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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

In the late 1990s, in response to poor national cancer survival figures, government monies were invested to enhance recruitment to clinical cancer research. Commencing with England in 2001 and then rolling out across all four countries, a network of clinical cancer research infrastructure was created, the new staff being linked to existing clinical care structures including multi-disciplinary teams. In parallel, a UK-wide co-ordination of cancer research funders driven by the 'virtual' National Cancer Research Institute, combined to create a 'whole-system approach' linking research funders, researchers and NHS clinicians all working to the same ends. Over the next 10 years, recruitment to clinical trials and other well-designed studies, increased 4-fold, reaching 17% of the incident cancer population, the highest national rate world-wide. The additional resources led to more studies opened, and more patients recruited across the country, for all types of cancers and irrespective of additional clinical research staff in some hospitals. In 2006, a co-ordinated decision was made to increasingly focus on randomized trials, leading to increased recruitment, without any fall-off in accrual to non-randomized and observational studies. The National Cancer Research Network has supported large successful trials which are changing clinical practice in many cancers. [ABSTRACT FROM AUTHOR]

There is a growing appreciation of the potential value of combining novel molecularly-targeted drugs with radiotherapy or chemoradiotherapy. Such approaches have the potential to improve locoregional disease control and cure rates across a diverse range of tumour types. In this report, we outline a rational framework for developing novel drug-radiation combinations. In doing so, we make recommendations regarding the core preclinical data sets that are required to serve as justification for studies in humans and describe potential clinical trial designs that may be adopted by investigators. [ABSTRACT FROM AUTHOR]

Objective The management of the asymptomatic primary in stage IV colorectal cancer presents a dilemma. There is an increased morbidity and mortality from surgical resection. Nonresectional management of the primary is associated with the risks of obstruction, perforation or haemorrhage. Our practice in patients with stage IV disease is palliative chemotherapy and symptom control. We reviewed our nonoperatively managed patients with colorectal liver metastases in order to identify the percentage of patients requiring urgent operative interventions for symptoms related to the primary. Subjects/patients and method A retrospective review of all patients treated for stage IV disease at our institution from 2003–2006 was undertaken. Patients were identified from multidisciplinary team (MDT) records. Demographic detail, treatment, and follow-up data were extracted from hospital records. These were analysed with Microsoft Excel. Results Thirty-seven patients were identified. 26 Male:11 Female. Median age 63 years (range 38–78). The median survival from diagnosis was 14 months. Three (8%) patients developed obstruction whilst having palliative chemotherapy. Two required a defunctioning stoma, and one was treated by means of a stent. There were no similarities between these three patients in terms of age, sex, site or stage of primary, volume of liver metastases, and alkaline phosphatase (ALP) or carcinoembryonic antigen (CEA) levels. Conclusion Of 37 patients initially treated palliatively for stage IV colorectal cancer, 92% required no surgical treatment of their primary. Therefore it is the experience of this MDT that it is acceptable to treat such patients in an expectant manner. It is not possible to predict those patients, likely to require surgical intervention. [ABSTRACT FROM AUTHOR]

Primary cutaneous T-cell lymphoproliferative disorders (PCTCLDs) are uncommon in organ transplant recipients. CD30+ PCTCLDs are rare in children and have not previously been reported following organ transplantation. We report a 15-year-old boy with Netherton's syndrome who developed CD30+ PCTCLD 6 years following a cardiac transplantation. [ABSTRACT FROM AUTHOR]

Background: This randomised trial compared three chemotherapy regimens in the first-line treatment of advanced colorectal cancer, in terms of their effect on overall and progression-free survival; other endpoints included toxicity, symptom palliation, and quality of life.Methods: 905 patients were randomly assigned the de Gramont regimen (n=303; folinic acid 200 mg/m(2), fluorouracil bolus 400 mg/m(2), and infusion 600 mg/m(2) on days 1 and 2, repeated every 14 days), the Lokich regimen (n=301; protracted venous infusion of fluorouracil 300 mg/m(2) daily), or raltitrexed (n=301; 3 mg/m(2) intravenously every 21 days). Analyses were by intention to treat.Findings: Median follow-up of survivors was 67 weeks. For the de Gramont, Lokich, and raltitrexed groups, respectively, median survival was 294, 302, and 266 days. The hazard ratios for overall survival were 0.88 (95% CI 0.70-1.12, p=0.17) for de Gramont versus Lokich, and 0.99 (0.79-1.25, p=0.94) for de Gramont versus raltitrexed. An increase in treatment-related deaths was seen on raltitrexed (de Gramont one, Lokich two, raltitrexed 18) due to combined gastrointestinal and haematological toxicity. Patients' assessment of quality of life showed that raltitrexed was inferior to the fluorouracil-based regimens, especially in terms of palliation and functioning.Interpretation: The deGramont and Lokich regimens were similar in terms of survival, quality of life, and response rates. The Lokich regimen was associated with more central line complications and hand-foot syndrome. Raltitrexed showed similar response rates and overall survival to the de Gramont regimen and was easier to administer, but resulted in greater toxicity and inferior quality of life. [ABSTRACT FROM AUTHOR]

Background: The SCOPE-1 study tested the role of adding cetuximab to conventional definitive chemoradiotherapy (dCRT), and demonstrated greater toxicity and worse survival outcomes. We present the long-term outcomes and patterns of recurrence.Methods: SCOPE-1 was a phase II/III trial in which patients were randomised to cisplatin 60 mg m-2 (day 1) and capecitabine 625 mg m-2 bd (days 1-21) for four cycles +/- cetuximab 400 mg m-2 day 1 then by 250 mg m-2 weekly. Radiotherapy consisted of 50 Gy/25# given concurrently with cycles 3 and 4. Recruitment was between February 2008 and February 2012, when the IDMC recommended closure on the basis of futility.Results: About 258 patients (dCRT=129; dCRT+cetuximab (dCRT+C)=129) were recruited from 36 centres. About 72.9% (n=188) had squamous cell histology. The median follow-up (IQR) was 46.2 (35.9-48.3) months for surviving patients. The median overall survival (OS; months; 95% CI) was 34.5 (24.7-42.3) in dCRT and 24.7 (18.6-31.3) in dCRT+C (hazard ratio (HR)=1.25, 95% CIs: 0.93-1.69, P=0.137). Median progression-free survival (PFS; months; 95% CI) was 24.1 (15.3-29.9) and 15.9 (10.7-20.8) months, respectively (HR=1.28, 95% CIs: 0.94-1.75; P=0.114). On multivariable analysis only earlier stage, full-dose RT, and higher cisplatin dose intensity were associated with improved OS.Conclusions: The mature analysis demonstrates that the dCRT regimen used in the study provided useful survival outcomes despite its use in patients who were largely unfit for surgery or who had inoperable disease. Given the competing risk of systemic and local failure, future studies should continue to focus on enhancing local control as well as optimising systemic therapy. [ABSTRACT FROM AUTHOR]

DNA repair and autophagy are distinct biological processes vital for cell survival. Although autophagy helps maintain genome stability, there is no evidence of its direct role in the repair of DNA lesions. We discovered that lysosomes process topoisomerase 1 cleavage complexes (TOP1cc) DNA lesions in vertebrates. Selective degradation of TOP1cc by autophagy directs DNA damage repair and cell survival at clinically relevant doses of topoisomerase 1 inhibitors. TOP1cc are exported from the nucleus to lysosomes through a transient alteration of the nuclear envelope and independent of the proteasome. Mechanistically, the autophagy receptor TEX264 acts as a TOP1cc sensor at DNA replication forks, triggering TOP1cc processing by the p97 ATPase and mediating the delivery of TOP1cc to lysosomes in an MRE11-nuclease- and ATR-kinase-dependent manner. We found an evolutionarily conserved role for selective autophagy in DNA repair that enables cell survival, protects genome stability, and is clinically relevant for colorectal cancer patients., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Prognosis of locally advanced pancreatic cancer (LAPC) remains poor with limited therapeutic options. Radiation therapy in pancreatic cancer has been restricted by the disease's proximity to radiosensitive organs at risk (OAR). However, stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) has demonstrated promise in delivering ablative doses safely. We sought to report clinical outcomes from a UK-based Compassionate Access Programme that provided access to SMART to patients with LAPC., Materials and Methods: This was a registry retrospective study conducted at a single centre with access to SMART. Patients with LAPC were treated with prescription dose of 40 Gy in 5 fractions. The planning objective was that 98% of PTV received ≥95% of the prescribed dose, prioritising duodenal, stomach and bowel UK SABR consortium constraints. Daily online adaptation was performed using magnetic resonance guidance and on-table re-optimisation. 0-3 months and > 3-month post-treatment-related toxicities, local progression-free survival, metastatic-free survival and overall survival were evaluated., Results: 55 patients were treated with SMART at our institution from 2020 to 2022. Median follow-up from date of diagnosis was 17 months (range 5-37 months). Median age was 69.87% of patients underwent induction chemotherapy. 71% of patients reported 0-1 grade acute toxicity only. No grade >3 acute toxicity was reported. 5 patients (9%) reported a grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal stricture). No grade >3 toxicity after 3 months was reported. 6 (10%) of patients had grade 3 toxicity (fatigue, nausea, abdominal pain, duodenal haemorrhage). Median local PFS post diagnosis was 17 months (95% CI 15.3-18.7). Median OS post diagnosis was 19 months (95% CI 15.9-22.1). One-year local control post SMART was 65%., Conclusion: This is the first UK-reported experience of MR-guided daily adaptive pancreatic SABR. SMART shows promise in delivering ablative doses with acceptable toxicity rates and good clinical outcomes., (Copyright © 2024. Published by Elsevier Ltd.)

Background: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit., Methods: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HR adj ) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis., Results: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HR adj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HR adj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HR adj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HR adj 1.04, 95% CI 0.86-1.26) (p interaction  = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (p interaction  = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (p interaction  = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (p interaction  = 0.004)., Conclusion: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases., (© 2024. The Author(s).)

The development of deep learning (DL) models to predict the consensus molecular subtypes (CMS) from histopathology images (imCMS) is a promising and cost-effective strategy to support patient stratification. Here, we investigate whether imCMS calls generated from whole slide histopathology images (WSIs) of rectal cancer (RC) pre-treatment biopsies are associated with pathological complete response (pCR) to neoadjuvant long course chemoradiotherapy (LCRT) with single agent fluoropyrimidine. DL models were trained to classify WSIs of colorectal cancers stained with hematoxylin and eosin into one of the four CMS classes using a multi-centric dataset of resection and biopsy specimens (n = 1057 WSIs) with paired transcriptional data. Classifiers were tested on a held out RC biopsy cohort (ARISTOTLE) and correlated with pCR to LCRT in an independent dataset merging two RC cohorts (ARISTOTLE, n = 114 and SALZBURG, n = 55 patients). DL models predicted CMS with high classification performance in multiple comparative analyses. In the independent cohorts (ARISTOTLE, SALZBURG), cases with WSIs classified as imCMS1 had a significantly higher likelihood of achieving pCR (OR = 2.69, 95% CI 1.01-7.17, p = 0.048). Conversely, imCMS4 was associated with lack of pCR (OR = 0.25, 95% CI 0.07-0.88, p = 0.031). Classification maps demonstrated pathologist-interpretable associations with high stromal content in imCMS4 cases, associated with poor outcome. No significant association was found in imCMS2 or imCMS3. imCMS classification of pre-treatment biopsies is a fast and inexpensive solution to identify patient groups that could benefit from neoadjuvant LCRT. The significant associations between imCMS1/imCMS4 with pCR suggest the existence of predictive morphological features that could enhance standard pathological assessment., (© 2024. The Author(s).)

Background: Berzosertib (M6620) is a highly potent (IC50  =  19 nM) and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. This trial assessed the safety, preliminary efficacy, and tolerance of berzosertib in oesophageal cancer (A1 cohort) with RT and advanced solid tumours (A2 cohort) with cisplatin and capecitabine., Methods: Single-arm, open-label dose-escalation (Time-to-Event Continual Reassessment Method) trial with 16 patients in A1 and 18 in A2. A1 tested six dose levels of berzosertib with RT (35 Gy over 15 fractions in 3 weeks)., Results: No dose-limiting toxicities (DLTs) in A1. Eight grade 3 treatment-related AEs occurred in five patients, with rash being the most common. The highest dose (240 mg/m 2 ) was determined as the recommended phase II dose (RP2D) for A1. Seven DLTs in two patients in A2. The RP2D of berzosertib was 140 mg/m 2 once weekly. The most common grade ≥3 treatment-related AEs were neutropenia and thrombocytopenia. No treatment-related deaths were reported., Conclusions: Berzosertib combined with RT is feasible and well tolerated in oesophageal cancer patients at high palliative doses. Berzosertib with cisplatin and capecitabine was well tolerated in advanced cancer. Further investigation is warranted in a phase 2 setting., Clinical Trials Identifier: EU Clinical Trials Register (EudraCT) - 2015-003965-27 ClinicalTrials.gov - NCT03641547., (© 2023. The Author(s).)

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.

Introduction: Online adaptive MR-guided radiotherapy allows for dose escalation to pancreatic cancer while sparing surrounding critical organs. We seek to evaluate the safety of delivering hypofractionated five-fraction, three-fraction and single-fraction MR-guided stereotactic ablative radiotherapy (SABR) to the pancreas., Methods and Analysis: This is a single-centre three-arm phase 1 non-randomised safety study. Patients with localised pancreatic cancer will receive either 50 Gy in five (biological equivalent dose (BED 10 )=100 Gy), 39 Gy in three (BED 10 =90 Gy) or 25 Gy in a single fraction (BED 10 =87.5 Gy) MR-guided daily online adaptive radiotherapy. Each fractionation regimen will be assessed as independent cohorts to determine tolerability, assessed continuously using Bayesian conjugate posterior beta distributions. The primary endpoint of the study is to establish the safety of five-fraction, three-fraction and single-fraction MR-guided hypofractionation SABR in localised pancreatic cancer by assessing dose-limiting toxicities. Secondary endpoints include overall survival, progression-free survival, local control rates, overall control rate, resection rates, long-term toxicities and freedom from second-line chemotherapy. This study plans to also explore imaging and immune biomarkers that may be useful to predict outcome and personalise treatment. The trial will recruit up to 60 patients with a safety run-in., Ethics and Dissemination: The trial is approved by the West Midlands-Black Country Research Ethics Committee 22/WM/0122. The results will be disseminated via conference presentations, peer-reviewed scientific journals and submission to regulatory authorities. The data collected for the study, including individual participant data, will be made available to researchers on request to the study team and with appropriate reason, via octo-enquiries@oncology.ox.ac.uk. The shared data will be deidentified participant data and will be available for 3 years following publication of the study. Data will be shared with investigator support, after approval of a proposal and with a signed data access agreement., Trial Registration Number: ISRCTN10557832., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain., Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18 F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m 2 )/capecitabine (625 mg/m 2 days 1-21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUV max ) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m 2 ) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.govNCT02741856., Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67-3.08; p = 0.35)., Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT., Funding: Cancer Research UK., Competing Interests: SM declares research funding from Celgene. TM declares consulting fees from AstraZeneca and Teysuno; reports participation fees from Pierre Fabre and Pfizer; and has a role at Perspectum. All other authors declare that they have no relevant conflicts of interest., (© 2023 The Author(s).)

Radiotheranostics is a field of rapid growth with some approved treatments including 131 I for thyroid cancer, 223 Ra for osseous metastases, 177 Lu-DOTATATE for neuroendocrine tumors, and 177 Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, and several more under investigation. In this review, we will cover the fundamentals of radiotheranostics, the key clinical studies that have led to current success, future developments with new targets, radionuclides and platforms, challenges with logistics and reimbursement and, lastly, forthcoming considerations regarding dosimetry, identifying the right line of therapy, artificial intelligence and more., Competing Interests: Disclosure KP reports consultation fees from ABX, outside the submitted work. BH has had advisory roles for ABX, Advanced Accelerator Applications (AAA)/Novartis, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen R&D, Lightpoint Medical, Inc., and Pfizer; has received research funding from Astellas, Bristol Myers Squibb, AAA/Novartis, German Research Foundation, Janssen R&D, and Pfizer; and has received compensation for travel from Astellas, AstraZeneca, Bayer and Janssen R&D, all outside the submitted work. OA is a consultant for AAA, Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janssen, Myovant, Myriad, Noria Therapeutics, Inc., Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics. He reports grant/research support from AAA, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, Tenebio, outside the submitted work. SG received (last 3 years) personal honoraria for participation in advisory boards from Amgen, Merck Sharp & Dohme (MSD), Orion; other honoraria from Radio-televisione Svizzera Italiana (RSI), German-speaking European School of Oncology (DESO); invited speaker for ESMO, Swiss group for Clinical Cancer Research (SAKK), Swiss Academy of Multidisciplinary Oncology (SAMO), Orikata academy research group, China Anti-Cancer Association Genitourinary Oncology Committee (CACA-GU); speaker’s bureau for Janssen Cilag; travel grant from Proteomedix and AstraZeneca. Institutional honoraria for participation in advisory boards or in independent data monitoring committees and steering committees from AAA International, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Modra Pharmaceuticals, MSD, Myriad Genetic, Novartis, Orion, Pfizer, Roche, Telixpharma Tolero Pharmaceuticals; other honoraria from Silvio Grasso Consulting, WebMD-Medscape. Patent royalties and other intellectual property for a research method for biomarker WO2009138392. CS is a consultant for Astellas, Bayer, Genentech/Roche, Janssen, Pfizer, AstraZeneca, Lilly, and Point BioPharma and reports research funding from Astellas, Bayer, Janssen, and AstraZeneca, outside the submitted work. TM reports consultancy fees from AstraZeneca, Perspectum, Pierre Fabre and research support from AstraZeneca, Merck KgAa, Bayer, PsiOxus, Almac Diagnostics, outside the submitted work. MSH acknowledged philanthropic/government grant support from the Prostate Cancer Foundation (PCF) funded by CANICA Oslo Norway, Peter MacCallum Foundation, Medical Research Future Fund, NHMRC investigator grant, Movember, U.S. Department of Defense and the Prostate Cancer Foundation of Australia (PCFA). MSH acknowledges grant support from AAA/Novartis, Australian Nuclear Science and Technology Organisation (ANSTO), Bayer, Isotopia. Consulting fees for lectures or advisory boards from Astellas, AstraZeneca, Janssen, Merck/MSD, Mundipharma and Point Biopharma, outside the submitted work. KH reports personal fees from Bayer, personal fees and other from Sofie Biosciences, personal fees from Sirtex, non-financial support from ABX, personal fees from Adacap, personal fees from Curium, personal fees from Endocyte, grants and personal fees from BTG, personal fees from Ipsen, personal fees from Siemens Healthineers, personal fees from GE Healthcare, personal fees from Amgen, personal fees from Novartis, personal fees from Y-mAbs, personal fees from Aktis Oncology, personal fees from Theragnostics, personal fees from Pharma15, personal fees from Debiopharm, personal fees from AstraZeneca, personal fees from Janssen, outside the submitted work., (Copyright © 2023 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Fluoropyrimidines (FPs) are an essential part of the majority of systemic regimens in the treatment of metastatic colorectal cancer (CRC). The use of the oral FP S-1 has been approved by the European Medicines Agency as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, for the treatment of patients with metastatic CRC in whom it is not possible to continue treatment with another FP due to hand-foot syndrome (HFS) or cardiovascular toxicity (CVT). Subsequently, this indication has been included in the 2022 ESMO guidelines for metastatic CRC. Recommendations for use in daily practice are not available., Patients and Methods: Based on peer-reviewed published data on the use of S-1 in Western patients with metastatic CRC who switched from infusional 5-fluorouracil (5-FU) or capecitabine to S-1 for reasons of HFS or CVT, recommendations for its use were formulated by an international group of medical oncologists with expertise in the treatment of metastatic CRC and a cardio-oncologist., Results: In patients who experience pain and/or functional impairment due to HFS during treatment with capecitabine or infusional 5-FU, a switch to S-1 is recommended without prior dose reduction of capecitabine/5-FU. S-1 should preferably be initiated at full dose when HFS has decreased to grade ≤1. In patients with cardiac complaints, in whom an association with capecitabine or infusional 5-FU treatment cannot be excluded, capecitabine/5-FU should be discontinued and a switch to S-1 is recommended., Conclusions: These recommendations should guide clinicians in daily practice in the treatment of patients with metastatic CRC with FP-containing regimens., Competing Interests: Disclosure CJAP reports an advisory role for Nordic Pharma. VH reports honoraria from Merck, Amgen, Roche, Sanofi, Servier, Pfizer, Pierre-Fabre, AstraZeneca, BMS, MSD, Novartis, Boehringer Ingelheim, Celgene, SIRTEX, Terumo, OncoSil, Nordic Pharma, Seagen; and research funding from Merck, Amgen, Roche, Sanofi, Boehringer-Ingelheim, SIRTEX, and Servier. TM reports an advisory role for Nordic Pharma, Perspectum, and AstraZeneca. CC reports honoraria from Amgen, Bayer, Servier, Merck-Serono, MSD, Organon, Pierre-Fabre, Roche, and Nordic Pharma; research grants from Merck-Serono, Bayer, and Servier. EVC reports participation in 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, and Zymeworks; and research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier paid to his institution. RM reports advisory board fees from Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, F. Hoffmann–La Roche, Ipsen Biopharm, Janssen Biotech, Merck, and Pfizer; and clinical trial fees from Regeneron Pharmaceuticals. GB reports advisory role for Amgen, Astellas, Bayer, Janssen, Lilly, MSD, Merck, Nordic Pharma, Novartis, Pfizer, Roche, and Ipsen; and lecture fees from Amgen, Bayer, GSK, Merck, Nordic Pharma, Novartis, and Roche. TA reports honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pierre Fabre, Roche/Vantana, Sanofi, and Servier; consulting or advisory roles for Amgen, Astellas Pharma, Bristol-Myers Squibb, GamaMabs Pharma, Gritstone Oncology, Merck Sharp & Dohme, Nordic Pharma, Pierre Fabre, Seagen, and Servier; and Transgène speaker’s bureaus for Bristol-Myers Squibb, Merck Sharp & Dohme, Seagen, and Servier; travel and accommodation expenses from Merck Sharp & Dohme, and Bristol-Myers Squibb; and nonremunerated activities for the ARCAD Foundation and GERCOR Group. PO reports honoraria from/advisory role for Amgen, Astra Zeneca/Daiichi Sankyo, Bristol-Myers Squibb, Eisai/Ewopharma, Fresenius, Incyte, Janssen, Merck, Merck, Sharp & Dome, Nordic Drugs/Pharma, Nutricia, Pierre Fabre, Roche, Sanofi, and Servier; research support to institution from Amgen, Eli Lilly, Merck, Roche, Sanofi, and Servier; and nonremunerated activities with Colores, Duodecim, ESMO faculty, ESMO scientific committee, ESMO guidelines committee, ASCO/ESMO global curriculum, and the ESMO Lines of therapy project. PP reports advisory role for Servier, Nordic Pharma, and MSD; and research funding for institution from Servier, Nordic Drugs, Shire, Merck, Egetis, Isofol, Lilly, Roche, Merck-Serono, Amgen, and Celgene. AJT has declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: A popular Normal tissue Complication (NTCP) model deployed to predict radiotherapy (RT) toxicity is the Lyman-Burman Kutcher (LKB) model of tissue complication. Despite the LKB model's popularity, it can suffer from numerical instability and considers only the generalized mean dose (GMD) to an organ. Machine learning (ML) algorithms can potentially offer superior predictive power of the LKB model, and with fewer drawbacks. Here we examine the numerical characteristics and predictive power of the LKB model and compare these with those of ML., Materials and Methods: Both an LKB model and ML models were used to predict G2 Xerostomia on patients following RT for head and neck cancer, using the dose volume histogram of parotid glands as the input feature. Model speed, convergence characteristics and predictive power was evaluated on an independent training set., Results: We found that only global optimization algorithms could guarantee a convergent and predictive LKB model. At the same time our results showed that ML models remained unconditionally convergent and predictive, while staying robust to gradient descent optimization. ML models outperform LKB in Brier score and accuracy but compare to LKB in ROC-AUC., Conclusion: We have demonstrated that ML models can quantify NTCP better than or as well as LKB models, even for a toxicity that the LKB model is particularly well suited to predict. ML models can offer this performance while offering fundamental advantages in model convergence, speed, and flexibility, and so could offer an alternative to the LKB model that could potentially be used in clinical RT planning decisions., Competing Interests: 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., (© 2023 The Author(s).)

The purpose of this study was to provide an evidence base for colorectal cancer research activity that might influence policy, mainly at the national level. Improvements in healthcare delivery have lengthened life expectancy, but within a situation of increased cancer incidence. The disease burden of CRC has risen significantly, particularly in Africa, Asia and Latin America. Research is key to its control and reduction, but few studies have delineated the volume and funding of global research on CRC. We identified research papers in the Web of Science (WoS) from 2007 to 2021, and determined the contributions of the leading countries, the research domains studied, and their sources of funding. We identified 62 716 papers, representing 5.7% of all cancer papers. This percentage was somewhat disproportionate to the disease burden (7.7% in 2015), especially in Eastern Europe. International collaboration increased over the time period in almost all countries except in China. Genetics, surgery and prognosis were the leading research domains. However, research on palliative care and quality-of-life in CRC was lacking. In Western Europe, the main funding source was the charity sector, particularly in the UK, but in most other countries government played the leading role, especially in China and the USA. There was little support from industry. Several Asian countries provided minimal contestable funding, which may have reduced the impact of their CRC research. Certain countries must perform more CRC research overall, especially in domains such as screening, palliative care and quality-of-life. The private-non-profit sector should be an alternative source of support., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Stroma-rich tumours represent a poor prognostic subtype in stage II/III colon cancer (CC), with high relapse rates and limited response to standard adjuvant chemotherapy., Design: To address the lack of efficacious therapeutic options for patients with stroma-rich CC, we stratified our human tumour cohorts according to stromal content, enabling identification of the biology underpinning relapse and potential therapeutic vulnerabilities specifically within stroma-rich tumours that could be exploited clinically. Following human tumour-based discovery and independent clinical validation, we use a series of in vitro and stroma-rich in vivo models to test and validate the therapeutic potential of elevating the biology associated with reduced relapse in human tumours., Results: By performing our analyses specifically within the stroma-rich/high-fibroblast (HiFi) subtype of CC, we identify and validate the clinical value of a HiFi-specific prognostic signature (HPS), which stratifies tumours based on STAT1-related signalling (High-HPS v Low-HPS=HR 0.093, CI 0.019 to 0.466). Using in silico, in vitro and in vivo models, we demonstrate that the HPS is associated with antigen processing and presentation within discrete immune lineages in stroma-rich CC, downstream of double-stranded RNA and viral response signalling. Treatment with the TLR3 agonist poly(I:C) elevated the HPS signalling and antigen processing phenotype across in vitro and in vivo models. In an in vivo model of stroma-rich CC, poly(I:C) treatment significantly increased systemic cytotoxic T cell activity (p<0.05) and reduced liver metastases (p<0.0002)., Conclusion: This study reveals new biological insight that offers a novel therapeutic option to reduce relapse rates in patients with the worst prognosis CC., Competing Interests: Competing interests: ML has received honoraria from Pfizer, EMF Serono and Roche for presentations unrelated to this work; ML has received an unrestricted educational grant from Pfizer for research unrelated to this work. PT has received honoraria and travel expenses from BMS, Merck, Roche, Lilly and Sanofi-Aventis for contributions that are not related to the present work. The authors declare no other potential conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: RSPO fusions that lead to WNT pathway activation are potential therapeutic targets in colorectal cancer (CRC), but their clinicopathological significance remains unclear., Methods: We screened 1019 CRCs for RSPO fusions using multiplex reverse transcription-PCR. The RSPO fusion-positive tumours were subjected to whole-exome sequencing (WES)., Results: Our analysis identified 29 CRCs with RSPO fusions (2.8%), consisting of five with an EIF3E-RSPO2 fusion and 24 with PTPRK-RSPO3 fusions. The patients were 17 women and 12 men. Thirteen tumours (45%) were right-sided. Histologically, approximately half of the tumours (13/29, 45%) had a focal or extensive mucinous component that was significantly more frequent than the RSPO fusion-negative tumours (13%; P = 8.1 × 10 -7 ). Four tumours (14%) were mismatch repair-deficient. WES identified KRAS, BRAF, and NRAS mutations in a total of 27 tumours (93%). In contrast, pathogenic mutations in major WNT pathway genes, such as APC, CTNNB1 and RNF43, were absent. RSPO fusion status did not have a statistically significant influence on the overall or recurrence-free survival. These clinicopathological and genetic features were also confirmed in a pooled analysis of previous studies., Conclusion: RSPO fusion-positive CRCs constitute a rare subgroup of CRCs with several characteristic clinicopathological and genetic features., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling., Experimental Design: Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets., Results: Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment., Conclusions: Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations., Methods: Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols., Results: We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement., Discussion: Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently., (© 2022. The Author(s).)

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures., Competing Interests: Declaration of interests S.J.L. has received grant income from UCB Pharma. V.H.K. has served as an invited speaker on behalf of Indica Labs. All other authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Meta-analysis based on individual participant data (IPD) is a powerful methodology for synthesizing evidence by combining information drawn from multiple trials. Hitherto, its principal application has been in questions of clinical management, but an increasingly important use is in clarifying trials methodology, for instance in the selection of endpoints, as discussed in this review. In oncology, the Aide et Recherche en Cancérologie Digestive (ARCAD) Metastatic Colorectal Cancer Database is a leader in the use of IPD-based meta-analysis in methodological research. The ARCAD database contains IPD from more than 38 000 patients enrolled in 46 studies and continues to collect phase III trial data. Here, we review the principal findings of the ARCAD project in respect of endpoint selection and examine their implications for cancer trials. Analysis of the database has confirmed that progression-free survival (PFS) is no longer a valid surrogate endpoint predictive of overall survival in the first-line treatment of colorectal cancer. Nonetheless, PFS remains an endpoint of choice for most first-line trials in metastatic colorectal cancer and other solid tumors. Only substantial PFS effects are likely to translate into clinically meaningful benefits, and accordingly, we advocate an oncology research model designed to identify highly effective treatments in carefully defined patient groups. We also review the use of the ARCAD database in assessing clinical response including novel response metrics and prognostic markers. These studies demonstrate the value of IPD as a tool for methodological studies and provide a reference point for the expansion of this approach within clinical cancer research., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose. To introduce a methodology to predict tissue sparing effects in pulsed ultra-high dose rate radiation exposures which could be included in a dose-effect prediction system or treatment planning system and to illustrate it by using three published experiments. Methods and materials. The proposed system formalises the variability of oxygen levels as an oxygen dose histogram (ODH), which provides an instantaneous oxygen level at a delivered dose. The histogram concept alleviates the need for a mechanistic approach. At each given oxygen level the oxygen fixation concept is used to calculate the change in DNA-damage induction compared to the fully hypoxic case. Using the ODH concept it is possible to estimate the effect even in the case of multiple pulses, partial oxygen depletion, and spatial oxygen depletion. The system is illustrated by applying it to the seminal results by Town (Nat. 1967) on cell cultures and the pre-clinical experiment on cognitive effects by Montay-Gruel et al (2017 Radiother. Oncol. 124 365-9). Results. The proposed system predicts that a possible FLASH-effect depends on the initial oxygenation level in tissue, the total dose delivered, pulse length and pulse repetition rate. The magnitude of the FLASH-effect is the result of a redundant system, in that it will have the same specific value for a different combination of these dependencies. The cell culture data are well represented, while a correlation between the pre-clinical experiments and the calculated values is highly significant ( p  < 0.01). Conclusions . A system based only on oxygen related effects is able to quantify most of the effects currently observed in FLASH-radiation., (Creative Commons Attribution license.)

Generation of transcriptional data has dramatically increased in the past decade, driving the development of analytical algorithms that enable interrogation of the biology underpinning the profiled samples. However, these resources require users to have expertise in data wrangling and analytics, reducing opportunities for biological discovery by 'wet-lab' users with a limited programming skillset. Although commercial solutions exist, costs for software access can be prohibitive for academic research groups. To address these challenges, we have developed an open source and user-friendly data analysis platform for on-the-fly bioinformatic interrogation of transcriptional data derived from human or mouse tissue, called Molecular Subtyping Resource (MouSR). This internet-accessible analytical tool, https://mousr.qub.ac.uk/, enables users to easily interrogate their data using an intuitive 'point-and-click' interface, which includes a suite of molecular characterisation options including quality control, differential gene expression, gene set enrichment and microenvironmental cell population analyses from RNA sequencing. The MouSR online tool provides a unique freely available option for users to perform rapid transcriptomic analyses and comprehensive interrogation of the signalling underpinning transcriptional datasets, which alleviates a major bottleneck for biological discovery. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests M.L. has received honoraria from Pfizer, EMF Serono and Roche for presentations unrelated to this work, and received an unrestricted educational grant from Pfizer for research unrelated to this work. O.J.S. has received funding from Novartis, Astra Zeneca, Cancer Research Technology and Redex for research unrelated to this work., (© 2022. Published by The Company of Biologists Ltd.)

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-characterised cohort of rectal cancer patients without prior radiotherapy., Methods and Results: A total of 143 patients were included. Haematoxylin and eosin (H&E) sections were scanned for (i) deep neural network (DNN, a machine-learning algorithm) tumour segmentation into compartments including desmoplastic stroma and inflamed stroma; and (ii) 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 concerning further management., (© 2021 The Authors. Histopathology published by John Wiley & Sons Ltd.)

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., (© 2021. The Author(s).)