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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]

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.)

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.)

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.)

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.)

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).)

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).)

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.

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.)

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.)

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.)

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).)

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).)

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.)

Background: In 2014, the COIN-B clinical trial demonstrated that intermittent cetuximab (IC) was a safe alternative to continuous cetuximab (CC), with less cytotoxic chemotherapy, in first-line treatment for KRAS wild-type metastatic colorectal cancer (mCRC). Cetuximab has been available for this indication in England since 2015, but treatment breaks beyond 6 weeks were prohibited, despite real-world evidence that therapy de-escalation maintains equivalent disease control, but with superior Quality-of-Life (QoL). We performed health economic analyses of IC versus CC and used this evidence to help underpin policy change and guide clinical practice through reduction in unnecessary treatment for mCRC patients., Methods: Employing cost-minimization analysis, we conducted partitioned survival modelling (PSM) and Markov Chain Monte-Carlo (MCMC) simulation to determine costs and quality-adjusted-life-years for IC versus CC., Results: IC reduced costs by £ 35,763 (PSM; p < 0.001) or £ 30,189 (MCMC) per patient annually, while preserving treatment efficacy and enhancing QoL. Extrapolating to all mCRC patients eligible for cetuximab therapy would have generated cost savings of ~£ 1.2 billion over this cohort's lifetime. These data helped underpin a request to NHS England to remove treatment break restrictions in first-line mCRC therapy, which has been adopted as an interim treatment option policy in colorectal cancer during the Covid-19 pandemic., Conclusions: Our results highlight substantial cost savings achievable by treatment de-escalation, while also reinforcing the importance of therapy breaks to potentially increase tumour responsiveness and reduce treatment toxicity. Our study also highlights how health economic evidence can influence health policy, championing reduced treatment intensity approaches without compromising patient outcomes, which is of particular relevance when addressing the reduced capacity and treatment backlogs experienced during the pandemic., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

Purpose: Colorectal cancer (CRC) affects many older adults. We investigated the efficacy and safety of adding anti-epidermal growth factor receptor (EGFR) agents to doublet chemotherapy (DC) in older patients., Methods: Patients with RAS wild-type (WT) metastatic CRC (mCRC) receiving first-line DC + anti-EGFR (n = 1191) or DC alone (n = 729) from seven trials in the Aide de Recherche en Cancerologie Digestive database were included. The prognostic and predictive effects of age were investigated. Progression-free and overall survival (OS) were evaluated between age groups (≥70 vs <70) for DC + anti-EGFR. In addition, outcomes were compared between DC+/-anti-EGFR within age groups in three trials with a DC alone arm. Subsequently, the same analysis was conducted for left-sided tumours. Adverse events grade ≥3 (G3+) were compared between age groups., Results: Older (vs younger) patients receiving DC + anti-EGFR had similar progression-free survival (PFS) (8.7 vs 10.3 months; hazard ratio (HR) = 1.20 [0.96-1.49];p = 0.107) but inferior OS (21.3 vs 26.3; HR = 1.36 [1.08-1.72];p = 0.011). DC + anti-EGFR (vs DC alone) improved OS (23.9 vs 20.3; HR = 0.82 [0.70-0.95];p = 0.008) and PFS (11.2 vs 8.9; HR = 0.70 [0.60-0.82];p < 0.001) in younger but not older patients: OS (24.7 vs 17.6; HR [95% confidence interval {CI}] = 0.77 [0.58-1.04];p = 0.092) and PFS (9.1 vs 8.7; HR [95% CI] = 0.85[0.63-1.15];p = 0.287). In left-sided 'only' tumours, the following outcomes for older (vs younger) patients were observed. For DC + anti-EGFR, PFS 9 versus 11.2 months; HR1.10 (95% CI 0.83-1.46); p = 0.52, OS 25.6 vs 30.3 HR 1.32 (95% CI 0.97-1.79), p = 0.086. For DC + anti-EGFR (vs DC alone), PFS and OS for younger patients were 11.9 vs 9.2 months HR 0.60 (95% CI 0.47-0.78) p < 0.001 and 24.1 versus 23.3 months HR 0.84 (95% CI 0.67-1.04), respectively. For older patients, PFS and OS were 13.1 versus 8.5 months, HR 0.51 (95% CI, 0.28-0.93), P = 0.027 and 26.3 versus 16.5 months HR 0.49 (95% CI, 0.28-0.85), respectively. There was no significant difference in toxicity among different age groups., Conclusions: Older (vs younger) patients with mCRC RAS WT patients had comparable toxicity and efficacy with the addition of anti-EGFR agents to chemotherapy., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DP: Merck Serono – AdBoards, invited speaker; Amgen – invited speaker. MSD – research grant. GSL reported no Conflict of interest to disclose. CLO reported no conflict of interest to disclose. JD reported no conflict of interest to disclose. RAA: honoraria – Amgen; Merck Serono; SERVIER. consulting or advisory role – Amgen; Bayer; Merck Serono; SERVIER. Speakers' Bureau – Merck Serono. Research funding – AstraZeneca (Inst); Merck Sharp & Dohme (Inst). Travel, accommodations, expenses – Amgen; AstraZeneca; Merck Serono; SERVIER. TSM: consulting or advisory role – vertex; vertex; vertex; vertex. EVC: consulting or advisory role – Array BioPharma; AstraZeneca; Bayer; Bristol-Myers Squibb; Celgene; Halozyme; Lilly; Merck KGaA; Merck Sharp & Dohme; Novartis; Roche; SERVIER. Research funding – Amgen (Inst); Bayer (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Ipsen (Inst); Lilly (Inst); Merck (Inst); Merck KGaA (Inst); Novartis (Inst); Roche (Inst); SERVIER (Inst). APV: consulting or advisory role – Bayer; Bayer; Bayer; Bayer; Eisai; Eisai; Eisai; Eisai; Halozyme; Halozyme; Halozyme; Halozyme; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical. Research funding – Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Bristol-Myers Squibb (Inst); Genentech/Roche (Inst); Genentech/Roche (Inst); Genentech/Roche (Inst); Genentech/Roche (Inst). Patents, royalties, other Intellectual property – Royalties from Now-UptoDate for authoring and maintaining two chapters; royalties from Now-UptoDate for authoring and maintaining two chapters; royalties from Now-UptoDate for authoring and maintaining two chapters; royalties from Now-UptoDate for authoring and maintaining two chapters. Travel, accommodations, expenses - Bayer; 275 Bayer; Bayer; Bayer; Genentech; Genentech; Genentech; Genentech; Halozyme; Halozyme; Halozyme; Halozyme; Roche; Roche; Roche; Roche. HL: Ad board/consulting. BMs Roche Merck kg Bayer oncocyte fulgent Jazz therapeutics G1 therapeutics. Astellas. Clinical trial support. SWOG NCI BMs Boehringer Ingelheim. NGM psioyx Genentech Pfizer Merck Bayer. VH: honoraria – Amgen; Amgen; Amgen; Amgen; Baxalta; Baxalta; Baxalta; Baxalta; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Celgene; Celgene; Celgene; Celgene; Lilly; Lilly; Lilly; Lilly; Merck; Merck; Merck; Merck; Roche; Roche; Roche; Roche; Sanofi; Sanofi; Sanofi; Sanofi; SERVIER; SERVIER; SERVIER; SERVIER; Sirtex Medical; Sirtex Medical; Sirtex Medical; Sirtex Medical; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical; Taiho Pharmaceutical Consulting or advisory role - Amgen; Amgen; Amgen; Amgen; Baxalta; Baxalta; Baxalta; Baxalta; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Boehringer Ingelheim; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Celgene; Celgene; Celgene; Celgene; Halozyme; Halozyme; Halozyme; Halozyme; Merck; Merck; Merck; Merck; MSD; MSD; MSD; MSD; MSD Oncology; MSD Oncology; MSD Oncology; MSD Oncology; Roche; Roche; Roche; Roche; Sanofi; Sanofi; Sanofi; Sanofi; SERVIER; SERVIER; SERVIER; SERVIER; Sirtex Medical; Sirtex Medical; Sirtex Medical; Sirtex Medical. Research funding - Amgen (Inst); Amgen (Inst); Amgen (Inst); Amgen (Inst); Boehringer Ingelheim (Inst); Boehringer Ingelheim (Inst); Boehringer Ingelheim (Inst); Boehringer Ingelheim (Inst); Celgene (Inst); Celgene (Inst); Celgene (Inst); Celgene (Inst); Merck (Inst); Merck (Inst); Merck (Inst); Merck (Inst); Roche (Inst); Roche (Inst); Roche (Inst); Roche (Inst); Servier (Inst); Servier (Inst); Servier 298 (Inst); Servier (Inst); Shire (Inst); Shire (Inst); Shire (Inst); Shire (Inst); Sirtex Medical (Inst); Sirtex Medical (Inst); Sirtex Medical (Inst); Sirtex Medical (Inst). Travel, accommodations, expenses – Amgen; Amgen; Amgen; Amgen; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Bristol-Myers Squibb; Merck; Merck; Merck; Merck; MSD; MSD; MSD; MSD; Roche; Roche; Roche; Roche; SERVIER; SERVIER; SERVIER; SERVIER; Shire; Shire; Shire; Shire; Sirtex Medical; Sirtex Medical; Sirtex Medical; Sirtex Medical. RK reported no conflict of interest to disclose. CB: honoraria – AstraZeneca; Bayer; Berlin Chemie; Berlin Chemie; Bristol-Myers Squibb; Merck KGaA; Merck Sharp Dohme; Roche; Sanofi. Consulting or advisory role – AOK Health Insurance; Bayer Schering Pharma; GSO; Lilly/ImClone; Merck Serono; Merck Sharp & Dohme; Novartis; Sanofi. Research funding – AbbVie (Inst); ADC Therapeutics (Inst); Agile Therapeutics (Inst); Alexion Pharmaceuticals (Inst); Amgen (Inst); Apellis Pharmaceuticals (Inst); Astellas Pharma (Inst); AstraZeneca (Inst); Bayer (Inst); BerGenBio (Inst); Blueprint Medicines (Inst); Boehringer Ingelheim (Inst); Bristol-Myers Squibb (Inst); Celgene (Inst); Daiichi Sankyo (Inst); Eisai (Inst); Gilead Sciences (Inst); GlaxoSmithKline (Inst); Glycotope GmbH (Inst); Incyte (Inst); IO Biotech (Inst); Isofol Medical (Inst); Janssen- Cilag (Inst); Karyopharm Therapeutics (Inst); Lilly (Inst); Millennium (Inst); MSD (Inst); Nektar (Inst); Novartis (Inst); Rafael Pharmaceuticals (Inst); Roche (Inst); Springworks Therapeutics (Inst); Taiho Pharmaceutical (Inst). Travel, accommodations, expenses – Bristol-Myers Squibb; Merck Serono; Pfizer; Sanofi. BC: honoraria - Bayer; Pfizer; Roche; Sanofi; SERVIER. Consulting or advisory role – BeiGene; Roche; Sanofi; SERVIER. Travel, accommodations, expenses – Merck; MSD; Roche; Sanofi. AG: honoraria – Aptitude Health; Elsevier; IMEDEX. Consulting or advisory role – Amgen (Inst); Array BioPharma (Inst); Bayer (Inst); Boston Biomedical (Inst); Bristol-Myers Squibb (Inst); Daiichi Sankyo (Inst); Genentech/Roche; Lilly (Inst); OBI Pharma. Research Funding - Array BioPharma (Inst); Bayer (Inst); Boston Biomedical (Inst); Daiichi Sankyo (Inst); Eisai (Inst); Genentech/Roche (Inst); Lilly (Inst); Pfizer (Inst). Travel, accommodations, expenses – Amgen; Array BioPharma; Bayer; Boston Biomedical; Bristol-Myers Squibb; Genentech/Roche. TY: Research funding from Taiho Pharmaceuticals, Sumitomo Dainippon Pharma Co., Ltd, Chugai Pharmaceutical Co., Ltd, Amgen KK, Sanofi KK, Daiichi Sankyo Co., Ltd, Meck Sharp and Dohme KK, Parexel International Inc., and ONO Pharmaceutical Co., Ltd. Honoraria - Bayer Yakuhin; Chugai Pharma; Lilly Japan; Merck; Takeda. Research Funding - Amgen (Inst); Chugai Pharma (Inst); DAIICHI SANKYO COMPANY, LIMITED (Inst); MSD (Inst); Ono Pharmaceutical (Inst); PAREXEL International Inc. (Inst); Sanofi (Inst); Sumitomo Dainippon (Inst); Taiho Pharmaceutical (Inst). JZ: stock and other ownership interests – Acceleron Pharma; Aimmune; Alnylam; Amarin Corporation; BioMarin; Concert Pharmaceuticals; Frequency Therapeutics; Gilead Sciences; Global Blood Therapeutics; GW Pharmaceuticals; Madrigal Pharmaceuticals; Moderna. Therapeutics; Myovant Sciences; Opthea; Orphazyme; Sangamo Bioscience; Twist Bioscience; UniQure; Vertex; Zogenix. Honoraria - Deciphera; Gilead Sciences; Halozyme; Merck Serono; Specialised Therapeutics; Targovax. Consulting or advisory role – Centre for Emerging and Neglected Diseases (CEND); Deciphera; H 342 Halozyme; Lipotec; Merck Serono; Merck Sharp & Dohme; Specialised Therapeutics; Targovax. Research funding - AstraZeneca (Inst); Bristol-Myers Squibb (Inst); Eisai (Inst); Ipsen (Inst); IQvia (Inst); Medtronic (Inst); Merck Serono (Inst); MSD Oncology (Inst); Mylan (Inst); Pfizer (Inst). Travel, accommodations, expenses – AstraZeneca; Deciphera; Merck Serono; Merck Sharp & Dohme; Sanofi. AdG: honoraria – Chugai Pharma; Chugai Pharma; Chugai Pharma; Chugai Pharma; Yakult Pharmaceutical; Yakult Pharmaceutical; Yakult Pharmaceutical; Yakult Pharmaceutical. QS: Dr. Shi reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network (to myself), honorarium/speaker role from Chugai Pharmaceutical Co., Ltd, stock from Johnson & Johnson, Amgen, and Merck & CO. (to myself), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: While genome-wide association studies (GWAS) have identified germline variants influencing the risk of developing colorectal cancer (CRC), there has been limited examination of the possible role of inherited variation as a determinant of patient outcome., Patients and Methods: We performed a GWAS for overall survival (OS) in 1926 patients with advanced CRC from the COIN and COIN-B clinical trials. For single nucleotide polymorphisms (SNPs) showing an association with OS (P < 1.0 × 10 -5 ), we conducted sensitivity analyses based on the time from diagnosis to death and sought independent replications in 5675 patients from the Study of Colorectal Cancer in Scotland (SOCCS) and 16,964 patients from the International Survival Analysis in Colorectal cancer Consortium (ISACC). We analysed the Human Protein Atlas to determine if ERBB4 expression was associated with survival in 438 patients with colon adenocarcinomas., Results: The most significant SNP associated with OS was rs79612564 in ERBB4 (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 1.16-1.32, P = 1.9 × 10 -7 ). SNPs at 17 loci had suggestive associations for OS and all had similar effects on the time from diagnosis to death. No lead SNPs were independently replicated in the meta-analysis of all patients from SOCCS and ISACC. However, rs79612564 was significant in stage-IV patients from SOCCS (P = 2.1 × 10 -2 ) but not ISACC (P = 0.89) and SOCCS combined with COIN and COIN-B attained genome-wide significance (P = 1.7 × 10 -8 ). Patients with high ERBB4 expression in their colon adenocarcinomas had worse survival (HR = 1.50, 95% CI = 1.1-1.9, P = 4.6 × 10 -2 )., Conclusions: Genetic and expression data support a potential role for rs79612564 in the receptor tyrosine kinase ERBB4 as a predictive biomarker of survival., Competing Interests: Conflict of interest statement 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 © 2021 Elsevier Ltd. All rights reserved.)

Background: Unplanned subgroup analyses from several studies have suggested primary tumor sidedness (PTS) as a potential prognostic and predictive parameter in metastatic colorectal cancer (mCRC). We aimed to investigate the impact of PTS on outcomes of mCRC patients., Methods: PTS data of 9277 mCRC patients from 12 first-line randomized trials in the ARCAD database were pooled. Overall survival (OS) and progression-free survival (PFS) were assessed using Kaplan-Meier and Cox models adjusting for age, sex, performance status, prior radiation/chemotherapy, and stratified by treatment arm. Predictive value was tested by interaction term between PTS and treatment (cetuximab plus chemotherapy vs chemotherapy alone). All statistical tests were 2-sided., Results: Compared with right-sided metastatic colorectal cancer patients (n = 2421, 26.1%), left-sided metastatic colorectal cancer patients (n = 6856, 73.9%) had better OS (median = 21.6 vs 15.9 months; adjusted hazard ratio [HRadj] = 0.71, 95% confidence interval [CI] = 0.67 to 0.76; P < .001) and PFS (median = 8.6 vs 7.5 months; HRadj = 0.80, 95% CI = 0.75 to 0.84; P < .001). Interaction between PTS and KRAS mutation was statistically significant (Pinteraction < .001); left-sidedness was associated with better prognosis among KRAS wild-type (WT) (OS HRadj = 0.59, 95% CI = 0.53 to 0.66; PFS HRadj =0.68, 95% CI = 0.61 to 0.75) but not among KRAS mutated tumors. Among KRAS-WT tumors, survival benefit from anti-EGFR was confirmed for left-sidedness (OS HRadj = 0.85, 95% CI = 0.75 to 0.97; P = .01; PFS HRadj = 0.77, 95% CI = 0.67 to 0.88; P < .001) but not for right-sidedness., Conclusions: The prognostic value of PTS is restricted to the KRAS-WT population. PTS is predictive of anti-EGFR efficacy, with a statistically significant improvement of survival for left-sidedness mCRC patients. These results suggest treatment choice in mCRC should be based on both PTS and KRAS status., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: Richard A. AdamsHonoraria: Merck Serono, Servier, AmgenConsulting or Advisory Role: Merck Serono, Amgen, Servier, BayerSpeakers' Bureau: Merck SeronoResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Servier, Amgen, Merck Serono, AstraZeneca Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Jenny F. SeligmannHonoraria: Pierre Fabre, Merck Serono, ServierConsulting or Advisory Role: Pierre Fabre, Roche Molecular DiagnosticsTravel, Accommodations, Expenses: Bristol Myers Squibb/Medarex Matthew SeymourResearch Funding: Amgen, AstraZeneca Richard KaplanResearch Funding: AstraZeneca Mahesh ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Philip QuirkeHonoraria: RocheConsulting or Advisory Role: Roche, Adlai Nortye, Avacta Life Sciences, Amgen, BayerResearch Funding: Roche, GeneFirst, ONIPatents, Royalties, Other Intellectual Property: Roche have filed a patent jointly with my UniversityTravel, Accommodations, Expenses: Roche, Bayer, Amgen Rachel ButlerSpeakers' Bureau: Bayer, Pfizer, Roche, AstraZeneca, MSD, Illumina, Lilly, Novartis, Amgen, Boehringer Ingelheim Ewan BrownResearch Funding: MSD Oncology Fiona CollinsonResearch Funding: Bristol Myers Squibb Stephen FalkStock and Other Ownership Interests: GlaxoSmithKlineSpeakers' Bureau: Merck Serono, Servier, AmgenResearch Funding: Gilead SciencesTravel, Accommodations, Expenses: CelgeneOther Relationship: Servier Harpreet WasanHonoraria: Merck KGaA, Celgene, Sirtex Medical, Servier, Array BioPharma, Roche/Genentech, ERYTECH Pharma, Incyte, ZymeworksConsulting or Advisory Role: Roche Pharma AG, ERYTECH Pharma, Shire, Incyte, Sirtex Medical, Pierre Fabre, Pfizer, BayerSpeakers' Bureau: Sirtex Medical, Celgene, Merck KGaA, Servier, IncyteResearch Funding: Sirtex Medical, Merck KGaA, Pfizer, Merck Sharp & Dohme Kai-Keen ShiuHonoraria: Merck Serono, MSD Oncology, Innovent Biologics, Servier, Daiichi Sankyo Europe GmbHConsulting or Advisory Role: MSD Oncology, Roche, Mirati TherapeuticsResearch Funding: MSD Oncology, Roche Gary MiddletonConsulting or Advisory Role: BMS, D2G, MSDSpeakers' Bureau: Roche, BMS, Servier, PierreFabre, AZTravel, Accommodations, Expenses: BMS Leslie SamuelHonoraria: ServierConsulting or Advisory Role: MerckResearch Funding: Merck, Array BioPharma, Tesaro, Servier, Hutchison MediPharma Richard H. WilsonHonoraria: Servier, Amgen, Bristol Myers SquibbConsulting or Advisory Role: Amgen, CV6 Therapeutics, Pierre Fabre, Amphista Therapeutics, NucanaTravel, Accommodations, Expenses: Amgen, Pierre Fabre Louise C. BrownResearch Funding: AstraZeneca Timothy S. MaughanConsulting or Advisory Role: AstraZeneca, Vertex, Pierre FabreResearch Funding: AstraZeneca, PsiOxus Therapeutics, Merck KgAA, Almac DiagnosticsNo other potential conflicts of interest were reported.

Purpose: Outcomes 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., Methods: Patients 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., Results: FOCUS4-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%)., Conclusion: In 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., Competing Interests: Jenny F. SeligmannHonoraria: Pierre Fabre, Merck Serono, ServierConsulting or Advisory Role: Pierre Fabre, Roche Molecular DiagnosticsTravel, Accommodations, Expenses: Bristol Myers Squibb/Medarex Louise C. BrownResearch Funding: AstraZeneca Richard A. AdamsHonoraria: Merck Serono, Servier, AmgenConsulting or Advisory Role: Merck Serono, Amgen, Servier, BayerSpeakers' Bureau: Merck Serono, AstraZeneca, Merck Sharp & DohmeTravel, Accommodations, Expenses: Servier, Amgen, Merck Serono, AstraZeneca Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Philip QuirkeHonoraria: RocheConsulting or Advisory Role: Roche, Adlai Nortye, Avacta Life Sciences, Amgen, BayerResearch Funding: Roche, GeneFirst, ONIPatents, Royalties, Other Intellectual Property: Roche has filed a patent jointly with my University; I may receive income but none to dateTravel, Accommodations, Expenses: Roche, Bayer, Amgen Rachel ButlerSpeakers' Bureau: Bayer, Pfizer, Roche, AstraZeneca, MSD, Illumina, Lilly, Novartis, Amgen, Boehringer Ingelheim Michael BraunHonoraria: Servier, Amgen, Pierre FabreTravel, Accommodations, Expenses: Servier Fiona CollinsonResearch Funding: Bristol Myers Squibb Rob JonesHonoraria: Astellas Pharma, Janssen, AstraZeneca, MSD Oncology, Bristol Myers Squibb, Pfizer, Novartis, Ipsen, Seattle Genetics, Sanofi, Bayer, Roche/Genentech, EUSA Pharma, Pharmacyclics, Clovis Oncology, Merck Serono, EisaiConsulting or Advisory Role: Clovis OncologyResearch Funding: Roche, Astellas Pharma, AstraZeneca, Pfizer, Novartis, Exelixis, Clovis Oncology, BayerTravel, Accommodations, Expenses: Ipsen, Bayer, Janssen, Astellas Pharma, MSD Ewan BrownResearch Funding: MSD Oncology Timothy C. HumphreyResearch Funding: Debiopharm Group Mahesh ParmarResearch Funding: AstraZeneca, Astellas Pharma, Janssen, Clovis Oncology Richard KaplanResearch Funding: AstraZeneca Richard WilsonHonoraria: Servier, Amgen, Bristol Myers SquibbConsulting or Advisory Role: Amgen, CV6 Therapeutics, Pierre Fabre, Amphista Therapeutics, NucanaTravel, Accommodations, Expenses: Amgen, Pierre Fabre Matthew SeymourResearch Funding: Amgen, AstraZeneca Timothy S. MaughanConsulting or Advisory Role: AstraZeneca, Vertex, Pierre FabreResearch Funding: AstraZeneca, PsiOxus Therapeutics, Merck KgAA, Almac DiagnosticsNo other potential conflicts of interest were reported.

Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10 -7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10 -7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0-8.3, P = 9.8 × 10 -10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10 -6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)