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Magnetic Resonance Tumour Regression Grade (mrTRG) as a Novel Biomarker - Phase III Non CTIMP Trial

ABSTRACT: Open to patients undergoing any pre-operative treatment for locally advanced rectal cancer, TRIGGER is the only phase III clinical trial in the UK offering watch and wait. All patients will have post treatment MRI scans routinely performed, no change from the MERCURY trials high resolution MRI protocol is required. Patients will be randomised to either the control arm for management according to national guidelines - conventional MDT, clinical assessment post-treatment planning using the baseline MRI. Patients in the interventional arm will have their post treatment MRI scans read by a radiologist trained and supported to reliably report the mrTRG grade and have their management directed accordingly - ‘Good response’ (mrTRG 1&2) - watch and wait (avoidance of surgery) offered. ‘Poor response’ (mrTRG 3-5) - local colorectal MDT is informed and uses information to discuss and agree next steps in treatment and surveillance. Patients are followed up for five years with QoL questionnaires completed at registration, 3 and 5 years.

DISEASE(S): Chemotherapy,Rectal Neoplasms,Gastrointestinal Surgery,Colorectal Cancer,Rectal Cancer

PROVIDER: 2209954 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Interventions: Cohort: 10 patients with histologically proven squamous cell carcinoma (SCC) of the anus, presenting to Austin Health for chemo-radiotherapy from June 2015. Observation: for up to 3 years post-radiotherapy. Interventions additional to standard procedures for purpose of study are administered by qualified health professionals and include: Pre-radiotherapy imaging: During standard MRI imaging session – non-standard diffusion weighted MRI (dwMRI) and dynamic contrast enhanced (DCE) MRI scans within Radiology facility. During standard CT simulation session – additional CT scan in prone position within Austin Radiation Oncology. Post-Radiotherapy - 3-4 weeks post completion of radiotherapy - non-standard timepoint for these scans MRI session – including dwMRI and DCE MRI scans within Radiology facility. PET session - PET imaging within Austin Nuclear & Molecular Imaging department. A number of imaging scans are required to map disease for targeting of radiotherapy (RT), including CT, PET and MRI. Each provides slightly different information about the position, shape and composition of the disease that is used by a Radiation Oncologist to define where to target the radiation and how much radiation to deliver. We aim to add an extra, non-standard MRI imaging sequence called a diffusion weighted (dwMRI) scan, to understand the characteristics of the disease and how its use may change the size or shape of the target area so as to ensure complete treatment coverage and improved outcomes from treatment. Additionally, the use of contrast with MRI, dynamic contrast enhanced MRI (DCEMRI) has been shown in other cancer sites to help better identify and show the disease and to show response to treatment, and we wish to verify this in anal Primary outcome(s): Identify the differences in radiotherapy target volume definition on standard (CT, T1/T2 MRI and PET) versus non-standard imaging modalities (dwMRI & DCE-MRI).[2 years post-radiotherapy] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group

Project description:Importance: Neoadjuvant chemoradiotherapy (CRT) is the standard of care for advanced rectal cancer. Yet, predicting response to CRT remains an unmet clinical challenge. Objective: To investigate the transcriptomic determinants to predict response to neoadjuvant CRT and survival in patients with advanced rectal cancer. Design: A single-center, retrospective, cohort study. Setting: A comprehensive cancer center. Participants: Pre-treatment biopsies from 298 patients with rectal cancer, who were later treated with neoadjuvant CRT between 2004 and 2020, were analyzed by RNA sequencing. Main measures and outcomes: Transcriptional subtyping was performed by consensus molecular subtype (CMS) classification. Immune cell infiltration was assessed using MCP-counter scores and single-sample gene set enrichment analysis (ssGSEA). Patients with surgical specimens of tumor regression grade (TRG) 3-4 or who were managed by the watch-and-wait approach for more than 3 years were defined as good responders. Results: Patients classified as CMS1 (6.4%) had a significantly higher rate of good responders; albeit survival was comparable among the four subtypes. Good responders exhibited an enrichment in various immune-related pathways (IFNg and a responses, allograft rejection, IL6 STAT3 signaling during acute phase response, and inflammation), as determined by ssGSEA. MCP-counter scores for cytotoxic lymphocytes were significantly higher for good responders than non-responders (p = 0.0003), and significantly higher for responders than non-responders in GSE109057 (p = 0.0137), GSE87211 (p = 0.0092), and GSE45404 (p = 0.0327) datasets. Cytotoxic lymphocyte MCP-counter score was thus considered an independent predictor of response to CRT, as determined in the multivariable Cox analysis (OR 3.810 [95% CI 1.820-7.970]; p = 0.0004). Multivariable Cox analysis, including post-operative pathological factors, revealed cytotoxic lymphocyte MCP-counter score to be independently associated with recurrence-free survival (HR 0.382 [95% CI 0.158-0.923]; p = 0.0325) and overall survival (HR 0.157 [95% CI 0.030-0.827]; p = 0.0290). ssGSEA showed significantly higher levels of four subpopulations of cytotoxic cells (effector memory CD8 T, natural killer T, natural killer, and activated CD8 T cells) among good responders than non-responders. Conclusions and Relevance: Cytotoxic lymphocyte score, as computed by RNA sequencing, could be a useful marker for predicting response to CRT and survival among patients with rectal cancer.

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Magnetic Resonance Tumour Regression Grade (mrTRG) as a Novel Biomarker - Phase III Non CTIMP Trial

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