The host anti-tumour inflammatory response is a strong prognostic indicator, and tumour infiltrating lymphocytes (TILs) are believed to have a complimentary role alongside TNM assessment in dictating future management. However, there is wide disagreement regarding the most efficacious and cost-effective method of assessment. Methods: A comprehensive literature search was performed of EMBASE, MedLine and PubMed as well as an assessment of references to identify all relevant studies relating to the assessment of the peri-tumoural inflammatory response or TILs and prognosis in colorectal cancer (CRC). A meta-analysis was performed of 67 studies meeting the REMARK criteria using RevMan software. Results: Intratumoural assessment of both CD3 and CD8 in CRC were significant for disease-free survival (DFS) (combined HRs 0.46; 95%CI: 0.39-0.54 and 0.54; 95%CI: 0.45-0.65), as well as overall survival (OS) and disease-specific survival (DSS). The same was true for assessment of CD3 and CD8 at the invasive margin (DFS: combined HRs 0.45; 95%CI: 0.33-0.61 and 0.51; 95%CI: 0.41-0.62). However, similar fixed effects summaries were also observed for H&E-based methods, like Klintrup-Makinen grade (DFS: HR 0.62; 95%CI: 0.43-0.88). Furthermore, inflammatory assessments were independent of MSI status. Conclusion: The evidence suggests that it is the density of a coordinated local inflammatory infiltrate that confers survival benefit, rather than any individual immune cell subtype. Furthermore, the location of individual cells within the tumour microenvironment does not appear to influence survival. The authors advocate a standardised assessment of the local inflammatory response, but caution against emphasizing the importance of any individual immune cell subtype.

BackgroundTumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC).ObjectiveThe aim of the present study was to use the ITBCC budding evaluation method to examine the relationship between tumor budding, tumor factors, tumor microenvironment, and survival in patients with primary operable CRC.MethodsHematoxylin and eosin-stained slides of 952 CRC patients diagnosed between 1997 and 2007 were evaluated for tumor budding according to the ITBCC criteria. The tumor microenvironment was evaluated using tumor stroma percentage (TSP) and Klintrup–Makinen (KM) grade to assess the tumor inflammatory cell infiltrate.ResultsHigh budding (n = 268, 28%) was significantly associated with TNM stage (p < 0.001), competent mismatch repair (MMR; p < 0.05), venous invasion (p < 0.001), weak KM grade (p < 0.001), high TSP (p < 0.001), and reduced cancer-specific survival (CSS) (hazard ratio 8.68, 95% confidence interval 6.30–11.97; p < 0.001). Tumor budding effectively stratifies CSS stage T1 through to T4 (all p < 0.05) independent of associated factors.ConclusionsTumor budding effectively stratifies patients’ survival in primary operable CRC independent of other phenotypic features. In particular, the combination of T stage and budding should form the basis of a new staging system for primary operable CRC.

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Background:The Glasgow Microenvironment Score (GMS) combines peritumoural inflammation and tumour stroma percentage to assess interactions between tumour and microenvironment. This was previously demonstrated to associate with colorectal cancer (CRC) prognosis, it now requires validation and assessment of interactions with adjuvant therapy.Patients and Methods: Two cohorts were utilised; 862 TNM I-III CRC validation cohort, and 2912 TNM II-III CRC adjuvant chemotherapy cohort (TransSCOT). Primary endpoints were disease-free survival (DFS) and relapse-free survival (RFS). Exploratory endpoint was adjuvant chemotherapy interaction.Results: GMS independently associated with DFS (p=0.001) and RFS (p<0.001). GMS significantly stratified RFS for both low-risk (GMS0 v GMS2: HR 3.24 95% CI 1.85-5.68, p<0.001) and high-risk disease (GMS0 v GMS2: HR 2.18 95% CI 1.39-3.41, p=0.001). In TransSCOT, chemotherapy type (p interaction =0.013), but not duration (p=0.64) was dependent on GMS. Furthermore, GMS 0 significantly associated with improved DFS in patients receiving FOLFOX compared with CAPOX p=0.012). Conclusions:This study validates the GMS as a prognostic tool for patients with stage I-III colorectal cancer, independent of TNM, with the ability to stratify both low-and high-risk disease. Furthermore, GMS 0 could be employed to identify a subset of patients that benefit from FOLFOX over CAPOX.

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206 Background: The Glasgow Microenvironment Score (GMS), comprised of assessment of the tumour inflammatory cell infiltrate (using Klintrup-Mäkinen (KM) grade) and tumour-associated stroma (TSP), has been reported as a stage-independent prognostic score in patients with colorectal cancer. The present study aims to validate the GMS and examines its prognostic utility in the context of stage and MMR status. Methods: Patients who had undergone resection of stage I-III colon cancer were included ( n= 495). GMS was scored by combining KM and TSP as follows: high KM scores 0; low KM with low TSP scores 1; low KM and high TSP scores 2. Cancer specific (CSS) and overall survival (OS) were primary endpoints. Subgroup analysis was performed to assess the utility of GMS according to TNM, venous invasion and MMR status. Results: There were 30% of patients with GMS 0, 56% with GMS 1 and 14% with GMS 2. Five-year survival for GMS 0, 1 and 2 across the whole cohort were 89%, 74% and 66%, respectively. GMS was associated with age, mode of presentation, TNM, venous invasion and MMR status. On multivariate analysis, GMS was independently associated with CSS (HR 1.35, 95% CI: 1.02-1.79, p= 0.04) and OS (HR 1.23, 95% CI: 1.02-1.48, p= 0.03); this was independent of emergency presentation ( p< 0.01), T-stage ( p= 0.03) and N-stage ( p< 0.001) for CSS. Subgroup analysis found that GMS was able to stratify CSS regardless of node-negative or node-positive disease (both p< 0.01), venous invasion ( p< 0.05), elective presentation ( p< 0.01) and MMR-proficient tumours ( p< 0.001), although it was not able to stratify emergency presentation ( n= 154) or MMR-deficient disease ( n= 102) due to small sample size. Universally, the prognosis for GMS 0 was good, but was poor for GMS 2. The prognosis for GMS 1 varied depending on MMR and nodal status. Conclusions: This study validates the use of the GMS as an independent prognostic pathology-based tool for stratification of colon cancer. It could be readily applied to routine clinical practice and may be used to aid decision making regarding adjuvant treatments in colorectal cancer. It should be further validated in prospective randomised trials.

Background Glasgow Microenvironment Score (GMS) stratifies long-term survival into three groups based on tumour phenotype: peritumoural inflammation (Klintrup–Mäkinen (KM)) and tumour stroma percentage (TSP). However, it is not known if the location of disease recurrence is influenced by the GMS category. Methods Seven hundred and eighty-three TNM I–III colorectal cancers (CRC) were included. GMS (GMS0—high KM; GMS1—low KM, low TSP; GMS2—low KM, high TSP) and cancer-specific survival (CSS), overall survival (OS) and disease recurrence were assessed using Cox regression analysis. Results Of the 783 patients, 221 developed CRC recurrence; 65 developed local recurrence + systemic disease. GMS was independent for CSS (HR 1.50, 95% CI 1.17–1.92, p < 0.001) and OS (HR 1.23, 1.05–1.44, p = 0.01). Higher GMS category was associated with T-stage, N-stage, emergency presentation and venous invasion. GMS was independent for local+systemic recurrence (HR 11.53, 95% CI 1.45–91.85, p = 0.04) and distant-only recurrence (HR 3.01, 95% CI 1.59–5.71, p = 0.002). GMS 2 disease did not appear to have statistically better outcomes with adjuvant chemotherapy in high-risk disease. Conclusion Although confounded by a higher rate of T4 and node-positive disease, GMS 1 and 2 are associated with an increased risk of local and distant recurrence. GMS is an independent poor prognostic indicator for recurrent colorectal cancer. Higher GMS patients may benefit from enhanced postoperative surveillance.

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