Erythropoietin-induced hepatocyte receptor A2 (EphA2) is a receptor tyrosine kinase that plays a key role in the development and progression of a variety of tumors. This article reviews the expression of EphA2 in gastrointestinal (GI) colorectal cancer (CRC) and its regulation of pyroptosis. Pyroptosis is a form of programmed cell death that plays an important role in tumor suppression. Studies have shown that EphA2 regulates pyrodeath through various signaling pathways, affecting the occurrence, development and metastasis of GI CRC. The overexpression of EphA2 is closely related to the aggressiveness and metastasis of GI CRC, and the inhibition of EphA2 can induce pyrodeath and improve the sensitivity of cancer cells to treatment. In addition, EphA2 regulates intercellular communication and the microenvironment through interactions with other cytokines and receptors, further influencing cancer progression. The role of EphA2 in GI CRC and its underlying mechanisms provide us with new perspectives and potential therapeutic targets, which have important implications for future cancer treatment.

Next-generation sequencing (NGS) provides a molecular rationale to inform prognostic stratification and to guide personalized treatment in cancer patients. Here, we determined the prognostic and predictive value of actionable mutated genes in metastatic colorectal cancer (mCRC). Among a total of 294 mCRC tumors examined by targeted NGS, 200 of them derived from patients treated with first-line chemotherapy plus/minus monoclonal antibodies were included in prognostic analyses. Discriminative performance was assessed by time-dependent estimates of the area under the curve (AUC). The most recurrently mutated genes were TP53 (64%), KRAS or NRAS (49%), PIK3CA (15%), SMAD4 (14%), BRAF (13%), and FBXW7 (9.5%). Mutations in FBXW7 correlated with worse OS rates (p = 0.036; HR, 2.24) independently of clinical factors. Concurrent mutations in TP53 and FBXW7 were associated with increased risk of death (p = 0.02; HR, 3.31) as well as double-mutated TP53 and SMAD4 (p = 0.03; HR, 2.91). Analysis of the MSK-IMPACT mCRC cohort (N = 1095 patients) confirmed the same prognostic trend for the previously identified mutated genes. Addition of the mutational status of these genes upon clinical factors resulted in a time-dependent AUC of 87%. Gene set enrichment analysis revealed specific molecular pathways associated with SMAD4 and FBXW7 mutations in TP53-defficient tumors. Conclusively, SMAD4 and FBXW7 mutations in TP53-altered tumors were predictive of a negative prognostic outcome in mCRC patients treated with first-line regimens.

Primary tumor location (PTL) is a major prognostic factor in metastatic colorectal cancer (mCRC) with left side which present better prognosis than right sided. Uncertainty exists regarding comparative effectiveness of irinotecan or oxaliplatin doublet in mCRC in function of PTL.

We conducted a retrospective comparing clinical outcomes from both regimens in function of sidedness. Patients with newly diagnosed mCRC candidates to first-line chemotherapy were selected. Clinical outcomes were assessed and stratified by tumor location (left, right and rectal) and type of treatment.

Overall, 702 patients met the inclusion criteria. Primary colon cancer was right-sided in 248 (35.3%) patients, left-sided in 296 (42.2%) and rectal in 158 (22.5%) patients. Whatever PTL monochemotherapy give poor progression-free survival (PFS) and overall survival (OS). Triplet give better PFS and OS only for rectal cancer. When looking at doublet in first line. Folinic acid, 5FU, and irinotecan (FOLFIRI) give better PFS in rectal cancer [PFS of 21.2 (95% CI: 14.9-NR) versus 12.2 (95% CI: 10.1-13.4) months for the folinic acid, 5FU, and oxaliplatin (FOLFOX) group, P=0.009] and at trend for better PFS in right side tumor [14.9 (95% CI: 8.8-20.8) versus 11.3 (95% CI: 8.4-13.2) months for the FOLFOX group. P=0.0755]. No difference was observed in term of OS.

our results support that either FOLFIRI or FOLFOX regimens give similar efficacy in both left and right metastatic colic cancer. FOLFIRI and FOLFIRINOX regimens might be preferred for metastatic rectal carcinoma.

Biomarkers are important in the study of tumor processes for early detection and precise treatment. The biomarkers that have been previously detected are not useful for clinical application for primary colorectal carcinoma (PCRC). The aim of this study was to explore clinically valuable biomarkers of PCRC based on integrated bioinformatic analysis.

Gene expression data were acquired from the GSE41258 dataset, and the differentially expressed genes were determined between PCRC and normal colorectal samples. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were implemented via Gene Set Enrichment Analysis. A protein-protein interaction (PPI) network was constructed. The significant modules and hub genes were screened and identified in the PPI network.

A total of 202 DEGs were identified, including 58 upregulated and 144 downregulated genes in PCRC samples compared to those in normal colorectal samples. Enrichment analysis demonstrated that the gene sets enriched in PCRC were significantly related to bicarbonate transport, regulation of sodium ion transport, potassium ion homeostasis, regulation of telomere maintenance, and other processes. A total of 10 hub genes was identified by cytoHubba: PYY, CXCL3, CXCL11, CXCL8, CXCL12, CCL20, MMP3, P2RY14, NPY1R, and CXCL1.

The hub genes, such as NPY1R, P2RY14, and CXCL12, and the electrolyte disequilibrium resulting from the differential expression of genes, especially bicarbonate imbalance, may provide novel insights and evidence for the future diagnosis and targeted therapy of PCRC.

Aim: To determine the impact of KRAS mutation status on survival in patients undergoing surgery for colorectal liver metastases (CLM). Patients & methods: Patients with resected CLM and KRAS mutations. Survival was compared between mt-KRAS and wt-KRAS. Results: Of 662 patients, 174 (26.3%) were mt-KRAS and 488 (73.7%) wt-KRAS. mt-KRAS patients had significantly lower recurrence-free survival (HR: 1.42; 95% CI: 1.10-1.84). There were no differences between the groups for sidedness. Poorer survival was associated with mt-KRAS with positive lymph nodes, >1 metastases, tumors >5 cm, synchronous tumors and R1-R2. Conclusion: KRAS mutation status can help predict recurrence-free survival. Primary tumor location was not a prognostic factor after resection. KRAS mutation status can help design a multidisciplinary approach after curative resection of CLM.

Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET).

The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS).

Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2-13.3 months) in the BEV group and 14.8 months (95% CI 9.7-17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively.

Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions.

This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209).

At present, there is uncertainty on the best systemic treatment in first-line setting for RAS wild-type (WT) metastatic colorectal cancer (mCRC) patients. Indeed, several chemotherapy and biologics combinations showed an improvement on survival. We performed a systematic review with a pair-wise and bayesan meta-analysis to rank the best strategy for these patients.

A systematic literature search through March 2017 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicity rate (TR) in RAS WT mCRC patients. Data were extracted from studies and pooled using the random-effect model for pair-wise meta-analyses and bayesan model for network meta-analysis (NMA).

Eight studies with a total of 2518 individuals were included in the meta-analyses. Pooled analyses for subgroups stratified by type of schedule and tumor location demonstrated that anti-EGFR + doublet had the best OS when compared to doublet ± bevacizumab (0.767; 95%CI, 0.695-0.846; P < 0.0001). This benefit is limited to LSCC when compared to a doublet-based schedule and doublet + bevacizumab (HRs, 0.692; 95%CI, 0.596-0.804; P < 0.001; 0.706; 95%CI, 0.584-0.854; P < 0.001; respectively). No significant differences are detected in PFS, whereas the cetuximab-based regimens showed the highest ORR and TR. In NMA our ranking showed the best performance for FOLFOX + panitumumab.

Our study indicates that FOLFOX + panitumumab has the major probability to provide an improvement of survival with a good safety profile in patients with RAS WT mCRC with an added value from selection based on sidedness.