Emotional engagement, family support and personal beliefs can influence how patients and healthcare professionals (HCPs) perceive cancer differently. This study examined the extent to which the views of patients and HCPs on cancer care align, and identified factors that may underlie disparities. Participants with colorectal cancer (CRC) were asked to describe their perception of their disease (i.e. whether they felt it was under control (DC), was progressing (PD), or was of an unknown status) and to complete psychometric assessments of anxiety, depression, PTSD and well-being. Two HCPs, who were blinded to the patients’ responses, examined the case files to determine the stage of treatment at which the patients were enrolled in the study. The concordance of perceptions between patients and HCPs was examined, along with associations with clinical variables and psychometric health outcomes, using both univariate and multivariate analyses. A total of 205 patients with CRC were included in the study. The mean age was 65 years, with 58

RNA is subject to many modifications, from small chemical changes like methylation to conjugation of biomolecules such as glycans. As well as endogenously written modifications, RNA is also exposed to damage induced by its environment. Certain clinical compounds are known to covalently modify RNA with a growing appreciation of how these impact clinical efficacy. To understand the regulation of these modifications, we need a reliable, sensitive, and rapid methodology for their quantification. Thus, we developed Aqueous Identification of RNA Elements (AquIRE) and applied it to the analysis of drug-induced RNA damage by 5FU, oxaliplatin, and temozolomide in clinically relevant cell models. We demonstrate that RNA damage is widespread and follows previously unappreciated temporal dynamics. AquIRE also provides a highly sensitive method to detect RNAs modified by glycans. We leverage this to expand the horizons of the glycoRNA world across the kingdoms of life as well as identifying cell-free glycoRNAs in multiple species. We demonstrate that glycoRNA expression is dynamic during embryo development, modulated during senescence, and elevated by RNA-damaging agents. Finally, we use RNA digestion to demonstrate that cell surface or cell-free RNA promotes the cytotoxicity of RNA-damaging chemotherapy. Together, the AquIRE platform provides an intrinsically flexible method to study diverse RNA modifications from any sample.

Abstract Background Capecitabine and Oxaliplatin (CAPOX) chemotherapy is a standard treatment for stage 2/3 colorectal cancer but is associated with dose-limiting toxicities. Short-term fasting may protect healthy cells from chemotherapy-related side effects via differential stress resistance. However, it is not known whether it is possible to recruit to a trial of short-term fasting in this population, or whether participants would adhere to the intervention. The aim was to test the feasibility and acceptability of a pre-chemotherapy, 36-h, water-only fast prior to the first three cycles of chemotherapy in people receiving CAPOX chemotherapy for stage 2/3 colorectal cancer. Methods A two-armed randomised controlled feasibility trial with an embedded qualitative interview study conducted in two NHS foundation trust hospital sites in England. Participants were randomly allocated, in a 1:1 ratio using random permuted blocks, by a secure online randomisation system, to either a 36-h fast immediately prior to chemotherapy administration or standard dietary advice. The intervention was delivered during chemotherapy cycles 1–3. Primary outcomes were adherence, recruitment, retention, data completion, and acceptability. Secondary outcomes included chemotherapy side effects, quality of life, metabolic and inflammatory markers, appetite, and sarcopenia. Results Seventy-nine patients were screened, of whom44 were eligible. Twelve consented and were randomised (intervention: n = 6; control: n = 6). The retention rates for chemotherapy cycles 1, 2, and 3 were 100%, 83%, and 83% for the intervention group and 100%, 100%, and 100% for the control. Five out of six participants adhered to the fast. The trends observed in levels of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding proteins 2 and 3 (IGFBP-2 and IGFBP-3) were consistent with effective fasting. Qualitative findings indicated that fasting was achievable but sometimes perceived as an additional burden alongside chemotherapy. Recruitment challenges were influenced by site-level factors, including competing priorities, COVID-19-related disruptions, and perceptions of the intervention. Conclusion The SWiFT study was feasible to deliver and adherence to the fast was high. In a future definitive trial, success in recruitment appears to depend more on specific local factors rather than the intervention being unattractive to most potential participants. Trial registration ISRCTN, ISRCTN17994717, registered 23 October 2018, https://www.isrctn.com/ISRCTN17994717

Abstract Background: Patients (pts) with operable, high risk stage II-III dMMR/MSI colorectal cancer (CRC) achieved a pathological complete response (pCR) of 59% in the phase 2 NEOPRISM-CRC trial of neoadjuvant pembrolizumab (pembro). Here we report longitudinal tumor informed ctDNA dynamics and T cell receptor (TCR) clonality as a marker of treatment response, minimal residual disease, and updated survival outcomes. Methods: 32 pts with newly diagnosed radiologically node positive or high risk T3/T4 dMMR/MSI CRC received 1 cycle of pembro 200 mg IV Q3W. 31 pts with TMB-medium (6-19 mutations/Mb) or TMB-high (TMB-H) (≥20 mutations/Mb) tumors, evaluated by FoundationOne®CDx, received 2 further cycles. Surgery was performed 4-6 weeks after the final cycle. Primary endpoint was pCR. Secondary endpoints included 3-year relapse free survival, overall survival and safety. ctDNA profiling was performed using the whole genome tumor-informed Personalis NeXT Personal® assay (LOD95 of 3.45 PPM), tracking up to 1800 patient-specific variants over 11 timepoints; at baseline, prior to each cycle, pre and post-surgery, and at 3,6,9,12,24,36 months (mo) follow up. RNA-based TCR sequencing (FUME-TCRseq) was conducted on pre-treatment tumor biopsies. Unique CDR3 amino acid sequences were quantified to derive TCR repertoire metrics. Repertoires were stratified by clonotype size and compared between histopathological responders and non-responders. Results: 23/31 (74%) pts with TMB-H tumors had evaluable paired tissue and plasma samples (n=207). Baseline ctDNA was detected in all pts (23/23, 100%). Pre-surgery ctDNA clearance was strongly associated with pCR in 13/14 pts (PPV=92.9%) while persistent pre-surgical ctDNA detection predicted residual disease in 8/9 pts (NPV=88.9%). 6/6 pts who cleared ctDNA prior to cycle 2 achieved pCR (PPV=100%). All pts had undetectable ctDNA up to 24 mo post-surgery. Tumour TCR analysis demonstrated that large clonotypes (relative abundance 0.001-0.01) occupied significantly greater clonal space in pts with pCR compared with non-pCR (p=0.011). In a Bayesian model incorporating ctDNA kinetics and baseline TCR clonality, combined multimodal profiling was highly predictive of response with posterior probabilities ≥0.7 identifying pts with pCR (14/14, PPV 100%). At data cut off of 1st November 2025, median follow up was 28.7 mo (23.0-36.5) with no disease relapse. Conclusions: Ultrasensitive longitudinal tumor-informed ctDNA monitoring may dynamically predict response to neoadjuvant immunotherapy. Expanded intratumoral TCR clonality in responders highlights the immunobiological basis of pathological response which may aid early patient stratification and guide de-escalated neoadjuvant strategies. Citation Format: Yanrong Jiang, Anna-Maria Militello, Charles Abbott, Bailiang Li, Monika Madrova, Mark Saunders, Jenny Seligmann, Timothy Iveson, Richard Wilson, Janet Graham, Sandra Irvine, Rubina Begum, Reshma Bhat, Gabriel Naylor-Leyland, Andrew Plumb, Austin Obichere, Evelyn Y. Wong, Sean Boyle, Richard Chen, Manuel Rodriguez-Justo, Marnix Jansen, Kai-Keen Shiu. Neoadjuvant pembrolizumab stratified by tumor mutation burden in high-risk stage II-III dMMR/MSI colorectal cancer (NEOPRISM-CRC): Perioperative ultrasensitive ctDNA monitoring and tumor-infiltrating TCR repertoire for treatment response prediction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT170.

AREG/EREG with variation in tissue processing

Background Neutralization of interferon (IFN)-γ abrogates the efficacy of anti-programmed death-ligand 1 (PD-(L)1) checkpoint inhibitors. Most epithelial cells do not constitutively express major histocompatibility complex (MHC) class II but can be induced to do so by IFN-γ. Inducible tumor-specific MHC class II (tsMHC-II) underlies responsiveness to anti-PD-(L)1. Retrospective studies show that tsMHC-II positivity associates with improved outcomes in patients treated with anti-PD-(L)1. The ANICCA-Class II single-arm Bayesian phase II trial prospectively explored whether positive tsMHC-II status could be a useful selection marker for anti-programmed cell death protein-1 (PD-1) in proficient mismatch repair colorectal cancer (pMMR CRC). In parallel, we retrospectively evaluated the potential predictive power of immunoscore-immune checkpoint (IS-IC) for outcome with single-agent immune checkpoint blockade.Methods Patients with histologically confirmed locally advanced/metastatic pMMR CRC with >1% MHC class II expression, Eastern Cooperative Oncology Group performance status 0–2, aged ≥18 years were eligible. Participants received 480 mg nivolumab every 28 days for up to 24 cycles. The primary outcome was durable clinical benefit (DCB) defined as participants remaining progression-free at their third trial-specific scan since treatment start (ie, at approximately 27 weeks). Secondary outcomes included progression-free survival time (PFS) and overall survival time (OS).Results 35 participants were treated: 65.7% of participants’ cancers were tsMHC-II ≥5%. 3/35 patients achieved DCB (8.6%), estimating the true DCB rate (R) of 11% (95% credible interval 3% to 22%) with 0.002 probability that the true DCBR was >30%, below the required 0.5 to warrant further research. The higher tsMHC-II cut-point ≥5% was not more useful in predicting duration of disease stabilization. All three participants who achieved DCB had no evidence of liver metastases (LM); DCBR 23.1% in those without versus 0% in those with LM. PFS and OS were significantly greater in those without LM. There was no evidence that IS-IC high predicted for prolonged time on treatment or improved tumor growth inhibition.Conclusions In pMMR CRC, tsMHC-II positivity fails to identify a subset of patients with metastatic pMMR CRC obtaining potentially meaningful benefit from single-agent anti-PD-1. Although numbers are limited, there is no clear evidence that IS-IC is predictive of outcome with single-agent anti-PD-1. The poor outcome in those with LM underscores the need for therapies that overcome the systemic immunosuppression driven by LM.

Example AREG and EREG immunohistochemistry

Ataxia telangiectasia and Rad3-related kinase (ATR) is a rational radiosensitization target. In this study, we explore the combination of the ATR inhibitor, ceralasertib, and palliative radiotherapy, with primary endpoint the identification of maximum tolerated dose, and secondary endpoints the determination of adverse event causality, pharmacokinetics (PK) and anti-tumor activity. Twenty-seven patients were dosed in escalating dose cohorts from 20 to 80 mg twice daily (BD) with concomitant radiation, 20 Gy in 10 fractions or 30 Gy in 15 fractions. Patients were assessed for acute and late toxicities and response after therapy. A non-tolerated dose was not reached. Maximum administered dose was 80 mg BD ceralasertib over 3 weeks with 30 Gy in 15 fractions, at which 1/6 evaluable patients had dose-limiting toxicities (radiation dermatitis and mucositis). PK was comparable to monotherapy. Of 23 efficacy-evaluable participants, 2 (9%) had complete response (CR), 6 (26%) partial response (PR), 13 (57%) stable disease (SD) and 2 (9%) progressive disease (PD) as best response in irradiated tumors. Response was not clearly linked to genomic aberrations. Increased T and natural killer cell activation as observed in peripheral blood as treatment progressed.

Abstract IntroductionAnal cancer is rare, but its incidence is increasing. Chemoradiotherapy is the primary treatment modality. Outcomes used in anal cancer trials vary which hinders evidence synthesis. Using a systematic review, patient interviews and a 2-stage Delphi consensus survey, the first CORMAC project brought together patients and healthcare professionals from across the world to agree shared priorities and make sure that studies of chemoradiotherapy treatments for anal cancer report outcomes that are meaningful to patients and health care professionals. CORMAC-1 established an internationally ratified core outcome set (COS) of 19 outcomes across 4 domains. These 19 outcomes are an agreed minimum that all clinical trials in chemoradiotherapy anal cancer trials should report. CORMAC-2 is the next phase which seeks to reach international agreement on the definitions for the 11 core outcomes in the domains of disease activity and survival. Agreeing definitions for these core outcomes will facilitate utilisation of the core outcome set, increasing outcome standardisation across trials thereby increasing the quality of data available for clinical decision-making and ultimately enhancing patient care.MethodsThe original CORMAC systematic review will be updated, focusing on 2 of the 4 COS domains, disease activity and survival domains. An international steering committee composed of international anal cancer trial experts will be formed. The committee will review the updated search results to develop a 2-stage Delphi consensus survey. The survey will be publicised through conferences, email lists, domestic and international bodies and will target healthcare and allied healthcare professional involved in the design, running, recruitment and publication of anal cancer trials. Following the 2-stage survey, a stakeholder meeting composed of the steering committee and selection of survey participants will ratify the results and agree a final set of core outcome definitions.Ethics and disseminationCORMAC-2 results will be disseminated through journal and conference publications to inform clinical teams and patient support groups to raise awareness and implementation of the core outcome set. Results will feed into the DECREASE study and it is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative (1,2). As per the University of Manchester ethic decision tool, no ethical approval is required. Further information is available at https://cormacstudy.wordpress.com.

89 Background: Oxaliplatin hypersensitivity is not uncommon in patients with gastrointestinal (GI) cancers receiving chemotherapy. The use of oral premeditations (dexamethasone, cetirizine and famotidine) starting 24 hours before treatment and continuing for a total of three days, further intravenous premedication (dexamethasone, chlorphenamine and famotidine) 30 minutes before treatment and the gradual administration of oxaliplatin over 6.5 hours in four separate escalating doses (desensitisation protocol) is commonly used in such cases. While desensitisation is an option, especially in severe cases, responses and survival outcomes upon rechallenge are not well described. Methods: A retrospective chart review of patients with various GI malignancies who received oxaliplatin-based desensitisation chemotherapy after a severe drug reaction between October 2019 and October 2022 at a single cancer centre was performed. Clinicopathological characteristics and oncological outcomes were assessed. Results: Forty-four patients with a median age of 61 years (range 38-81) were studied. The majority had a diagnosis of CRC (n=22; 50%), followed by oesophago-gastric (n=19; 4%), appendiceal (n=1), cholangiocarcinoma (n=1), and cancer of unknown primary (n=1). More than two thirds of patients (n=32, 73%) were treated with palliative intent. The most common regimens associated with oxaliplatin hypersensitivity reactions after a median of 3 cycles (range 1-10) were FOLFOX (n=24, 55%), CAPOX (n=18, 41%), FLOT (n=1) and FOLFOXIRI (n=1). Seven patients (16%) had another reaction after desensitisation, leading to discontinuation of treatment. Thirty-seven patients (84%) completed treatment as planned. Treatment outcomes after desensitisation included 5 (11%) patients with no evidence of disease (NED) after adjuvant treatment, 16 (37%) patients with disease control, including 3 (7%) partial responders (PR) and 13 (30%) patients with stable disease (SD), and 23 (52%) patients with progressive disease (PD). Conclusions: Oxaliplatin desensitisation is feasible with low discontinuation rates and leads to acceptable oncological outcomes. All patients should be offered desensitisation to allow continuation of active systemic therapy.

Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.

BACKGROUND:Early onset Colorectal Cancer (EOCRC), defined as those diagnosed under the age of 50, has been increasing rapidly since 1970. UK data on EOCRC are currently limited and better understanding of the condition is needed. MATERIALS AND METHODS:A single-center retrospective study of patients with EOCRC treated over 9 years (2013-2021) at a large UK cancer center was performed. Clinicopathological features, risk factors, molecular drivers, treatment, and survival were analyzed. RESULTS:In total, 203 patients were included. A significant increase in cases was reported from 2018-2019 (n = 33) to 2020-2021 (n = 118). Sporadic EOCRC accounted for 70% of cases and left-sided tumors represented 70.9% (n = 144). Median duration of symptoms was 3 months, while 52.7% of the patients had de-novo metastatic disease. Progression-free survival after first-line chemotherapy was 6 months (95% CI, 4.85-7.15) and median overall survival (OS) was 38 months (95% CI, 32.86-43.14). In the advanced setting, left-sided primary tumors were associated with a median OS benefit of 14 months over right-sided primaries (28 vs 14 months, P = .009). Finally, primary tumor resection was associated with median OS benefit of 21 months compared with in situ tumors (38 vs 17 months, P < .001). CONCLUSIONS:The incidence of EOCRC is increasing, and survival outcomes remain modest. Raising public awareness and lowering the age for colorectal cancer screening are directions that could improve EOCRC clinical outcomes. There is also a need for large prospective studies to improve the understanding of the nature of EOCRC and the best therapeutic approaches.

BACKGROUND:Cytoreductive surgery (CRS) is effective for colorectal cancer peritoneal metastases (CRPM) at increasing overall survival (OS) compared to systemic anticancer treatment (SACT) alone. The addition of Oxaliplatin heated intraperitoneal chemotherapy (HIPEC) has been shown in a randomized controlled trial to result in increased complications without significant OS benefit. This study evaluates outcomes for CRPM patients undergoing CRS+HIPEC with Oxaliplatin (Ox) 368mg/m2 (30 min), versus Mitomycin C (MMC) 35mg/m2 (90min).  METHODS: A prospective CRPM real-world database was used to collect outcomes for patients undergoing CRS+HIPEC at a single center. OS, recurrence-free (RFS), peritoneal RFS (PeRFS) were compared amongst all patients with histologically proven CRPM, those with completeness of cytoreduction (CC) score =0/1, and those with CC score=0/1 who were SACT naïve.  RESULTS: Between April 2005 and April 2021, 409 patients underwent CRS+HIPEC: 271 (66%) had MMC, 138 (34%) Ox. Of these, 395 (97%) had histologically confirmed CRPM, 336 (85%) achieved CC=0/1, 188 (47%) were SACT naïve; median OS =39.5, 44.4, and 47.2 months respectively. MMC versus Ox median OS in CC0/1=43.7 (95% CI 35.9-48.3) versus 50.1 (39.7-70.2) months, P = .28; Median OS in SACT naïve=45.7 (39.4-65.9) versus 59.9 (38.3-82.0) months, P = .31; multivariable analysis for CC0/1, SACT naïve patients showed Ox was comparable to MMC: HR=0.90, (0.64-1.27) P = .55 versus HR=0.88, (0.53-1.44) P = .60, respectively. Ox resulted in a significantly improved PeRFS in CC0/1 patients (MMC=9.0 versus Ox=12.6months, P = .01). A multivariable model for PeRFS showed a HR=0.63, (0.43-0.95), P = .03 for Ox.  CONCLUSION: This study suggests a role for Ox HIPEC in CRPM which should be explored further in clinical trials.