About 20 percent of TNM-stage II colon cancer patients who are treated by surgical resection develop recurrence, and adjuvant chemotherapy in this group is still debated among researchers and ...clinicians. Currently, adverse histopathological and clinical factors are used to select patients for adjuvant chemotherapy following surgery. However, additional biomarkers to classify patients at risk of recurrence are needed. We have conducted a study using fresh frozen tumor tissue from 54 TNM-stage II colon cancer patients and performed microRNA profiling using next-generation sequencing. For the selection of the prognostic microRNAs, a LASSO Cox Regression model was employed. For the validation, we used the publically available TCGA-COAD cohort (n = 122). A prognostic panel of four micorRNAs (hsa-miR-5010-3p, hsa-miR-5100, hsa-miR-656-3p and hsa-miR-671-3p) was identified in the study cohort and validated in the TCGA-COAD cohort. The four-microRNA classifier successfully identified high-risk patients in the study cohort (P < 0.001) and the validation cohort (P = 0.005). Additionally, a number of established risk factors and the four-miRNA classifier were used to construct a nomogram to evaluate risk of recurrence. We identified a four-microRNA classifier in patients with TNM-stage II colon cancer that can be used to discriminate between patients at low- and high risk of recurrence.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite advances in colon cancer research and novel therapies, high risk of recurrence remains a major challenge. This study reports miRNA expression profiling as a biomarker for the prognosis of TNM ...stage II and III colon cancer. Fresh frozen biopsies from the study cohort (N=111) were analyzed for miRNA by RT-qPCR and LASSO regression analysis was used to build a classifier of miRNAs. The prognostic accuracy was tested and the classifier was validated in an independent colon cohort (TCGA-COAD, N=209). The LASSO regression analysis identified a 16-miRNA signature including miR-143-5p, miR-27a-3p, miR-31-5p, miR-181a-5p, miR-30b-5p, miR-30d-5p, miR-146a-5p, miR-23a-3p, miR-150-5p, miR-210-3p, miR-25-3p, miR-196a-5p, miR-148a-3p, miR-222-3p, miR-30c-5p and miR-223-3p. A low 16-miRNA signature was associated with better 5-year disease-free survival (DFS) in the study cohort than a high signature (93 % versus 58 %; p< 0.001). The signature was an independent prognostic factor for better 5-year DFS in multivariate analyses (HR 21.4; 95% CI: 4.21-108.7; p< 0.001). The results in the validation cohort were consistent with the study cohort in univariate (77 % versus 65 %; p= 0.045) and multivariate analyses (HR 2.0; 95% CI: 1.04-3.89; p=0.039). We identified a 16-miRNA signature as a reliable prognostic biomarker for classification of colon cancer stage II and III patients into groups with low and high risk for recurrence.
Better stratification of the risk of relapse will help select the right patients for adjuvant treatment and improve targeted therapies for patients with colon cancer.
To understand why a subset of ...tumors relapse, we compared the proteome of two groups of patients with colon cancer with similar stage, stratified based on the presence or absence of recurrence.
Using tumor biopsies from the primary operation, we identified dissimilarity between recurrent and nonrecurrent mismatch satellite stable colon cancer and found that signaling related to immune activation and inflammation was associated with relapse.
Immune modulation may have an effect on mismatch satellite stable colon cancer. At present, immune therapy is offered primarily to microsatellite instable colon cancer. Hopefully, immune therapy in mismatch satellite stable colon cancer beyond PD-1 and PD-L1 inhibitors can be implemented.
Abstract
Introduction: The risk of recurrence after surgery for colon cancer is not only determined by cancer stage and molecular characteristics, but also by the tumor microenvironment. This study ...aims to assess the prognostic value of CD3+ and CD8+ T lymphocyte infiltration and the relation to mismatch repair (MMR) deficiency.
Material and methods: The study cohort includes 289 patients with surgically treated colon cancer stage I-III (no adjuvant chemotherapy) with clinical- and follow-up data. Immunohistochemistry for CD3+ and CD8+ T lymphocytes and MMR proteins MLH1, MSH2, MSH 6 and PMS2 was performed on Tissue Micro Arrays. (Results were available from 242/258 patients, respectively). Tumors were characterized as MMR deficient/proficient according to expression pattern. Densities of CD3+ and CD8+ lymphocytes were assessed within the tumor margins (tumor infiltrating lymphocytes, TILs) and stroma <100 μm from tumor margin (stromal lymphocytes) and results were combined into semi-quantitative composite scores. In cases of intratumoral heterogeneity, the cylinder with the highest density of TILs was included in the analyses. Results were dichotomized at the median value into low and high density.
Results: MMR deficiency (60 patients, 24.8%) was significantly associated with high density of CD3+ and CD8+ TILs and stromal lymphocytes (p<0.001, p=0.001 Chi square test), but no independent prognostic value of MMR deficiency was demonstrated in our multivariate models. CD3+ and CD8+ TILs and stromal CD3+ and CD8+ lymphocytes were analyzed in separate multivariate cox regression models adjusting for TNM-stage, sex, age, MMR status, histology and tumor differentiation. Low density of CD3+ and CD8+ TILs was an adverse independent prognostic marker of recurrence in colon cancer stages I-III (HR 4.63, CI 1.72-12.49, p=0.002) and the colon cancer stage III subgroup (HR 4.83, CI 1.06-21.97, p=0.042). TNM-stage and differentiation grade were other statistically significant variables in the colon cancer stage I-III model. The stromal lymphocyte score did not reach statistical significance in our multivariate models. Kaplan Meier plots illustrate marked differences in survival between groups of various TIL densities. The low TIL density group had a mean recurrence-free survival of 50.5 months (SE 1.89) versus 63.5 months (SE 1.11) for patients with high TIL density (p<0.001) in colon cancer stage I-III.
Conclusions: Our results support the prognostic impact of tumor infiltrating CD3+ and CD8+ lymphocyte density in colon cancer stage I-III and indicate that a high TIL density is a stronger predictor of survival than MMR deficiency.
Citation Format: Kjersti E. Hestetun, Luka Stanisavljević, Mette P. Myklebust, Olav Dahl. Density of CD3+ and CD8+ tumor-infiltrating T lymphocytes as predictor of survival in colon cancer stage I-III abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3122.
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