Association of miR-21 and miR-335 to microsatellite instability and prognosis in stage III colorectal cancer

2021 ◽  
pp. 1-10
Author(s):  
Tania Calvo-López ◽  
Mateo Paz-Cabezas ◽  
Patricia Llovet ◽  
Maria Dolores Ibañez ◽  
Javier Sastre ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Disease Free Survival ◽  
High Expression ◽  
Stage Iii ◽  
Positive Trend ◽  
Braf Mutations ◽  
The Poor ◽  
Prognostic Group ◽  
Prognosis Group

BACKGROUND: MicroRNAs (miRs) are frequently altered in colorectal cancer (CRC) and can be used as prognostic factors. OBJECTIVE: To confirm in stage III CRC patients a reported miR signature that was associated to the presence of metastatic disease. To correlate miR expression with microsatellite instability (MSI) and mutations in RAS and BRAF. METHODS: miR-21, miR-135a, miR-206, miR-335 and miR-Let-7a expression was analyzed by RT-qPCR in 150 patients out of the 329 patients used to analyze MSI and RAS and BRAF mutations. Association with disease free survival (DFS) and overall survival (OS) was analyzed. Data was confirmed by a multivariate analysis. RESULTS: MiR-21 high expression (p= 0.034) and miR-335 low expression (p= 0.0061) were significantly associated with MSI-H. A positive trend (p= 0.0624) between miR-135a high expression and RAS mutations was found. Lower miR-21 expression levels are associated with DFS (HR = 2.654, 95% CI: 1.066–6.605, p= 0.036) and a trend with OS (HR = 2.419, 95% CI: 0.749–7.815, p= 0.140). MiR-21 high expression significantly improves DFS of the poor prognosis group (T4 or N2) (p= 0.03). CONCLUSIONS: Association of increased expression of miR-21 and better prognosis in the poor prognostic group may be of interest and could be explored in future prospective clinical trials.

scholarly journals Is microsatellite instability-high really a favorable prognostic factor for advanced colorectal cancer? A meta-analysis

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Bingyan Wang ◽  
Fei Li ◽  
Xin Zhou ◽  
Yanpeng Ma ◽  
Wei Fu
Keyword(s):  
Colorectal Cancer ◽  
Beneficial Effect ◽  
Microsatellite Instability ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Stage Iv ◽  
Stage Iii ◽  
Beneficial Result ◽  
Beneficial Effects

Abstract Background Stage II colorectal cancer with microsatellite instability-high (MSI-H) has been proven to have a better prognosis. However, in advanced stage, this trend remains controversial. This study aimed to explore the prognostic role of MSI-H in stage III and IV colorectal cancer (CRC) through meta-analysis. Methods A comprehensive search was performed in PubMed, Cochrane Central Library, and Embase databases. All randomized clinical trials and non-randomized studies were included based on inclusion and exclusion criteria and on survival after a radical operation with or without chemotherapy. The adjusted log hazard ratios (HRs) were used to estimate the prognostic value between MSI-H and microsatellite-stable CRCs. The random-effects model was used to estimate the pooled effect size. Results Thirty-six studies were included. Randomized controlled trials (RCT) and non-RCT were analyzed separately. For stage III CRCs, pooled HR for overall survival (OS) was 0.96 (95% confidence interval [CI] 0.75–.123) in the RCT subgroup and 0.89 (95% CI 0.62–1.28) in the non-RCT subgroup. For disease-free survival (DFS), the HR for the RCT group was 0.83 (95% CI 0.65–1.07), similar to the non-RCT subgroup (0.83, 95% CI 0.65–1.07). Disease-specific survival (DSS) was also calculated, which had an HR of 1.07 (95% CI 0.68–1.69) in the non-RCT subgroup. All these results showed that MSI-H has no beneficial effects in stage III CRC. For stage IV CRC, the HR for OS in the RCT subgroup was 1.23 (95% CI 0.92–1.64) but only two RCTs were included. For non-RCT study, the combined HR for OS and DFS was 1.10 (95% CI 0.77–1.51) and 0.72 (95% CI 0.53–0.98), respectively, suggesting the beneficial effect for DFS and non-beneficial effect for OS. Conclusion For stage III CRC, MSI-H had no prognostic effect for OS, DFS, and DSS. For stage IV CRC, DFS showed a beneficial result, whereas OS did not; however, the included studies were limited and needed further exploration.

scholarly journals Retrospective analysis of the effect of CAPOX and mFOLFOX6 dose intensity on survival in colorectal patients in the adjuvant setting

2016 ◽  
Vol 23 (3) ◽  
pp. 171 ◽  
Author(s):  
A. Mamo ◽  
J. Easaw ◽  
F. Ibnshamsah ◽  
A. Baig ◽  
Y.S. Rho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dose Reduction ◽  
Real Life ◽  
Disease Free Survival ◽  
Dose Intensity ◽  
Sensory Neuropathy ◽  
Stage Iii ◽  
Cancer Centre ◽  
Peripheral Sensory ◽  
Disease Free

Background Despite lack of a true comparative study, the FOLFOX (5-fluorouracil–leucovorin–oxaliplatin) and CAPOX (capecitabine–oxaliplatin) regimens are believed to be similar in their efficacy and tolerability in the treatment of stage III colorectal cancer. However, that belief has been disputed, because real-life data suggest that the CAPOX regimen is more toxic, leading to more frequent reductions in the delivered dose intensity—thus raising questions about the effect of dose intensity on clinical outcomes.Methods A retrospective data review for two Canadian institutions, the Segal Cancer Centre and the Tom Baker Cancer Centre, considered patients diagnosed with stage III colorectal cancer during 2006–2013. Primary endpoints were dose intensity and toxicity, with a secondary endpoint of disease-free survival.Results The study enrolled 180 eligible patients (80 at the Segal Cancer Centre, 100 at the Tom Baker Cancer Centre). Of those 180 patients, 75 received CAPOX, and 105 received mFOLFOX6. In the CAPOX group, a significant dose reduction was identified for capecitabine compared with 5-fluorouracil in mFOLFOX6 group (p = 0.0014). Similarly, a significant dose reduction was observed for oxaliplatin in mFOLFOX6 compared with oxaliplatin in CAPOX (p = 0.0001). Compared with the patients receiving CAPOX, those receiving mFOLFOX6 were twice as likely to experience a treatment delay of more than 1 cycle-length (p = 0.03855). Toxicity was more frequent in patients receiving mFOLFOX6 (nausea: 30% vs. 18%; diarrhea: 47% vs. 24%; peripheral sensory neuropathy: 32% vs. 3%). At a median follow-up of 40 months, preliminary data showed no difference in disease-free survival (p = 0.598). Pooled data from both institutions were also separately analyzed, and no significant differences were found.Conclusions Our results support the use of CAPOX despite a lack of head-to-head randomized trial data.

scholarly journals Efficacy of aspirin for stage III colorectal cancer: a randomized double-blind placebo-controlled trial (JCOG1503C, EPISODE-III trial)

2019 ◽  
Vol 49 (10) ◽  
pp. 985-990 ◽  
Author(s):  
Kenichi Miyamoto ◽  
Atsuo Takashima ◽  
Junki Mizusawa ◽  
Yuya Sato ◽  
Yasuhiro Shimada ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Adverse Events ◽  
Curative Resection ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Stage Iii ◽  
Double Blind ◽  
Free Survival ◽  
Double Blind Placebo

Abstract Adjuvant chemotherapy is the current standard treatment for stage III colorectal cancer after curative resection. However, the prognosis of stage III colorectal cancer is still poor even after curative resection and adjuvant chemotherapy. Several observational studies suggested that the anti-tumor effect of aspirin. Therefore, we planned a randomized double-blind placebo-controlled phase III trial, which commenced in Japan in March 2018, to confirm the superiority of aspirin over placebo added to adjuvant chemotherapy in terms of disease-free survival (DFS) for stage III colorectal cancer patients after curative resection. A total of 880 patients will be accrued from 20 Japanese institutions within 3 years. The primary endpoint is DFS and the secondary endpoints are overall survival, relapse-free survival, relative dose intensity, adverse events, and serious adverse events. This trial has been registered at Japan Registry of Clinical Trials as jRCTs031180009 (https://jrct.niph.go.jp/detail/589).

scholarly journals Methylation in p14ARF is Frequently Observed in Colorectal Cancer with Low-level Microsatellite Instability

2009 ◽  
Vol 37 (4) ◽  
pp. 1038-1045 ◽  
Author(s):  
K Kominami ◽  
T Nagasaka ◽  
HM Cullings ◽  
N Hoshizima ◽  
H Sasamoto ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Gene Promoters ◽  
Braf Mutations ◽  
Low Level ◽  
Methylguanine Dna Methyltransferase ◽  
High Level

Colorectal cancer (CRC) can be classified as high-level microsatellite instability (MSI-H), low-level MSI (MSI-L) and microsatellite stable (MSS) depending on levels of MSI. MSI-H CRC relies on a distinct molecular pathway due to the mismatch repair (MMR) deficiency and shows methylation in multiple gene promoters. The genetic pathway leading to MSI-L is unknown, although higher levels of promoter methylation are observed in this group compared with MSS CRCs. This study explored how promoter methylation affects MSI phenotype, by analysing the methylation status of eight CRC-related promoters, MSI phenotype and KRAS/BRAF mutations in a series of 234 CRCs. Promoter methylation of p14ARF was significantly related to MSI-L CRC with KRAS mutation. The MSI-H phenotype was related to methylation of MLH1 as expected, while the MSS phenotype was related to methylation of p16INK4a and O6-methylguanine-DNA methyltransferase, although this was not statistically significant. Thus, promoter methylation of p14ARF could be a significant alteration leading to CRC with MSI-L.

Does microsatellite instability predict the effect of adjuvant chemotherapy in stage III colorectal cancer? A meta-analysis

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4121-4121
Author(s):  
G. Des Guetz ◽  
B. Uzzan ◽  
P. Nicolas ◽  
K. Chouahnia ◽  
G. Perret ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Microsatellite Instability ◽  
Colorectal Neoplasm ◽  
Meta Analysis ◽  
Stage Iii ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Electronic Search ◽  
Survival Difference

4121 Background: Microsatellite instability (MSI) is a prognostic factor in colorectal cancer. Whether it predicts the effect of adjuvant chemotherapy (CT) on overall survival (OS) and relapse-free survival (RFS) is controversial. Methods: Studies were identified by an electronic search using online PubMed, with simultaneous keywords (colorectal neoplasm, microsatellite instability, chemotherapy, prognosis). Abstracts from ASCO and AACR proceedings were reviewed. Articles were obtained from cross-checking of references and from a previous prognostic meta-analysis (MA) (Popat, 2005). We used EasyMA software, available online. A Hazard Ratio (HR) < 1 for MSI-high (MSI-H) status compared with microsatellite stable (MSS) meant a better survival. Results: Our MA found 21 studies (4 abstracts). Statistical calculations were performed in 11 studies (5087 patients including 2879 receiving 5FU-based CT; mean age: 63 years; 1489 stage II, 2648 stage III (64%)). MSI-H was found in 644 patients (15% of total), MSS in 3624. Seven studies (2 randomized) assessed 2 cohorts receiving or not adjuvant CT, 4 studies only included patients receiving CT. Global HR OS (9 studies) was 0.79 (95% confidence interval or CI: 0.64–0.98; p = 0.03). Global HR RFS (8 studies) was 0.67 (95% CI: 0.54–0.83; p < 0.001). A MA on stage III patients (4 studies, 719 patients, 137 MSI-H) found a higher survival among MSI-H than MSS patients receiving CT (HR OS: 0.71, 95% CI 0.49–1.03; HR RFS 0.56, 95% CI 0.42–0.75). Interaction between MSI status and CT status was statistically significant on OS and RFS (4 studies). A MA among MSI-H patients (7 studies) found no survival difference between patients under CT or not: HR OS: 0.70 (95% CI 0.44–1.09), HR RFS: 0.96 (95% CI: 0.62–1.49). Conclusions: Adjuvant CT significantly improved survival in MSI-H compared with MSS patients. MSI-H stage III patients receiving CT survived more than MSS. MSI-H status did not predict response to CT compared with no treatment. No significant financial relationships to disclose.

Effect of preoperative hepatic and regional arterial chemotherapy on metachronous liver metastasis after curative colorectal cancer resection: A prospective, multicenter, randomized controlled trial.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 511-511
Author(s):  
Jianmin Xu ◽  
Jianguo Xia ◽  
Yan Gu ◽  
Jianjiang Lin ◽  
Kefeng Ding ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Adjuvant Therapy ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Stage Iii ◽  
Metachronous Liver Metastasis ◽  
Colorectal Cancer Resection ◽  
Multicenter Randomized Controlled Trial ◽  
Metastasis Rate

511 Background: To evaluate the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis for stage II and III colorectal cancer in a multicenter setting. Methods: Patients with clinical stage II or stage III colorectal cancer (CRC) were randomly assigned to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary end point was disease free survival (DFS). Second end points were incidence of metachronous liver metastasis, overall survival (OS) and safety. Results: A total of 688 patients from 5 centers of China were randomly assigned to each arm. Five-year DFS were 75% for PHRAC arm and 61% for control arm (HR 0.60; 95% CI, 0.45 to 0.80; p<0.001). Five-year liver-metastasis rate was 8% and 18% in PHRAC arm and control arm, respectively (HR 0.39; 95% CI, 0.24 to 0.64; p<0.001). Five-year OS was 81% in PHRAC arm and 72% in control arm (HR 0.59; 95% CI, 0.42 to 0.84; p=0.003). There were no significant differences in morbidity or mortality between two arms. The results of eligible patients were barely changed. Subgroup analysis shows differences of DFS, liver-metastasis rate and OS were significant in stage III patients, but not in stage II patients. Conclusions: Additional PHRAC could reduce the incidence of metachronous liver metastasis and improve DFS and OS in patients with stage III CRC, without compromising patient safety. Clinical trial information: NCT00643877.

Long-term followup of bi-shRNAfurin and GMCSF augmented autologous tumor cell immunotherapy treated colorectal cancer patients in phase I and IIa studies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
Minal A. Barve ◽  
Anton M. Melnyk ◽  
Luisa Manning ◽  
Gladice Wallraven ◽  
Martin Birkhofer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cell ◽  
Phase I ◽  
Checkpoint Inhibitors ◽  
Disease Free Survival ◽  
Stage Iii ◽  
Autologous Tumor Cell ◽  
Autologous Tumor ◽  
Disease Free

e15100 Background: Vigil is an immuno-stimulatory autologous tumor cell therapy, which uses patient tumor cells transfected with a plasmid encoding genes to upregulate GM-CSF and down regulate TGFβ 1&2. It is administered monthly by intra-dermal injection. In Phase I and IIa trials patients with over 19 different tumor types were safely treated. Rapid and durable systemic immune activation was demonstrated using an IFNγ ELISPOT assay. Methods: Data are summarized for a group of 9 patients with advanced colorectal cancer followed for up to 3.5 years. Results: Six women and 3 men with Stage III or IV colorectal cancer were treated between March, 2010 and September, 2013. Six patients received Vigil as a monotherapy and 3 in combination with FOLFOX chemotherapy. Results: Demographics and treatment details are displayed below. Two patients with Stage III disease received combination therapy after complete surgical resection, and remain disease free over 3 years from surgery. The patients received 9 and 12 Vigil injections with a brisk and durable ELISPOT reactions. Conclusions: Preliminary results suggest that Vigil can be combined safely with FOLOX chemotherapy and still elicit a systemic immune response. Long term disease free survival has been observed in several patients justifying further exploration of this combination. More detailed molecular characterization and neoantigen identification of patient tumor will be undertaken in future studies. A combination with immune checkpoint inhibitors may also be explored. [Table: see text]

Vascular emboli as a prognostic factor in patients with stage III colorectal cancer undergoing radical surgery.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 570-570
Author(s):  
Haiping Pei ◽  
Qian Pei ◽  
Hong Zhu ◽  
Fengbo Tan
Keyword(s):  
Colorectal Cancer ◽  
Risk Factors ◽  
Lymph Node ◽  
Adjuvant Chemotherapy ◽  
Radical Surgery ◽  
Disease Free Survival ◽  
Stage Iii ◽  
Lymph Node Status ◽  
Node Status ◽  
Therapy Strategy

570 Background: The significance of vascular emboli (VE) in stage III colorectal cancer (CRC), the mechanism of their formation and their therapy strategy remain obscure demanding enhanced research. Methods: Data from 323 consecutive patients (192 non-VE, 131 VE) receiving radical surgery and adjuvant chemotherapy in our institution between Jan. 2009 and Nov. 2014 were retrospectively collected. The follow-up deadline was Feb. 2016. Potential prognostic risk factors were tested using univariate and multivariate survival analyses. mRNAs differentially expressed between VE and non-VE stage III CRC were analyzed using Agilent Gene Expression oligo-microarrays (Version 6.5). Patient-derived xenograft (PDX) nude mouse models were constructed to evaluate the efficacy of adjuvant chemotherapy plus targeted drugs (cetuximab or bevacizumab) on VE and non-VE stage III CRC. Results: VE was significantly associated with gross tumor morphology (p = 0.001), histologic type (p < 0.001), lymph node status (p < 0.001), sub-class of stage III (p =0.001), and serum CA199 level (p = 0.022). VE and lymph node status were independent risk factors for overall survival (OS) (p < 0.001, p = 0.008) and disease-free survival (DFS) (p < 0.001, p = 0.007). The median OS and DFS in VE stage III CRC patients were 38 months and 24 months, respectively. Compared with pericarcinous tissue, 809 genes (396 up-, 413 down-regulated) were differently expressed in no-VE tissue, and 1513 genes (898 up-, 615 down-regulated) in VE tissue. The top ten up-regulated protein-coding genes in VE stage III CRC were ITGBL1 (p<0.001), PROCR (p<0.001), CENPW (p<0.001), ZNF485 (p<0.001), VEGFA (p<0.001), DSG3 (p<0.001), CYP24A1 (p=0.001), COL10A1 (p=0.001), HIST3H2A (p=0.001)and PSAT1 (p=0.002). Conclusions: VE appears to be an independent risk factor for the prognosis of stage III CRC patients treated with radical surgery and adjuvant chemotherapy. Differently regulated genes seem to be involved in the formation and progress of VE. The therapy scheme should be more individualized taking into account the VE status.

Combined microsatellite instability andBRAFgene status as biomarkers for adjuvant chemotherapy in stage III colorectal cancer

2014 ◽  
Vol 110 (8) ◽  
pp. 982-988 ◽  
Author(s):  
Akira Ooki ◽  
Kiwamu Akagi ◽  
Toshimasa Yatsuoka ◽  
Masako Asayama ◽  
Hiroki Hara ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Microsatellite Instability ◽  
Stage Iii

Irinotecan Fluorouracil Plus Leucovorin Is Not Superior to Fluorouracil Plus Leucovorin Alone As Adjuvant Treatment for Stage III Colon Cancer: Results of CALGB 89803

2007 ◽  
Vol 25 (23) ◽  
pp. 3456-3461 ◽  
Author(s):  
Leonard B. Saltz ◽  
Donna Niedzwiecki ◽  
Donna Hollis ◽  
Richard M. Goldberg ◽  
Alexander Hantel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Metastatic Colorectal Cancer ◽  
Adjuvant Treatment ◽  
Disease Free Survival ◽  
Patient Characteristics ◽  
Stage Iii ◽  
Stage Iii Colon Cancer ◽  
First Line Therapy ◽  
Weekly Bolus

Purpose Randomized studies have shown that irinotecan (CPT-11) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil (FU) plus leucovorin (LV) in first-line therapy of metastatic colorectal cancer. When this study was initiated, FU plus LV was standard adjuvant treatment for stage III colon cancer. We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer. Methods A total of 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS). Results Treatment arms were well-balanced for patient characteristics and prognostic variables. There were no differences in either DFS or OS between the two treatment arms. Toxicity, including lethal toxicity, was significantly higher on the CPT-11 plus FU plus LV arm. Conclusion The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.

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