Evaluation of a Tumor Microenvironment–Based Prognostic Score in Primary Operable Colorectal Cancer

525 Background: The tumor microenvironment and host inflammatory responses are important determinants of outcome in colorectal cancer (CRC), however their impact on survival in patients receiving adjuvant chemotherapy remains unclear. The aim of the present study was to examine the relationship between these factors, clinicopathological characteristics and survival in patients receiving adjuvant chemotherapy for CRC. Methods: 365 patients who had undergone CRC resection at a single institution between 1997-2008 were included; 88 patients subsequently received chemotherapy. Tumor stroma percentage (TSP) and necrosis were assessed on H and E sections and graded as low or high. Local inflammatory response was assessed using the Klintrup-Mäkinen (K-M), Galon and revised Immunoscore (CD45RO+ /CD8+, and CD3+/CD8+at the invasive margin and tumor center, respectively). Systemic inflammation was assessed using modified Glasgow Prognostic Score (mGPS). Results: Patients receiving adjuvant chemotherapy were younger with a lower ASA (both P<0.05), had advanced T- and N-stage (P<0.05 and P<0.001, respectively), poor tumor differentiation (P<0.05), venous invasion (VI) (P<0.01), margin involvement, infiltrative invasive margin (both P<0.05) and high TSP (P<0.01). In those patients who received adjuvant chemotherapy, on multivariate analysis of clinicopathological factors, VI (HR 3.00, 95%CI 1.22-7.37, P=0.017), TSP (HR 3.00, 95%CI 1.26-7.12, P=0.013), K-M score (HR 5.24, 95%CI 1.21-22.68, P=0.027) and mGPS (HR 3.10 95%CI 1.47-6.55, P=0.003) were independently associated with cancer-specific survival. When the interrelationships between factors independently associated with cancer survival were examined, VI, mGPS, K-M score and TSP were independent of each other (all P>0.05). Conclusions: Compared to standard CRC pathological staging, the present results suggest that assessment of both tumor microenvironment and host inflammatory responses may have superior prognostic value compared with TNM in patients receiving adjuvant chemotherapy.

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Abstract B171: A novel tumor-microenvironment-based prognostic score in patients with primary operable colorectal cancer

10.1158/2326-6074.cricimteatiaacr15-b171 ◽

2016 ◽

Author(s):

James H. Park ◽

Donald C. McMillan ◽

Joanne Edwards ◽

Paul G. Horgan ◽

Campbell S.D. Roxburgh

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Prognostic Score

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The clinical utility of a tumour microenvironment-based histopathological score in patients with primary operable colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.664 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 664-664

Author(s):

James Hugh Park ◽

Donald C. Mcmillan ◽

Paul G. Horgan ◽

Campbell S.D. Roxburgh

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Clinical Utility ◽

Prognostic Score ◽

Tumor Stroma ◽

Stage Ii ◽

Stage Iii ◽

Inflammatory Cell Infiltrate ◽

Cancer Specific Survival ◽

Cumulative Score

664 Background: The tumor microenvironment is increasingly recognized as an important determinant of disease progression and outcome in colorectal cancer (CRC). The aim of the present study was to examine the clinical utility of a novel histopathological prognostic score based on both the tumor inflammatory cell infiltrate and the tumor stroma percentage, termed the Glasgow Microenvironment Score (GMS), in patients with primary operable CRC. Methods: Using routine H&E pathological sections, Klintrup-Mäkinen (KM) grade was graded as strong or weak, and tumor stroma percentage (TSP) was assessed as high (>50%) or low (≤50%) retrospectively in 319 patients undergoing resection of stage II-III CRC. The relationship between a cumulative score based on these factors and cancer-specific survival (CSS) was examined. Results: Median survival of survivors was 122 months with 106 cancer deaths. 63% of patients had stage II CRC. 5-year CSS of patients with stage II and stage III CRC was 82% and 58% respectively (p<0.001). 33% of patients were GMS=0 (strong KM/high or low TSP), 47% were GMS=1 (weak KM/low TSP), and 20% GMS=2 (weak KM/high TSP), with 5-year CSS of 86%, 74%, and 48% (p<0.001) respectively. On multivariate analysis, GMS was associated with CSS (HR 1.77, p<0.001), independent of age, emergency presentation, TNM stage and venous invasion (all p<0.01), and peritoneal involvement (p<0.05). The combination of TNM and GMS stratified 5-year CSS from 92% (stage II, GMS=0) to 35% (stage III, GMS=2) (Table). Conclusions: The present study shows the clinical utility of a novel, routinely available assessment of the tumor microenvironment in patients undergoing curative resection of CRC. [Table: see text]

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A tumor microenvironment-specific gene expression signature predicts chemotherapy resistance in colorectal cancer patients

npj Precision Oncology ◽

10.1038/s41698-021-00142-x ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Xiaoqiang Zhu ◽

Xianglong Tian ◽

Linhua Ji ◽

Xinyu Zhang ◽

Yingying Cao ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Drug Sensitivity ◽

Chemotherapy Resistance ◽

Gene Expression Signature ◽

Prediction Algorithm ◽

Specific Gene ◽

Chemotherapy Response ◽

Rna Seq ◽

Mesenchymal Transition

AbstractStudies have shown that tumor microenvironment (TME) might affect drug sensitivity and the classification of colorectal cancer (CRC). Using TME-specific gene signature to identify CRC subtypes with distinctive clinical relevance has not yet been tested. A total of 18 “bulk” RNA-seq datasets (total n = 2269) and four single-cell RNA-seq datasets were included in this study. We constructed a “Signature associated with FOLFIRI resistant and Microenvironment” (SFM) that could discriminate both TME and drug sensitivity. Further, SFM subtypes were identified using K-means clustering and verified in three independent cohorts. Nearest template prediction algorithm was used to predict drug response. TME estimation was performed by CIBERSORT and microenvironment cell populations-counter (MCP-counter) methods. We identified six SFM subtypes based on SFM signature that discriminated both TME and drug sensitivity. The SFM subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics, specific enrichments of gene signatures, signaling pathways, prognosis, gut microbiome patterns, and tumor lymphocytes infiltration. Among them, SFM-C and -F were immune suppressive. SFM-F had higher stromal fraction with epithelial-to-mesenchymal transition phenotype, while SFM-C was characterized as microsatellite instability phenotype which was responsive to immunotherapy. SFM-D, -E, and -F were sensitive to FOLFIRI and FOLFOX, while SFM-A, -B, and -C were responsive to EGFR inhibitors. Finally, SFM subtypes had strong prognostic value in which SFM-E and -F had worse survival than other subtypes. SFM subtypes enable the stratification of CRC with potential chemotherapy response thereby providing more precise therapeutic options for these patients.

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IL15RA and SMAD3 Genetic Variants Predict Overall Survival in Metastatic Colorectal Cancer Patients Treated with FOLFIRI Therapy: A New Paradigm

Cancers ◽

10.3390/cancers13071705 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1705

Author(s):

Elena De Mattia ◽

Jerry Polesel ◽

Rossana Roncato ◽

Adrien Labriet ◽

Alessia Bignucolo ◽

...

Keyword(s):

Colorectal Cancer ◽

Overall Survival ◽

Metastatic Colorectal Cancer ◽

Cancer Patients ◽

Prognostic Score ◽

Chemotherapeutic Agents ◽

Rank Test ◽

P Value ◽

Genetic Determinants ◽

New Paradigm

A new paradigm in cancer chemotherapy derives from the interaction between chemotherapeutics, including irinotecan and 5-fluorouracil (5-FU), and the immune system. The patient’s immune response can modulate chemotherapy effectiveness, and, on the other hand, chemotherapeutic agents can foster tumor cell immunogenicity. On these grounds, the analysis of the cancer patients’ immunogenetic characteristics and their effect on survival after chemotherapy represent a new frontier. This study aims to identify genetic determinants in the immuno-related pathways predictive of overall survival (OS) after FOLFIRI (irinotecan, 5-FU, leucovorin) therapy. Two independent cohorts comprising a total of 335 patients with metastatic colorectal cancer (mCRC) homogeneously treated with first-line FOLFIRI were included in the study. The prognostic effect of 192 tagging genetic polymorphisms in 34 immune-related genes was evaluated using the bead array technology. The IL15RA rs7910212-C allele was associated with worse OS in both discovery (HR: 1.57, p = 0.0327, Bootstrap p-value = 0.0280) and replication (HR:1.71, p = 0.0411) cohorts. Conversely, SMAD3 rs7179840-C allele was associated with better OS in both discovery (HR:0.65, p = 0.0202, Bootstrap p-value = 0.0203) and replication (HR:0.61, p = 0.0216) cohorts. A genetic prognostic score was generated integrating IL15RA-rs7910212 and SMAD3-rs7179840 markers with inflammation-related prognostic polymorphisms we previously identified in the same study population (i.e., PXR [NR1I2]-rs1054190, VDR-rs7299460). The calculated genetic score successfully discriminated patients with different survival probabilities (p < 0.0001 log-rank test). These findings provide new insight on the prognostic value of genetic determinants, such as IL15RA and SMAD3 markers, and could offer a new decision tool to improve the clinical management of patients with mCRC receiving FOLFIRI.

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The Relationship Between Tumor Budding, Tumor Microenvironment, and Survival in Patients with Primary Operable Colorectal Cancer

Annals of Surgical Oncology ◽

10.1245/s10434-019-07931-6 ◽

2019 ◽

Vol 26 (13) ◽

pp. 4397-4404 ◽

Cited By ~ 10

Author(s):

Hester C. van Wyk ◽

Antonia Roseweir ◽

Peter Alexander ◽

James H. Park ◽

Paul G. Horgan ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Evaluation Method ◽

Venous Invasion ◽

Staging System ◽

Consensus Conference ◽

Tumor Budding ◽

Inflammatory Cell Infiltrate ◽

Cancer Specific Survival ◽

The Relationship

Abstract Background Tumor budding is an independent prognostic factor in colorectal cancer (CRC) and has recently been well-defined by the International Tumour Budding Consensus Conference (ITBCC). Objective The 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. Methods Hematoxylin 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. Results High 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. Conclusions Tumor 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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