotek, PRAXIS; Stock from Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, Teladoc; Honoraria from Gilead Sciences, MSD Oncology, Viatris; Consulting & Advisory Role from Merck Sharp & Dohme, Specialized Therapeutics, CEND, Deciphera, REVOLUTION MEDICINE, FivePHusion, Genorbio, 1Global, Novatech, Alloplex Biotherapeutics Inc, Oncology Republic; Research Funding from BMS, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology, Servier; Travel from MSD Oncology, ICON Group, PRAXIS.Eric Van Cutsem repors participation to advisory boards for Abbvie, ALX, Amgen, Array, Astellas, Astrazeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier paid to his institution. Takayuki Yoshino reports honoraria from Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., MSD K.K.; consulting fee from Sumitomo Corp.; research grant from Amgen K.K., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd, FALCO biosystems Ltd., Genomedia Inc., MEDICAL & BIOLOGICAL LABORATORIES CO., LTD., Merus N.V., Molecular Health GmbH, MSD K.K., Nippon Boehringer Ingelheim Co ., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc.,Roche Diagnostics K.K., Sanofi K.K., Sysmex Corp., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. Richard Adams reports receiving consulting fees from Takeda, Bayer, GSK; honoraria from Amgen, Bayer, Seagen; Support for attending meetings and/or travel from Servier, Takeda; Participation on Advisory Board from Takeda, Seagen. Carsten Bokemeyer repors receiving consulting fees as advisory boards from Astra Zeneca, Bayer Healthcare, BioNTech, Heaxal, Lindis Biotech, and Sanofi Aventis; as Invited Speaker from AOK Germany, med update, and Roche Pharma; reports honoraria from DGHO, Hamburg Cancer Society, National Network of German Cancer Centers (DKH), Northern German Society of Internal Medicine, DGHO, German Cancer Society. Cornelis J. A. Punt repors receiving consulting fees as advisory boards from Nordic Pharma. Richard M Goldberg receiving consulting fees as advisory boards from Fight for Colorectal Cancer, US NCI. Volker Heinemann repors receiving consulting fees from Merck, Amgen, Roche, AstraZeneca, Celgene, Servier, Novartis, Pierre-Fabre, Halozyme, MSD, BMS, GSK, Janssen, Terumo, Sirtex, Oncosil, Nordic, Boehringer-Ingelheim; honoraria from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Boehringer-Ingelheim, Celgene, Sirtex, Seagen, GSK; support for attending from Merck, Amgen, MSD, Nordic, AstraZeneca, Servier: reports stock from BionTech. Chiara Cremolini repors receiving consulting fees from Nordic Pharma, Merck, Pierre Fabre, Servier, Takeda; reports honoraria from Takeda, MSD, Amgen, Merck, Pierre Fabre, Servier, Bayer; participation to advisory board from Mirat. Miriam Koopman repors receiving consulting fees from Bayer, Bristol Myers Squibb, Merck, Personal Genome Diagnostics (PGDx), Pierre Fabre, Roche, Sirtex, Servier and PI participation from the international cohort study PROMETCO with Servier as sponsor; participation to advisory board from Eisai, Nordic Farma, Merck-Serono, Pierre Fabre, Servier; as leadership or fiduciary role in Chair ESMO RWDD working group, co-chair DCCG, PI PLCRC (national observational cohort study), involved in several clinical trials as PI or co-investigator in CRC. Alan Venook repors receiving consulting fees from Amgen, Genentech/Roche, Deciphera; participation on Advisory Board in Amgen, Agenus. Timothy Maughan repors receiving consulting fees from Merck KGAa, Cancer Research UK, Astrazeneca, Ground Truth Laboratories, Perspectum, Nordin Pharma; participation on Advisory Board and leadership in Cancer Research UK, National Cancer Research Institute-University of Liverpool. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2024
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38. Identification and validation of a machine learning model of complete response to radiation in rectal cancer reveals immune infiltrate and TGFβ as key predictors.

Author: Domingo E, Rathee S, Blake A, Samuel L, Murray G, Sebag-Montefiore D, Gollins S, West N, Begum R, Richman S, Quirke P, Redmond K, Chatzipli A, Barberis A, Hassanieh S, Mahmood U, Youdell M, McDermott U, Koelzer V, Leedham S, Tomlinson I, Dunne P, Buffa FM, and Maughan TS
Subjects: Adult, Aged, Female, Humans, Male, Middle Aged, Biomarkers, Tumor genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Prognosis, Transcriptome, Treatment Outcome, Machine Learning, Rectal Neoplasms genetics, Rectal Neoplasms radiotherapy, Rectal Neoplasms pathology, Rectal Neoplasms therapy, Rectal Neoplasms metabolism, Rectal Neoplasms immunology, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta genetics
Abstract: Background: It is uncertain which biological features underpin the response of rectal cancer (RC) to radiotherapy. No biomarker is currently in clinical use to select patients for treatment modifications., Methods: We identified two cohorts of patients (total N = 249) with RC treated with neoadjuvant radiotherapy (45Gy/25) plus fluoropyrimidine. This discovery set included 57 cases with pathological complete response (pCR) to chemoradiotherapy (23%). Pre-treatment cancer biopsies were assessed using transcriptome-wide mRNA expression and targeted DNA sequencing for copy number and driver mutations. Biological candidate and machine learning (ML) approaches were used to identify predictors of pCR to radiotherapy independent of tumour stage. Findings were assessed in 107 cases from an independent validation set (GSE87211)., Findings: Three gene expression sets showed significant independent associations with pCR: Fibroblast-TGFβ Response Signature (F-TBRS) with radioresistance; and cytotoxic lymphocyte (CL) expression signature and consensus molecular subtype CMS1 with radiosensitivity. These associations were replicated in the validation cohort. In parallel, a gradient boosting machine model comprising the expression of 33 genes generated in the discovery cohort showed high performance in GSE87211 with 90% sensitivity, 86% specificity. Biological and ML signatures indicated similar mechanisms underlying radiation response, and showed better AUC and p-values than published transcriptomic signatures of radiation response in RC., Interpretation: RCs responding completely to chemoradiotherapy (CRT) have biological characteristics of immune response and absence of immune inhibitory TGFβ signalling. These tumours may be identified with a potential biomarker based on a 33 gene expression signature. This could help select patients likely to respond to treatment with a primary radiotherapy approach as for anal cancer. Conversely, those with predicted radioresistance may be candidates for clinical trials evaluating addition of immune-oncology agents and stromal TGFβ signalling inhibition., Funding: The Stratification in Colorectal Cancer Consortium (S:CORT) was funded by the Medical Research Council and Cancer Research UK (MR/M016587/1)., Competing Interests: Declaration of interests TSM is now employed by the University of Liverpool and acknowledges consultancy payments from Astrazeneca, Ground Truth Laboratories and Nordic Pharma. V.H.K. has served as an invited speaker on behalf of Indica Labs. U.M is now employed by and holds stocks in Astrazeneca. Other authors declare no conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2024
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39. Stratification to Neoadjuvant Radiotherapy in Rectal Cancer by Regimen and Transcriptional Signatures.

Author: Mahmood U, Blake A, Rathee S, Samuel L, Murray G, Sebag-Montefiore D, Gollins S, West NP, Begum R, Bach SP, Richman SD, Quirke P, Redmond KL, Salto-Tellez M, Koelzer VH, Leedham SJ, Tomlinson I, Dunne PD, Buffa FM, Maughan TS, and Domingo E
Subjects: Humans, Male, Female, Middle Aged, Aged, Capecitabine therapeutic use, Capecitabine administration & dosage, Fluorouracil therapeutic use, Fluorouracil administration & dosage, Fluorouracil pharmacology, Gene Expression Profiling, Oxaliplatin therapeutic use, Oxaliplatin administration & dosage, Oxaliplatin pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Gene Expression Regulation, Neoplastic drug effects, Rectal Neoplasms pathology, Rectal Neoplasms genetics, Rectal Neoplasms therapy, Rectal Neoplasms radiotherapy, Rectal Neoplasms mortality, Neoadjuvant Therapy, Transcriptome
Abstract: Response to neoadjuvant radiotherapy (RT) in rectal cancer has been associated with immune and stromal features that are captured by transcriptional signatures. However, how such associations perform across different chemoradiotherapy regimens and within individual consensus molecular subtypes (CMS) and how they affect survival remain unclear. In this study, gene expression and clinical data of pretreatment biopsies from nine cohorts of primary rectal tumors were combined (N = 826). Exploratory analyses were done with transcriptomic signatures for the endpoint of pathologic complete response (pCR), considering treatment regimen or CMS subtype. Relevant findings were tested for overall survival and recurrence-free survival. Immune and stromal signatures were strongly associated with pCR and lack of pCR, respectively, in RT and capecitabine (Cap)/5-fluorouracil (5FU)-treated patients (N = 387), in which the radiosensitivity signature (RSS) showed the strongest association. Upon addition of oxaliplatin (Ox; N = 123), stromal signatures switched direction and showed higher chances to achieve pCR than without Ox (p for interaction 0.02). Among Cap/5FU patients, most signatures performed similarly across CMS subtypes, except cytotoxic lymphocytes that were associated with pCR in CMS1 and CMS4 cases compared with other CMS subtypes (p for interaction 0.04). The only variables associated with survival were pCR and RSS. Although the frequency of pCR across different chemoradiation regimens is relatively similar, our data suggest that response rates may differ depending on the biological landscape of rectal cancer. Response to neoadjuvant RT in stroma-rich tumors may potentially be improved by the addition of Ox. RSS in preoperative biopsies provides predictive information for response specifically to neoadjuvant RT with 5FU., Significance: Rectal cancers with stromal features may respond better to RT and 5FU/Cap with the addition of Ox. Within patients not treated with Ox, high levels of cytotoxic lymphocytes associate with response only in immune and stromal tumors. Our analyses provide biological insights about the outcome by different radiotherapy regimens in rectal cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)
Published: 2024
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40. Author Correction: Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Author: Malla SB, Byrne RM, Lafarge MW, Corry SM, Fisher NC, Tsantoulis PK, Mills ML, Ridgway RA, Lannagan TRM, Najumudeen AK, Gilroy KL, Amirkhah R, Maguire SL, Mulholland EJ, Belnoue-Davis HL, Grassi E, Viviani M, Rogan E, Redmond KL, Sakhnevych S, McCooey AJ, Bull C, Hoey E, Sinevici N, Hall H, Ahmaderaghi B, Domingo E, Blake A, Richman SD, Isella C, Miller C, Bertotti A, Trusolino L, Loughrey MB, Kerr EM, Tejpar S, Maughan TS, Lawler M, Campbell AD, Leedham SJ, Koelzer VH, Sansom OJ, and Dunne PD
Published: 2024
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41. New role of fat-free mass in cancer risk linked with genetic predisposition.

Author: Harris BHL, Di Giovannantonio M, Zhang P, Harris DA, Lord SR, Allen NE, Maughan TS, Bryant RJ, Harris AL, Bond GL, and Buffa FM
Subjects: Male, Humans, Body Mass Index, Genetic Predisposition to Disease, Electric Impedance, Body Composition genetics, Neoplasms etiology, Neoplasms genetics
Abstract: Cancer risk is associated with the widely debated measure body mass index (BMI). Fat mass and fat-free mass measurements from bioelectrical impedance may further clarify this association. The UK Biobank is a rare resource in which bioelectrical impedance and BMI data was collected on ~ 500,000 individuals. Using this dataset, a comprehensive analysis using regression, principal component and genome-wide genetic association, provided multiple levels of evidence that increasing whole body fat (WBFM) and fat-free mass (WBFFM) are both associated with increased post-menopausal breast cancer risk, and colorectal cancer risk in men. WBFM was inversely associated with prostate cancer. We also identified rs615029[T] and rs1485995[G] as associated in independent analyses with both PMBC (p = 1.56E-17 and 1.78E-11) and WBFFM (p = 2.88E-08 and 8.24E-12), highlighting splice variants of the intriguing long non-coding RNA CUPID1 (LINC01488) as a potential link between PMBC risk and fat-free mass., (© 2024. The Author(s).)
Published: 2024
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42. Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Author: Malla SB, Byrne RM, Lafarge MW, Corry SM, Fisher NC, Tsantoulis PK, Mills ML, Ridgway RA, Lannagan TRM, Najumudeen AK, Gilroy KL, Amirkhah R, Maguire SL, Mulholland EJ, Belnoue-Davis HL, Grassi E, Viviani M, Rogan E, Redmond KL, Sakhnevych S, McCooey AJ, Bull C, Hoey E, Sinevici N, Hall H, Ahmaderaghi B, Domingo E, Blake A, Richman SD, Isella C, Miller C, Bertotti A, Trusolino L, Loughrey MB, Kerr EM, Tejpar S, Maughan TS, Lawler M, Campbell AD, Leedham SJ, Koelzer VH, Sansom OJ, and Dunne PD
Subjects: Humans, Prognosis, Cell Differentiation genetics, Phenotype, Biomarkers, Tumor genetics, Gene Expression Profiling, Colorectal Neoplasms pathology
Abstract: Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5 + stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1 + stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers., (© 2024. The Author(s).)
Published: 2024
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43. Integrated Clinical-Molecular Classification of Colorectal Liver Metastases: A Biomarker Analysis of the Phase 3 New EPOC Randomized Clinical Trial.

Author: Katipally RR, Martinez CA, Pugh SA, Bridgewater JA, Primrose JN, Domingo E, Maughan TS, Talamonti MS, Posner MC, Weichselbaum RR, and Pitroda SP
Subjects: Humans, Male, Middle Aged, Female, Retrospective Studies, Oxaliplatin, Fluorouracil, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Colorectal Neoplasms pathology, Liver Neoplasms drug therapy, Liver Neoplasms genetics, Liver Neoplasms secondary, MicroRNAs genetics, MicroRNAs therapeutic use
Abstract: Importance: Personalized treatment approaches for patients with oligometastatic colorectal liver metastases are critically needed. We previously defined 3 biologically distinct molecular subtypes of colorectal liver metastases: (1) canonical, (2) immune, and (3) stromal., Objective: To independently validate these molecular subtypes in the phase 3 New EPOC randomized clinical trial., Design, Setting, and Participants: This retrospective secondary analysis of the phase 3 New EPOC randomized clinical trial included a bi-institutional discovery cohort and multi-institutional validation cohort. The discovery cohort comprised patients who underwent hepatic resection for limited colorectal liver metastases (98% received perioperative chemotherapy) from May 31, 1994, to August 14, 2012. The validation cohort comprised patients who underwent hepatic resection for liver metastases with perioperative chemotherapy (fluorouracil, oxaliplatin, and irinotecan based) with or without cetuximab from February 26, 2007, to November 1, 2012. Data were analyzed from January 18 to December 10, 2021., Interventions: Resected metastases underwent RNA sequencing and microRNA (miRNA) profiling in the discovery cohort and messenger RNA and miRNA profiling with microarray in the validation cohort., Main Outcomes and Measures: A 31-feature (24 messenger RNAs and 7 miRNAs) neural network classifier was trained to predict molecular subtypes in the discovery cohort and applied to the validation cohort. Integrated clinical-molecular risk groups were designated based on molecular subtypes and the clinical risk score. The unique biological phenotype of each molecular subtype was validated using gene set enrichment analyses and immune deconvolution. The primary clinical end points were progression-free survival (PFS) and overall survival (OS)., Results: A total of 240 patients were included (mean [range] age, 63.0 [56.3-68.0] years; 151 [63%] male), with 93 in the discovery cohort and 147 in the validation cohort. In the validation cohort, 73 (50%), 28 (19%), and 46 (31%) patients were classified as having canonical, immune, and stromal metastases, respectively. The biological phenotype of each subtype was concordant with the discovery cohort. The immune subtype (best prognosis) demonstrated 5-year PFS of 43% (95% CI, 25%-60%; hazard ratio [HR], 0.37; 95% CI, 0.20-0.68) and OS of 63% (95% CI, 40%-79%; HR, 0.38; 95% CI, 0.17-0.86), which was statistically significantly higher than the canonical subtype (worst prognosis) at 14% (95% CI, 7%-23%) and 43% (95% CI, 32%-55%), respectively. Adding molecular subtypes to the clinical risk score improved prediction (the Gönen and Heller K for discrimination) from 0.55 (95% CI, 0.49-0.61) to 0.62 (95% CI, 0.57-0.67) for PFS and 0.59 (95% CI, 0.52-0.66) to 0.63 (95% CI, 0.56-0.70) for OS. The low-risk integrated group demonstrated 5-year PFS of 44% (95% CI, 20%-66%; HR, 0.38; 95% CI, 0.19-0.76) and OS of 78% (95% CI, 44%-93%; HR, 0.26; 95% CI, 0.08-0.84), superior to the high-risk group at 16% (95% CI, 10%-24%) and 43% (95% CI, 32%-52%), respectively., Conclusions and Relevance: In this prognostic study, biologically derived colorectal liver metastasis molecular subtypes and integrated clinical-molecular risk groups were highly prognostic. This novel molecular classification warrants further study as a possible predictive biomarker for personalized systemic treatment for colorectal liver metastases., Trial Registration: isrctn.org Identifier: ISRCTN22944367.
Published: 2023
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44. FOCUS4 biomarker laboratories: from the benefits to the practical and logistical issues faced during 6 years of centralised testing.

Author: Richman SD, Hemmings G, Roberts H, Gallop N, Dodds R, Wilkinson L, Davis J, White R, Yates E, Jasani B, Brown L, Maughan TS, Butler R, Quirke P, and Adams R
Subjects: Humans, Laboratories, State Medicine, Proto-Oncogene Proteins B-raf genetics, Mutation, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Colorectal Neoplasms diagnosis, Colorectal Neoplasms genetics, Colorectal Neoplasms drug therapy
Abstract: Aims: FOCUS4 was a phase II/III umbrella trial, recruiting patients with advanced or metastatic colorectal cancer, between 2014 and 2020. Molecular profiling of patients' formalin-fixed, paraffin-embedded tumour blocks was undertaken at two centralised biomarker laboratories (Leeds and Cardiff), and the results fed directly to the Medical Research Council Clinical Trials Unit, and used for subsequent randomisation. Here the laboratories discuss their experiences., Methods: Following successful tumour content assessment, blocks were sectioned for DNA extraction and immunohistochemistry (IHC). Pyrosequencing was initially used to determine tumour mutation status (KRAS, NRAS, BRAF and PIK3CA), then from 2018 onwards, next-generation sequencing was employed to allow the inclusion of TP53. Protein expression of MLH1, MSH2, MSH6, PMS2 and pTEN was determined by IHC. An interlaboratory comparison programme was initiated, allowing sample exchanges, to ensure continued assay robustness., Results: 1291 tumour samples were successfully analysed. Assay failure rates were very low; 1.9%-3.3% for DNA sequencing and 0.9%-1.3% for IHC. Concordance rates of > 98% were seen for the interlaboratory comparisons, where a result was obtained by both laboratories., Conclusions: Practical and logistical problems were identified, including poor sample quality and difficulties with sample anonymisation. The often last-minute receipt of a sample for testing and a lack of integration with National Health Service mutation analysis services were challenging. The laboratories benefitted from both pretrial validations and interlaboratory comparisons, resulting in robust assay development and provided confidence during the implementation of new sequencing technologies. We conclude that our centralised approach to biomarker testing in FOCUS4 was effective and successful., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)
Published: 2023
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45. Germline variation in RASAL2 may predict survival in patients with RAS-activated colorectal cancer.

Author: Wills C, Watts K, Maughan TS, Fisher D, Al-Tassan NA, Houlston RS, Escott-Price V, and Cheadle JP
Subjects: Humans, Proto-Oncogene Proteins B-raf genetics, Mutation, Mitogen-Activated Protein Kinases genetics, Mitogen-Activated Protein Kinases metabolism, Germ Cells metabolism, Proto-Oncogene Proteins p21(ras) genetics, GTPase-Activating Proteins genetics, Genome-Wide Association Study, Colorectal Neoplasms pathology
Abstract: Background: Therapeutic agents that specifically target patients with RAS mutant colorectal cancer (CRC) are needed. We sought potential drug targets by relating genome-wide association study and survival data in patients with advanced CRC profiled for mitogen-activated protein kinase (MAPK) pathway mutations., Methods: In total, 694 patients from the clinical trials COIN and COIN-B had MAPK-activated CRCs (assigned as KRAS, NRAS, or BRAF mutant). Genome-wide single nucleotide polymorphism (SNP), gene, and gene-set analyses were performed to identify determinants of survival. For rs12028023 in RAS protein activator-like 2 (RASAL2), we studied its effect by MAPK pathway activation status (by comparing to 760 patients without MAPK-activated CRCs), MAPK gene mutation status, surface area of the primary tumor (as a marker of proliferation), and expression on RASAL2., Results: In MAGMA genome-wide analyses, RASAL2 was the most significant gene associated with survival (p = 2.0 × 10 -5 ). Patients carrying the minor (A) allele in the lead SNP, rs12028023 in intron 1 of RASAL2, had a median increase in survival of 167 days as compared with patients carrying the major allele. rs12028023 was predictive for survival by MAPK-activation status (p Z-test = 2.1 × 10 -3 ). Furthermore, rs12028023 improved survival in patients with RAS mutant (hazard ratio [HR] = 0.62, 95% confidence intervals [CI] = 0.5-0.8, p = 3.4 × 10 -5 ) but not BRAF mutant (p = 0.87) CRCs. The rs12028023 A-allele was associated with reduced surface area of the primary tumor (Beta = -0.037, standard error [SE] = 0.017, p = 3.2 × 10 -2 ) and reduced RASAL2 expression in cultured fibroblasts (p = 1.6 × 10 -11 )., Conclusion: Our data demonstrate a prognostic role for RASAL2 in patients with MAPK-activated CRCs, with potential as a therapeutic target., (© 2023 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)
Published: 2023
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46. Author Correction: Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.

Author: Flanagan DJ, Amirkhah R, Vincent DF, Gunduz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, and Sansom OJ
Published: 2023
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47. Relationship between 233 colorectal cancer risk loci and survival in 1926 patients with advanced disease.

Author: Wills C, Houseman A, Watts K, Maughan TS, Fisher D, Houlston RS, West HD, Escott-Price V, and Cheadle JP
Abstract: Background: Genome, transcriptome and methylome-wide association studies have identified single-nucleotide polymorphisms (SNPs) or genes at 258 loci associated with colorectal cancer (CRC) risk. We studied the relationship between these and patient outcome., Methods: We studied 1926 unrelated patients with advanced CRC from COIN and COIN-B. Of 205 CRC-risk SNPs, 19 were directly genotyped and 162 were imputed, and of 53 risk genes, 52 were tested. An additive Cox model for overall survival was adjusted for known prognostic factors. For nominally significant SNPs or genes, we considered a recessive model with a Bonferroni corrected threshold of P = 2.1 × 10 -4 . We examined SNPs as expression quantitative trait loci (eQTL) and the relationship between gene expression in colorectal tumours and survival in 597 unrelated patients., Results: Eleven SNPs or genes were nominally associated with survival under an additive model. Only rs117079142 mapping to UTP23 and EIF3H (Hazard Ratio [HR] = 2.79, 95% Confidence Intervals [CI] = 1.70-4.58, P = 4.7 × 10 -5 ) and rs9924886 mapping to CDH1 and CDH3 (HR = 1.24, 95% CI = 1.12-1.38, P = 5.2 × 10 -5 ) passed the multiple testing threshold under a recessive model. rs117079142 was an eQTL for UTP23 and rs9924886 for CDH1 , CDH3 and ZFP90 . Decreased CDH1 expression in CRCs was associated with worse survival (HR = 2.18, 95% CI = 1.3-3.5, P = 1.8 × 10 -3 )., Conclusion: rs117079142 and rs9924886 may represent potential prognostic biomarkers for CRC., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)
Published: 2023
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48. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.

Author: Flanagan DJ, Amirkhah R, Vincent DF, Gunduz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, and Sansom OJ
Subjects: Humans, Transforming Growth Factor beta, Apoptosis genetics
Abstract: The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC's with born to be bad traits., (© 2022. The Author(s).)
Published: 2022
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49. A proliferative subtype of colorectal liver metastases exhibits hypersensitivity to cytotoxic chemotherapy.

Author: Spurr LF, Martinez CA, Katipally RR, Iyer SC, Pugh SA, Bridgewater JA, Primrose JN, Domingo E, Maughan TS, D'Angelica MI, Talamonti M, Posner MC, Connell PP, Weichselbaum RR, and Pitroda SP
Abstract: Personalized treatment approaches for patients with limited liver metastases from colorectal cancer are critically needed. By leveraging three large, independent cohorts of patients with colorectal liver metastases (n = 336), we found that a proliferative subtype associated with elevated CIN70 scores is linked to immune exclusion, increased metastatic proclivity, and inferior overall survival in colorectal liver metastases; however, high CIN70 scores generate a therapeutic vulnerability to DNA-damaging therapies leading to improved treatment responses. We propose CIN70 as a candidate biomarker to personalize systemic treatment options for patients with metastatic colorectal cancer. These findings are potentially broadly applicable to other human cancers., (© 2022. The Author(s).)
Published: 2022
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50. Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand-foot syndrome.

Author: Watts K, Wills C, Madi A, Palles C, Maughan TS, Kaplan R, Al-Tassan NA, Kerr R, Kerr DJ, Houlston RS, Escott-Price V, and Cheadle JP
Subjects: Antineoplastic Combined Chemotherapy Protocols adverse effects, Cetuximab therapeutic use, Colorectal Neoplasms drug therapy, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Fluorouracil, Genetic Variation, Genome-Wide Association Study, Humans, Inflammation complications, Psoriasis genetics, Antigens, CD genetics, Capecitabine adverse effects, Hand-Foot Syndrome genetics, Oxaliplatin adverse effects, Sialyltransferases genetics
Abstract: Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand-foot syndrome (HFS) or palmar-plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type-2 diabetes (T2D), a disease also associated with HFS. We analysed genome-wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN-B trials. One thousand and fifty-five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN-B with grade 2-3 HFS responded to treatment as compared to 58% with grade 0-1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02-1.2, P = 2.0 × 10 -4 ). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84-0.99, P = 4.6 × 10 -2 ). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1-4.6, P = 4.3 × 10 -8 ) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42-1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92-0.96, P = 1.2 × 10 -8 ) and the rs6783836-T allele was associated with lowered HbA1c levels (P = 5.9 × 10 -3 ) and lymphocyte count (P = 2.7 × 10 -3 ), and psoriasis (P = 7.5 × 10 -3 ) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Published: 2022
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