scholarly journals Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Anil K. Giri
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Locally Advanced ◽  
Therapy Response ◽  
Predictive Biomarker ◽  
The Cancer Genome Atlas ◽  
Stage Ii ◽  
Epigenetic Mechanism ◽  
Cancer Tissue ◽  
Colon Cancers

Discovery of markers predictive for 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (adjCTX) response in patients with locally advanced stage II and III colon cancer (CC) is necessary for precise identification of potential therapy responders. PEA3 subfamily of ETS transcription factors (ETV1, ETV4, and ETV5) are upregulated in multiple cancers including colon cancers. However, the underlying epigenetic mechanism regulating their overexpression as well as their role in predicting therapy response in colon cancer are largely unexplored. In this study, using gene expression and methylation data from The Cancer Genome Atlas (TCGA) project, we showed that promoter DNA methylation negatively correlates with ETV4 expression (ρ = −0.17, p = 5.6 × 10–3) and positively correlates with ETV5 expression (ρ = 0.22, p = 1.43 × 10–4) in colon cancer tissue. Further, our analysis in 1,482 colon cancer patients from five different cohorts revealed that higher ETV5 expression associates with shorter relapse-free survival (RFS) of adjCTX treated colon cancer patients (Hazard ratio = 2.09–5.43, p = 0.004–0.01). The present study suggests ETV5 expression as a strong predictive biomarker for 5-FU-based adjCTX response in stage II/III CC patients.

scholarly journals ETV5 expression positively correlates with promoter methylation and predicts response for 5-FU-based adjuvant therapy response in proximal colon cancer

2020 ◽  
Author(s):  
Anil K Giri
Keyword(s):  
Colon Cancer ◽  
Cellular Proliferation ◽  
Locally Advanced ◽  
Therapy Response ◽  
Predictive Biomarker ◽  
Therapy Resistance ◽  
The Cancer Genome Atlas ◽  
Stage Ii ◽  
Epigenetic Mechanism ◽  
Cancer Tissue

AbstractDiscovery of markers predictive for 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (adjCTX) response in patients with locally advanced stage II and III colorectal cancer (CRC) is necessary for early identification of potential responders as only 20-65% of CRC patients benefit from the treatment. PEA3 subfamily of ETS transcription factors (ETV1, ETV4, and ETV5) are upregulated in multiple cancers including colon cancers. However, the underlying epigenetic mechanism regulating their overexpression and their role in predicting therapy response in colon cancer is largely unexplored. In this study, using gene expression and methylation data from The Cancer Genome Atlas (TCGA) project, we showed that promoter DNA methylation negatively correlates with ETV4 expression (ρ= -0.17, p=5.6×10−3) and positively correlates with ETV5 expression (ρ= 0.22, p=1.43×10−4) in colon cancer tissue. Further, our analysis in 662 colon cancer patients treated with 5-FU-based-adjCTX revealed that higher ETV5 expression associated with shorter relapse-free survival (RFS) of treated patients with proximal tumors (Hazard ratio = 3.30 - 6.22, p=0.005-0.02). We also observed higher expression of signaling molecules involved in cellular proliferation (e.g. GNB5, DUSP4, FYN) in patients with high ETV5 level, suggesting that the increased cellular proliferation due to overexpression of these genes could drive the therapy resistance. The present study suggests ETV5 expression as a strong predictive biomarker for 5-FU-based adjCTX response in stage II/III CRC patients with proximal tumors.

scholarly journals Framing the potential of public frameshift peptides as immunotherapy targets in colon cancer

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0251630
Author(s):  
Ide T. Spaanderman ◽  
Fleur S. Peters ◽  
Aldo Jongejan ◽  
Egbert J. W. Redeker ◽  
Cornelis J. A. Punt ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Mrna Level ◽  
The Cancer Genome Atlas ◽  
Nonsense Mediated Decay ◽  
Reading Frame ◽  
Colon Cancers ◽  
Cancer Genome Atlas ◽  
Frameshift Peptides ◽  
Rna And Dna

Approximately 15% of Colon Cancers are Microsatellite Instable (MSI). Frameshift Peptides (FPs) formed in MSI Colon Cancer are potential targets for immunotherapeutic strategies. Here we comprehensively characterize the mutational landscape of 71 MSI Colon Cancer patients from the cancer genome atlas (TCGA). We confirm that the mutations in MSI Colon Cancers are frequently frameshift deletions (23% in MSI; 1% in microsatellite stable), We find that these mutations cluster at specific locations in the genome which are mutated in up to 41% of the patients. We filter these for an adequate variant allele frequency, a sufficient mean mRNA level and the formation of a Super Neo Open Reading Frame (SNORF). Finally, we check the influence of Nonsense Mediated Decay (MMD) by comparing RNA and DNA sequencing results. Thereby we identify a set of 20 NMD-escaping Public FPs (PFPs) that cover over 90% of MSI Colon, 62.2% of MSI Endometrial and 58.8% of MSI Stomach cancer patients and 3 out of 4 Lynch patients in the TCGA-COAD. This underlines the potential for PFP directed immunotherapy, both in a therapeutic and a prophylactic setting in multiple types of MSI cancers.

scholarly journals Framing the potential of public frameshift peptides as immunotherapy targets in colon cancer

2020 ◽  
Author(s):  
Ide T. Spaanderman ◽  
Fleur S. Peters ◽  
Aldo Jongejan ◽  
Egbert J.W. Redeker ◽  
Cees J.A. Punt ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Mrna Level ◽  
The Cancer Genome Atlas ◽  
Nonsense Mediated Decay ◽  
Reading Frame ◽  
Colon Cancers ◽  
Cancer Genome Atlas ◽  
Frameshift Peptides ◽  
Rna And Dna

AbstractApproximately 15% of Colon Cancers are Microsatellite Instable (MSI). Frameshift Peptides (FPs) formed in MSI Colon Cancer are potential targets for immunotherapeutic strategies. Here we comprehensively characterize the mutational landscape of 71 MSI Colon Cancer patients from the cancer genome atlas (TCGA-COAD). We confirm that the mutations in MSI Colon Cancers are frequently frameshift deletions (23% in MSI; 1% in microsatellite stable), We find that these mutations cluster at specific locations in the genome which are mutated in up to 41% of the patients. We filter these for an adequate variant allele frequency, a sufficient mean mRNA level and the formation of a Super Neo Open Reading Frame (SNORF). Finally, we check the influence of Nonsense Mediated Decay by comparing RNA and DNA sequencing results. Thereby we identify a set of 20 NMD-escaping Public FPs (PFPs) that cover over 90% of MSI Colon Cancer patients and 3 out of 4 Lynch patients in the TCGA-COAD. This underlines the potential for PFP directed immunotherapy, both in a therapeutic and a prophylactic setting.

Early survival outcomes in stage I-III operated colon cancer patients from a low prevalence, lower-middle income country: The Indian experience.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 857-857
Author(s):  
Rushabh Kiran Kothari ◽  
Vikas S. Ostwal ◽  
Anant Ramaswamy ◽  
Tara Chand Gupta ◽  
Sandeep Kumar Bairwa ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Adjuvant Chemotherapy ◽  
Cancer Patients ◽  
Stage I ◽  
Stage Ii ◽  
Stage Iii ◽  
Survival Outcomes ◽  
Middle Income ◽  
Colon Cancers ◽  
Low Prevalence

857 Background: Data regarding survival and outcomes in operated colon cancer patients from a lower-middle income and low prevalence nation like India is scarce. Methods: Patients who underwent curative resection for non-metastatic, non-rectal colon cancer from January 2013 to December 2016 were retrospectively analyzed from a prospectively maintained database for baseline demographics, disease characteristics, adjuvant chemotherapy, recurrence free survival (RFS) and overall survival (OS). RFS and OS were calculated by Kaplan Meier method. Results: 505 patients underwent resection in the pre-defined time-period. Median age of the patients was 53 years (range: 17 – 87) and 339 patients (67.3%) were male. Patients with stage I, stage II and stage III disease were 43(8.6%), 233(46.1%) and 217(42.9%), respectively, while 12 patients(2.4%) were not adequately staged, though non-metastatic. Right sided colon cancers were more prevalent as compared to left sided (56% vs. 44%) and 41 patients (8%) had signet ring adenocarcinoma on cytomorphology. Median number of nodes retrieved during surgery was 22 nodes(range:1-96 ). Adjuvant chemotherapy was planned for 406 patients (80.4%), with the common regimens used being capecitabine-oxaliplatin, capecitabine , 5-fluorouracil – oxaliplatin and 5-fluorouracil in 280 (55.2%), 80 (16%), 34 (7%) and 6 patients (1.2%), respectively. Planned adjuvant chemotherapy was completed in 334 patients(82.3%; n = 406) with 27 patients (6%) required dose reduction. 35 patients (7%) required permanent cessation of adjuvant treatment due to chemotherapy related toxicity. With a median follow up of 21.8 months (range: 0-56),estimated 3 year RFS for the entire cohort was 86.2% and estimated median OS was 95.2%. Estimated RFS in stage I, Stage II, stage III patients were 90.3%, 89.5% and 78% respectively (p-0.006). Conclusions: Early survival outcomes with Stage I-III colon cancers in a low prevalence country like India appears to be comparable or potentially superior to outcomes published from high prevalence countries. Adjuvant chemotherapy in Stage II and Stage III colon cancers in a real world scenario in India appears to be well tolerated.

Nomogram incorporated the number of adjuvant chemotherapy cycles for predicting the prognosis in stage II-III rectal cancer patients without neoadjuvant therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15163-e15163
Author(s):  
Weiwei Chen ◽  
Wenling Wang
Keyword(s):  
Rectal Cancer ◽  
Colon Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Adjuvant Chemotherapy ◽  
Neoadjuvant Therapy ◽  
Cancer Patients ◽  
Locally Advanced ◽  
Stage Ii

e15163 Background: Current recommendations for adjuvant chemotherapy in rectal cancer are based on the studies in colon cancer. However, it is now known that rectal cancer differs from colon cancer significantly regarding clinical course and biology. No RCTs in the TME era have evaluated the value of postoperative chemotherapy and are unlikely to be performed as neoadjuvant treatment has become a “gold standard” approach. However, we found that not all patients with locally advanced rectal cancer underwent neoadjuvant chemoradiotherapy before TME in real-world clinical practice in China. Whether the number of adjuvant chemotherapy cycles is significantly related to the prognosis of these patients deserves further study. Methods: A total of 246 patients with stage II-III rectal cancer from January 2013 to April 2018 were enrolled. All patients underwent surgery and had not received neoadjuvant therapy. The survival curve was drawn by the Kaplan-Meier method, and the log-rank method was used for statistical analysis. The Cox proportional hazard model was used for multivariate analysis to determine the independent prognostic factors. Then, MFP(Multiple Fractional Polynominal) and stepwiseAIC were used for variable selection. The R software was used to establish the nomogram. The bootstrap method was employed to internal verification. Concordance index(C-index) was applied to evaluate the predictive power of nomogram. Calibration curves were drawn to compare the 3-year overall survival rate predicted by nomogram and that of actual observation. Results: 87.8% of patients received adjuvant chemotherapy including oxaliplatin combined with fluorouracil or capecitabine. Univariate and multivariate analysis showed that the number of adjuvant chemotherapy cycles was independent prognostic factors. Patients who received more than 5 cycles of chemotherapy (HR = 0.09, 95%CI(0.01,0.80)) had a significantly better overall survival than patients with less than 5 cycles (HR = 0.33,95%CI(0.12,0.89)) or no chemotherapy (p < 0.05).Through MFP and the stepwiseAIC screening, a nomogram was established based on CEA, PLR, N, and the number of chemotherapy cycles, and the C-index of the model was 0.86. Conclusions: The number of adjuvant chemotherapy cycles is an independent prognostic factor in stage II-III rectal cancer patients without neoadjuvant therapy. Moreover, nomogram incorporated the number of chemotherapy cycles was accurate and visible.

scholarly journals Genomic profiling of stage II and III colon cancers reveals APC mutations to be associated with survival in stage III colon cancer patients

Oncotarget ◽  
2016 ◽  
Vol 7 (45) ◽  
pp. 73876-73887 ◽  
Author(s):  
Evert van den Broek ◽  
Oscar Krijgsman ◽  
Daoud Sie ◽  
Marianne Tijssen ◽  
Sandra Mongera ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Stage Ii ◽  
Stage Iii ◽  
Genomic Profiling ◽  
Stage Iii Colon Cancer ◽  
Colon Cancers ◽  
Apc Mutations

Prognostic impact of MSI in stage II colon cancers: An additional translational study of the SACURA trial.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15155-e15155 ◽  
Author(s):  
Toshiaki Ishikawa ◽  
Megumi Ishiguro ◽  
Eiji Nakatani ◽  
Hiroyuki Uetake ◽  
Hideki Ueno ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Adjuvant Treatment ◽  
Stage Ii ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Translational Study ◽  
Colon Cancers ◽  
Stage Ii Colon Cancer ◽  
Better Than

e15155 Background: The SACURA trial is a phase III study to evaluate the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone for stage II colon cancer. Superiority of adjuvant treatment with UFT to surgery alone was not demonstrated (ASCO2016 abst#3617). In an additional translational study, we assessed microsatellite instability (MSI) status of cancer tissues and prospectively examined the association of MSI with prognosis in stage II colon cancer patients. Methods: Formalin-fixed, paraffin-embedded samples were prospectively collected from 1026 patients enrolled in the SACURA trial. MSI was evaluated using 5 markers; BAT25, BAT26, D2S123, D5S346, and D17S250. MSI-high (MSI-H) was defined as the presence of instability in more than 20% of the markers. Median follow-up time was 69.6 months. Results: MSI-H, MSI-low (MSI-L) and microsatellite-stable (MSS) was observed in 74 (7.2%), 24 (2.3%), and 928 (90.5%) samples, respectively. Patients with MSI-H was significantly frequent in female, right-sided colon cancers, > 5cm tumors, poor histological type, and elevated CEA. Relapse rate for MSI-H patients (4.1%) was significantly lower than that for MSI-L/MSS cancer (13.4%, p = 0.02). Relapse free survival (RFS) in MSI-H patients was significantly better than in MSI-L/MSS patients (hazard ratio: 0.40, 95%CI: 0.17-0.98, p = 0.045), as well as adjusted results by prognostic factors. The 5-year RFS rates in MSI-H and MSI-L/MSS patients were 92.9% and 84.1%, respectively. Although there was no statistical significance, the 5-year RFS rate in MSI-H patients was tended to be better than that in MSI-L/MSS patients in the surgery alone group (94.3% vs. 83.1%, p = 0.086) as well as in the UFT group (91.7% vs. 85.1%, p = 0.233). Conclusions: MSI was an independent prognostic factor in stage II colon cancers. By considering their favorable RFS, adjuvant chemotherapy for stage II colon cancer patients with MSI-H may be unnecessary. Clinical trial information: NCT00392899.

scholarly journals Differences in effectiveness and use of laparoscopic surgery in locally advanced colon cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. Schootman ◽  
Matthew Mutch ◽  
T. Loux ◽  
J. M. Eberth ◽  
N. O. Davidson
Keyword(s):  
Colon Cancer ◽  
Length Of Stay ◽  
Cancer Patients ◽  
Postoperative Ileus ◽  
Locally Advanced ◽  
Composite Outcome ◽  
Improvement Program ◽  
Advanced Colon Cancer ◽  
Outcome Score ◽  
T4 Colon Cancer

AbstractPatients with locally advanced colon cancer have worse outcomes. Guidelines of various organizations are conflicting about the use of laparoscopic colectomy (LC) in locally advanced colon cancer. We determined whether patient outcomes of LC and open colectomy (OC) for locally advanced (T4) colon cancer are comparable in all colon cancer patients, T4a versus T4b patients, obese versus non-obese patients, and tumors located in the ascending, descending, and transverse colon. We used data from the 2013–2015 American College of Surgeons’ National Surgical Quality Improvement Program. Patients were diagnosed with nonmetastatic pT4 colon cancer, with or without obstruction, and underwent LC (n = 563) or OC (n = 807). We used a composite outcome score (mortality, readmission, re-operation, wound infection, bleeding transfusion, and prolonged postoperative ileus); length of stay; and length of operation. Patients undergoing LC exhibited a composite outcome score that was 9.5% lower (95% CI − 15.4; − 3.5) versus those undergoing OC. LC patients experienced a 11.3% reduction in postoperative ileus (95% CI − 16.0; − 6.5) and an average of 2 days shorter length of stay (95% CI − 2.9; − 1.0). Patients undergoing LC were in the operating room an average of 13.5 min longer (95% CI 1.5; 25.6). We found no evidence for treatment heterogeneity across subgroups (p > 0.05). Patients with locally advanced colon cancer who receive LC had better overall outcomes and shorter lengths of stay compared with OC patients. LC was equally effective in obese/nonobese patients, in T4a/T4b patients, and regardless of the location of the tumor.

scholarly journals Association of chemotherapy with survival in stage II colon cancer patients who received radical surgery: a retrospective cohort study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhihao Lv ◽  
Yuqi Liang ◽  
Huaxi Liu ◽  
Delong Mo
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Prediction Models ◽  
Radical Surgery ◽  
Survival Rates ◽  
Stage Ii ◽  
Survival Prediction ◽  
Stage Ii Colon Cancer ◽  
Overall Survival Rates

Abstract Background It remains controversial whether patients with Stage II colon cancer would benefit from chemotherapy after radical surgery. This study aims to assess the real effectiveness of chemotherapy in patients with stage II colon cancer undergoing radical surgery and to construct survival prediction models to predict the survival benefits of chemotherapy. Methods Data for stage II colon cancer patients with radical surgery were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (1:1) was performed according to receive or not receive chemotherapy. Competitive risk regression models were used to assess colon cancer cause-specific death (CSD) and non-colon cancer cause-specific death (NCSD). Survival prediction nomograms were constructed to predict overall survival (OS) and colon cancer cause-specific survival (CSS). The predictive abilities of the constructed models were evaluated by the concordance indexes (C-indexes) and calibration curves. Results A total of 25,110 patients were identified, 21.7% received chemotherapy, and 78.3% were without chemotherapy. A total of 10,916 patients were extracted after propensity score matching. The estimated 3-year overall survival rates of chemotherapy were 0.7% higher than non- chemotherapy. The estimated 5-year and 10-year overall survival rates of non-chemotherapy were 1.3 and 2.1% higher than chemotherapy, respectively. Survival prediction models showed good discrimination (the C-indexes between 0.582 and 0.757) and excellent calibration. Conclusions Chemotherapy improves the short-term (43 months) survival benefit of stage II colon cancer patients who received radical surgery. Survival prediction models can be used to predict OS and CSS of patients receiving chemotherapy as well as OS and CSS of patients not receiving chemotherapy and to make individualized treatment recommendations for stage II colon cancer patients who received radical surgery.

scholarly journals Comparison between oxaliplatin therapy and capecitabine monotherapy for high-risk stage II–III elderly colon cancer patients

2021 ◽  
Author(s):  
Jueun Park ◽  
HyungJoo Baik ◽  
Sang Hyun Kang ◽  
Sang Hyuk Seo ◽  
Kwang Hee Kim ◽  
...  
Keyword(s):  
Colon Cancer ◽  
High Risk ◽  
Cancer Patients ◽  
Stage Ii
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