Systemic inflammatory response predicts oncological outcomes in patients undergoing elective surgery for mismatch repair-deficient colorectal cancer.

INTRODUCTION: A variety of inflammatory scoring systems and their prognostic value have been reported in many solid organ cancers. This study aimed to examine the association between the systemic and local inflammatory responses, and oncological outcomes in patients undergoing elective surgery for mismatch repair-deficient (dMMR) phenotype colorectal cancer (CRC). MATERIALS AND METHODS: Consecutive patients undergoing resection for dMMR CRC were identified from a prospectively maintained database and compared with a cohort of patients with proficient mismatch repair system tumours. Systemic inflammatory response was assessed by the modified Glasgow prognostic score (mGPS), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio, lymphocyte-monocyte ratio, C-reactive protein/albumin ratio, prognostic index and prognostic nutritional index. Local inflammatory response was defined by the presence of tumour infiltrating lymphocytes, tumour infiltrating neutrophils, plasma cells or macrophages at the invasive front. The inflammatory infiltrate was assessed using the Klintrup-Mäkinen (KM) score. RESULTS: On univariable analysis, preoperative NLR ≥ 5 (hazard ratio [HR] 2.5; 95% confidence interval [CI] 1.25-5.19; p = 0.007) and mGPS (HR 1.6; 95% CI 1.1-2.6; p = 0.03) predicted worse overall survival, but only NLR was associated with greater recurrence (HR 3.6; 95% CI 1.5-8.8; p = 0.004). Increased local inflammatory response, as measured by KM score (HR 0.31; 95% CI 0.1-0.7; p = 0.009) and the presence of macrophages in the peritumoral infiltrate (HR 0.17; 95% CI 0.07-0.3; p < 0.001), was associated with better outcomes. NLR was the only independent prognostic factor of overall and disease-free survival. CONCLUSION: Systemic inflammatory response predicts oncological outcomes in CRC patients, but only NLR has prognostic value in the dMMR group.

Personalised mapping of tumour development in synchronous colorectal cancer patients.

Synchronous colorectal cancers (syCRCs) are two or more primary tumours identified simultaneously in a patient. Previous studies report high inter-tumour heterogeneity between syCRCs, suggesting independent origin and different treatment response, making their management particularly challenging, with no specific guidelines currently in place. Here, we performed in-depth bioinformatic analyses of genomic and transcriptomic data of a total of eleven syCRCs and one metachronous CRC collected from three patients. We found mixed microsatellite status between and within patients. Overlap of mutations between synchronous tumours was consistently low (<0.5%) and heterogeneity of driver events across syCRCs was high in all patients. Microbial analysis revealed the presence of Fusobacterium nucleatum species in patients with MSI tumours, while quantification of tumour immune infiltration showed varying immune responses between syCRCs. Our results suggest high heterogeneity of syCRCs within patients but find clinically actionable biomarkers that help predict responses to currently available targeted therapies. Our study highlights the importance of personalised genome and transcriptome sequencing of all synchronous lesions to aid therapy decision and improve management of syCRC patients.

Tumor Budding and PDC Grade Are Stage Independent Predictors of Clinical Outcome in Mismatch Repair Deficient Colorectal Cancer.

Mismatch repair deficient (dMMR) colorectal cancer (CRC) despite its association with poor histologic grade often has improved prognosis compared with MMR proficient CRC. Tumor budding and poorly differentiated clusters (PDCs) may predict metastatic potential of colorectal adenocarcinoma (CRC). In addition, their assessment may be more reproducible than the evaluation of other histopathologic parameters. Therefore, we wished to determine their potential as prognostic indicators in a cohort of dMMR CRC patients relative to histologic grade. We investigated the predictive value of conventional WHO grade, budding, PDC grade and other histopathologic parameters on the presence of lymph node metastasis (LNM) and clinical outcome in 238 dMMR CRCs. MMR status was determined by immunohistochemistry for the mismatch repair proteins hMLH1, hMSH2, hMSH6, and hPMS2. Tumor budding and PDCs were highly correlated (r=0.701; P<0.000). Both budding and PDC grade were associated with WHO grade, perineural invasion, lympho-vascular invasion, and extramural vascular invasion, and the presence of LNM in dMMR CRC (P<0.009). Independent predictors of LNM were PDC grade (odds ratio, 4.12; 95% confidence interval [CI], 1.69-10.04; P=0.011) and EMVI (odds ratio, 3.81; 95% CI, 1.56-9.19; P<0.000). Only pTstage (hazard ratio [HR], 4.11; 95% CI, 1.48-11.36; P=0.007) and tumor budding (HR, 2.99; 95% CI, 1.72-5.19; P<0.000) were independently associated with worse disease-free survival (DFS). If tumor budding was excluded from the model, PDC grade became significant for DFS (HR, 2.34; 95% CI, 1.34-4.09; P=0.003). WHO Grade does not independently correlate with clinical outcome in dMMR CRC. PDC grade and extramural vascular invasion are independent predictors of LNM. Tumor budding and pTstage are the best predictors of DFS. If tumor budding cannot be assessed, PDC grade may be used as a prognostic surrogate.