The objective of this work was to establish prognostic models in stage III colon cancer (CC) on the basis of transcriptomic signatures of the tumor microenvironment (TME) and cell cycle from the PETACC-8 (training set) and IDEA-France (validation set) trials.

3'RNA sequencing was performed in 1,733 patients from the PETACC-8 trial and 1,248 patients from the IDEA-France trial. Four transcriptomic signatures were analyzed: T-cell and macrophage M2 signatures, the expression of CXCL13, and a score on the basis of the Oncotype DX CC Recurrence Score using the same formula from the stromal score and the cell cycle score. The Immune Proliferative Stromal (IPS) score was defined as the number of dichotomized signatures that fall under the category of a dismal prognosis (from 0 to 4). Time to recurrence (TTR) was defined as the time from the date of random assignment to local and/or metastatic relapse and/or death because of CC, whichever occurs first.

High Oncotype-like and M2 scores and low CXCL13 expression and T-cell score were associated with a shorter TTR. A multivariable model including these signatures and all known prognostic factors applied to the IDEA-France cohort by obtaining a value of this model for each patient showed TTR significantly different depending on the quartile of this value and a 3-year rate of patients without recurrence ranging from 56% for the lowest quartile to 89% for the highest quartile (P < .0001). The IPS score was significantly associated with TTR in multivariable analysis.

Using transcriptomic data of patients with stage III CC from two large-scale adjuvant trials, a prognostic model on the basis of signatures of the TME and the cell cycle provides important information in addition to known prognostic factors for patient stratification on risk of recurrence.

We recently proposed Stroma AReactive Invasion Front Areas (SARIFA), defined as direct tumor-adipocyte interaction at the invasion front, as a novel hematoxylin-and-eosin (H&E)-based histopathological prognostic biomarker in various cancers. Given that microsatellite instability, BRAF, and RAS mutation status are routinely tested for colorectal cancers (CRC), studying SARIFA's additional prognostic value within these molecular subgroups is crucial. In addition, exploring whether the survival benefit from adjuvant therapy differs according to SARIFA-status may enhance patient treatment and outcome. SARIFA-status, BRAF, RAS, and DNA mismatch repair (MMR) status were available for 1726 CRC patients from the prospective Netherlands Cohort Study (NLCS, 1986-2006). In this study, we investigated (1) the relationship between SARIFA-status and CRC molecular characteristics, (2) the prognostic value of SARIFA-status within these molecular subgroups, and (3) whether SARIFA-status was associated with survival benefit from adjuvant therapy. SARIFA-positive CRCs more frequently showed a BRAF mutation compared to SARIFA-negative CRCs (P<0.001). BRAF-mutant/MMR-proficient CRCs were enriched in SARIFA-positive cases. SARIFA-positivity was associated with poor CRC-specific (HRrange: 1.47 to 1.78) and overall survival (HRrange: 1.35 to 1.70) within all molecular subgroups except MMR-deficient CRCs. Patients with SARIFA-positive CRC showed a CRC-specific survival benefit from adjuvant therapy compared to surgery alone (HRCRC-specific: 0.59; 95% CI: 0.44-0.79), while no CRC-specific survival benefit was observed for patients with SARIFA-negative CRC. To conclude, our results indicate that SARIFA-positivity is more common in the aggressive subset of BRAF-mutant and BRAF-mutant/MMR-proficient CRCs. Moreover, SARIFA-positivity provides additional prognostic value within molecular subgroups based on BRAF, RAS, and MMR status, suggesting that it may enhance prognostic stratification of CRC patients.

The prognostic significance of KRAS and BRAF mutations is well-established in metastatic colorectal cancer (CRC) but remains uncertain in early-stage tumors. This study retrospectively analyzed 47 stage II/III CRC patients undergoing curative surgery to assess the association of mutations in KRAS, NRAS, BRAF, and PIK3CA with overall survival (OS) and disease-free survival (DFS). Additionally, a meta-analysis was conducted to validate the prognostic relevance of these gene mutations. We included post hoc analyses of phase III randomized controlled trials (RCTs) in stage II/III patients receiving adjuvant therapy after curative resection in the meta-analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated using a random-effect model in the overall population, stratified subgroups adjusted for microsatellite instability (MSI) status, and within MSI-high (MSI-H) and microsatellite-stable (MSS) populations. In the retrospective cohort, mutations in KRAS, NRAS, BRAF, and PIK3CA were identified in 29.8%, 4.3%, 8.5%, and 14.9% of patients, respectively. No significant association between individual genes and survival was observed. However, in MSS patients, concurrent mutations were significantly associated with shorter OS and DFS (log-rank test, P < 0.05). The meta-analysis incorporated 13 eligible studies, including 15,034 patients. Pooled analyses revealed that KRAS and BRAF mutations were significantly linked to poor OS (KRAS: HR = 1.25, 95%CI: 1.06-1.47, P = 0.008; BRAF: HR = 1.43, 95%CI: 1.26-1.63, P < 0.001) and DFS (KRAS: HR = 1.36, 95%CI: 1.21-1.53, P < 0.001; BRAF: HR = 1.21, 95%CI: 1.02-1.44, P = 0.032). The prognostic impact of BRAF mutation increased with MSI adjustment compared those without MSI adjustment. In MSS tumors, KRAS-mutant patients demonstrated significantly shorter DFS (HR = 1.63, 95%CI: 1.25-2.13, P < 0.001), while BRAF-mutant patients exhibited reduced OS (HR = 1.53, 95%CI: 1.24-1.89, P < 0.001) and DFS (HR = 1.72, 95%CI: 1.20-2.46, P = 0.003) compared to wildtype patients. Conversely, no significant survival differences were found between mutant and wildtype patients in the MSI-H population. Although PIK3CA mutation was nominally associated with OS (HR = 0.86, 95%CI: 0.75-1.00, P = 0.046), the pooled result lacked robustness. In conclusion, KRAS and BRAF mutations had a negative prognostic impact on MSS stage II/III CRC patients receiving adjuvant therapy following curative resection. These patients may benefit from more effective adjuvant treatment strategies.

BRAF mutations are critical drivers in cancers such as melanoma, colorectal cancer, and non-small-cell lung cancer. The most common mutation, BRAF V600E, is a key therapeutic target. Targeted treatments with BRAF and MEK inhibitors have significantly improved progression-free and overall survival in melanoma patients. However, in cancers like metastatic colorectal cancer, BRAF mutations are associated with poor outcomes due to aggressive disease behavior and resistance to conventional chemotherapy. Despite progress, resistance to BRAF/MEK inhibitors remains a major challenge, often driven by secondary mutations in the mitogen-activated protein kinase (MAPK) pathway, activation of alternative pathways such as phosphoinositide 3-kinases (PI3Ks)/protein kinase B (AKT), or changes in the tumor microenvironment. These challenges have motivated ongoing research into combining BRAF inhibitors with immunotherapies to enhance and prolong treatment effectiveness. Future research must also account for the role of the cancer's tissue of origin, as the biological context significantly influences response to targeted therapies, highlighting the need for a deeper understanding of tumor biology, micro-environment, and genetics.

Precision medicine has brought revolutionary changes to the diagnosis and treatment of cancer patients, and is currently a hot and challenging research topic. Currently, the treatment regimens for most colorectal cancer (CRC) patients are mainly determined by several biomakers, including Microsatellite Instability (MSI), RAS, and BRAF. However, the roles of promising biomarkers such as HER-2, consensus molecular subtypes (CMS), and circulating tumor DNA (ctDNA) in CRC are not yet fully clear. Therefore, it is urgent to explore the potential of these emerging biomarkers in the diagnosis and treatment of CRC patients. In this paper, we discuss recent advances in CRC biomarkers, especially clinical data, and focus on the roles of biomarkers in prognosis, prediction, treatment strategies, and the intrinsic connections with clinical pathological features, hoping to promote better precision medicine for colorectal cancer.

Tumor mutations and the composition of the tumor microenvironment have prognostic and therapeutic significance in colorectal cancer (CRC). However, immunotherapy remains a challenge for patients with proficient mismatch repair (pMMR) CRC. In this paper, the association between tumor-infiltrating lymphocytes (TILs) and tumor mutations on survival outcomes in patients with localized pMMR CRC was examined.

A systematic review of the literature and a meta-analysis were conducted in accordance with the PRISMA guidelines. The literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. The outcomes of interest were overall survival, disease-free survival, and cancer-specific survival. The risk of bias was assessed through the Newcastle-Ottawa Scale and the quality of the cumulative evidence was evaluated through the modified GRADE approach.

In total, 8498 articles were screened for eligibility and 44 articles were included in the meta-analysis with 33,704 patients in total. Patients with high infiltration of any TILs showed significantly improved overall survival (HR = 0.57, 95 % CI: 0.49-0.67, I2: 0 %), especially for the subgroup of CD3 + (HR = 0.52, 95 % CI: 0.38-0.71, I2: 0 %) and CD8 + (HR = 0.60, 95 % CI: 0.37-0.99, I2: 10 %) TILs. Patients with BRAF mutation (HR = 2.68, 95 % CI: 1.47-4.89, I2: 83 %) and KRAS mutation (HR = 1.25, 95 % CI: 1.18-1.33, I2: 0 %) showed decreased overall survival.

High infiltration of TILs, especially CD3 + and CD8 + , was associated with significantly improved survival, while BRAF and KRAS mutations were correlated with worse survival outcomes for patients with non-metastatic pMMR CRC.

To compare early recurrence patterns, safety, survival and investigate the clinical risk factors of early recurrence (ER) after liver resection or thermal ablation (TA) for patients with colorectal liver metastases (CRLM) with number ≤ 5 and largest diameter ≤ 3 cm.

This retrospective study included patients with CRLM who underwent liver resection or TA between January 2016 and December 2021 at two hospitals in China. The Kaplan-Meier method and log-rank test were used to assess recurrence-free survival (RFS) and overall survival (OS). Risk factors for ER were analysed using univariate and multivariate Cox regression analyses.

303 patients with 632 liver metastases were enrolled. The most common early recurrence pattern was intrahepatic recurrence (IHR) in resection group and TA group. There was no significant difference in 6-month RFS rate (65.81% vs 66.23%) and median OS (P = 0.10) between two groups. Patients without ER had better OS than those with ER (P < 0.05). The incidence of serious complications (P = 0.013), length of hospitalization (P < 0.01), and albumin-bilirubin (ALBI) score (P = 0.038) in TA group were significantly better than resection group. The diameter of liver metastases (HR: 4.89, 95% CI: 1.16-20.60; P = 0.031) and clinical risk score (CRS) (HR: 1.86, 95% CI: 1.06-3.25; P = 0.029) were independent risk factors for ER.

For CRLM with largest diameter ≤ 3 cm and number ≤ 5, the efficacy of receiving resection or TA is comparable, and the safety of TA is better. TA may be considered as the first-line local treatment option for patients with CRLM.

Background/Objective: The prognostic value of specific hot-spot mutations within KRAS, NRAS, and BRAF genes in metastatic colorectal cancer (mCRC) genes remains debatable. This study explores whether certain KRAS, NRAS, and BRAF mutations are associated with the risk of all-cause mortality in mCRC. Methods: We retrospectively analyzed records of 494 patients with mCRC treated at the University of Texas Medical Branch between January 2016 and July 2023. Data on genetic mutations and clinicopathological features were collected for this analysis. We estimated survival probabilities and conducted multivariable Cox proportional hazards regression to evaluate the impact of specific mutations on all-cause mortality risk. Results:KRAS c.35G>T (p.Gly12Val) and c.34G>T (p.Gly12Cys) mutations were significantly associated with an increased risk of all-cause mortality in the overall mCRC population and the treated mCRC subgroup. KRAS c.38G>A (p.Gly13Asp) was significantly associated with an increased risk of all-cause mortality in the treated mCRC subgroup but BRAF c.1799T>A (p.Val600Glu) was significantly associated with an increased risk of all-cause mortality in the overall mCRC population. No significant association was observed between NRAS mutations and mortality risk in mCRC, possibly due to their lower frequency or different biological effects compared to KRAS and BRAF mutations. Conclusions: These findings suggest that specific KRAS [c.35G>T (p.Gly12Val), c.34G>T (p.Gly12Cys), and c.38G>A (p.Gly13Asp)] and BRAF c.1799T>A (p.Val600Glu) mutations may have prognostic value in mCRC. However, given the single-center study design and lack of direct therapeutic implications, larger multicenter studies are needed to substantiate these results and better define the clinical relevance of these mutations.

Mutations in KRAS and BRAF genes are prevalent in colorectal cancer (CRC), which strikingly promote tumorigenesis and lead to poor response to a variety of treatments including immunotherapy by activating the MAPK/ERK pathway. Thus, there is an urgent need to discover effective therapeutic targets and strategies.

CRISPR-Cas9 lentiviral knockout library was used to screen the suppressors of anti-PD1 immunotherapy. Bioinformatic analysis was used to analyze the correlation between PHF8 expression and immune indicators in CRC. In vitro and in vivo experiments were utilized to determine the effects of PHF8 on the immune indexes and malignant phenotypes of CRC cells. qRT-PCR, western blotting, immunohistochemical (IHC) staining, and chromatin immunoprecipitation (ChIP)-qPCR assays were used to determine the regulatory effects of PHF8 on PD-L1, KRAS, BRAF, and c-Myc and the regulatory effect c-Myc/miR-22-3p signaling axis on PHF8 expression in CRC cells.

This study identified histone lysine demethylase PHF8 as a negative regulator for the efficacy of anti-PD1 therapy and found that it was highly expressed in CRCs and strongly associated with poor patient survival. Functional studies showed that PHF8 played an oncogenic role in KRAS- or BRAF-mutant CRC cells, but not in wild-type ones. Mechanistically, PHF8 up-regulated the expression of PD-L1, KRAS, BRAF, and c-Myc by increasing the levels of transcriptional activation marks H3K4me3 and H3K27ac and decreasing the levels of transcriptional repression mark H3K9me2 within their promoter regions, promoting immune escape and tumor progression. Besides, our data also demonstrated that PHF8 was up-regulated by the c-Myc/miR-22-3p signaling axis to form a positive feedback loop. Targeting PHF8 substantially improved the efficacy of anti-PD1 therapy and inhibited the malignant phenotypes of KRAS- or BRAF-mutant CRC cells.

Our data demonstrate that PHF8 may be an effective therapeutic target for KRAS- or BRAF-mutant CRCs.

Colorectal cancer is a leading cause of cancer-related morbidity and mortality worldwide, with more than 1.9 million new cases reported in 2020, and is associated with major survival challenges, particularly in patients with locally advanced colon cancer (LACC). LACC often involves T4 invasion or extensive nodal involvement and requires a multidisciplinary approach for management. Radical surgery followed by adjuvant chemotherapy remains the primary treatment strategy for LACC. However, achieving complete tumor resection (R0) is challenging because locally advanced colon tumors typically infiltrate adjacent organs or nodes. Advancements in LACC treatment have involved neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiotherapy (NACRT), and neoadjuvant immunotherapy (NAIT). Studies such as FOxTROT and PRODIGE 22 have demonstrated that NACT, particularly with FOLFOX or CAPOX, can lead to major tumor downstaging, improved survival rates, and increased R0 resection rates. Predictive biomarkers, such as mismatch repair (MMR) status and T stage, are crucial in identifying candidates who may benefit from NACT. NACRT has demonstrated promise in enhancing tumor regression, particularly in patients with rectal cancer, underscoring its potential for use with LACC. NAIT, particularly for deficient MMR tumors, has emerged as a novel approach, with studies such as NICHE-2 and NICHE-3 reporting excellent pathologic responses and pathologic complete responses. Integrating these therapies can enhance the surgical and survival outcomes of patients with LACC, highlighting the importance of personalized treatment strategies based on tumor characteristics and response to neoadjuvant interventions. This review discusses the evolving landscape of LACC management, focusing on optimizing treatment approaches for improved patient outcomes.

Understanding the mutational landscape of colon cancer (CC) is crucial for targeted therapy development. Microsatellite instability (MSI-H), rat sarcoma (RAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations (MT) are pivotal markers. Further investigation into clinicopathological features of RAS and BRAF MT in microsatellite stable (MSS) and MSI-H tumors is warranted.

A retrospective analysis of 4883 localized CC patients (pts.) was conducted. Molecular profiling assessed MSI, KRAS, NRAS, and BRAF MT. Correlation with clinicopathological data employed ANOVA and Chi-square tests. Disease-free survival (DFS) and overall survival (OS) were analyzed adjusting for age, gender, sidedness, UICC stage, Charlson Comorbidity Index (CCI). A Cox model incorporated all variables as covariates.

This analysis included 4883 pts. (2302 female/2572 male, 3865 (79.2%) MSS, 1018 (20.8%) MSI-H). MSS pts. had more All-Wild Type (WT), KRAS MT, and NRAS MT tumors vs. MSI-H pts. (42.1% vs. 21.1%; 39.8% vs. 15.4%; 3.6% vs. 0.7%; p<0.001 for each). BRAF MT tumors (95.5% BRAF V600E MT) were more prevalent in MSI-H individuals (62.8% vs. 8.1%, p<0.001). KRAS and BRAF MT tumors were more frequently right-sided, while BRAF MT tumors were associated with female gender, advanced disease stage, lymph node positivity, and poorer differentiation in the MSS subset (p<0.001). Common KRAS mutations included p.G12D (30.44%) and p.G12V (21.3%) in MSS and p.G13D (28.9%) and p.G12D (22.37%) in MSI-H. NRAS MT tumors were dominated by codon 61 mutations (51.7%). Survival analysis revealed worst prognosis in BRAF MT MSS tumors (DFS: HR 1.74 (95% CI 1.15-2.62, p=0.009; OS: HR 1.61 (95% CI 0.99-2.6), p=0.055). The 3-years DFS and 5-years OS rates were lowest in this subset (61.6% and 57.7% respectively).

These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.

The authors aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients.

The authors performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival after long-term follow-up was performed in patients analyzed on an intention-to-treat basis.

From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection ( n =341) or curative surgical resection alone ( n =344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients [3-year disease-free survival (DFS): 91.1 vs. 90.0%, P =0.328; 3-year OS: 94.4 vs. 95.9%, P =0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P =0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P =0.032). Meanwhile, patients with colon cancer and abnormal pretreatment carcinoembryonic antigen (CEA) levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P =0.029 and OS: HR=0.476, 95% CI: 0.223-1.017, P =0.049).

Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

Semaphorins (SEMAs), ADAM, and ADAMTS family members are implicated in various cancer progression events within the tumor microenvironment across different cancers. In this study, we aimed to evaluate the expression of SEMA7A, SEMA4D, ADAM8, and ADAMTS10 in colorectal cancer (CRC) in relation to the mutational landscape of KRAS, NRAS, BRAF, PIK3CA, and AKT genes, microsatellite instability (MSI) status, and clinicopathological features. We also examined the associations between the expression of these proteins and selected cytokines, chemokines, and growth factors, assessed using a multiplex assay. Protein concentrations were quantified using ELISA in CRC tumors and tumor-free surgical margin tissue homogenates. Gene mutations were evaluated via RT-PCR, and MSI status was determined using immunohistochemistry (IHC). GSEA and statistical analyses were performed using R Studio. We observed a significantly elevated expression of SEMA7A in BRAF-mutant CRC tumors and an overexpression of ADAM8 in KRAS 12/13-mutant tumors. The expression of ADAMTS10 was decreased in PIK3CA-mutant CRC tumors. No significant differences in the expression of the examined proteins were observed based on MSI status. The SEMA7A and SEMA4D expressions were correlated with the expression of numerous cytokines associated with various immune processes. The potential immunomodulatory functions of these molecules and their suitability as therapeutic targets require further investigation.

Colorectal cancer is a heterogeneous disease which can be divided into proximal colon cancer, distal colon cancer and rectal cancer according to the anatomical location of the tumor. Each anatomical location of colorectal cancer exhibits distinct characteristics in terms of incidence, clinical manifestations, molecular phenotypes, treatment, and prognosis. Notably, proximal colon cancer differs significantly from cancers of other anatomical subsites. An increasing number of studies have highlighted the presence of unique tumor biological characteristics in proximal colon cancer. Gaining a deeper understanding of these characteristics will facilitate accurate diagnosis and treatment approaches.

T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables.

We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression.

CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS.

In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination.

This research received no external funding.

Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value.

The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists.

Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively.

In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.

As one of the most prevalent digestive system tumours, colorectal cancer (CRC) poses a significant threat to global human health. With the emergence of immunotherapy and target therapy, the prognosis for the majority of CRC patients has notably improved. However, the subset of patients with BRAF exon 15 p.V600E mutation (BRAFV600E) has not experienced remarkable benefits from these therapeutic advancements. Hence, researchers have undertaken foundational investigations into the molecular pathology of this specific subtype and clinical effectiveness of diverse therapeutic drug combinations. This review comprehensively summarised the distinctive molecular features and recent clinical research advancements in BRAF-mutant CRC. To explore potential therapeutic targets, this article conducted a systematic review of ongoing clinical trials involving patients with BRAFV600E-mutant CRC.

The Dickkopf family proteins (DKKs) are strong Wnt signaling antagonists that play a significant role in colorectal cancer (CRC) development and progression. Recent work has shown that DKKs, mainly DKK1, are associated with the induction of chemoresistance in CRC and that DKK1 expression in cancer cells correlates with that of protein arginine N-methyltransferase 5 (PRMT5). This points to the presence of a regulatory loop between DKK1 and PRMT5. Herein, we addressed the question of whether PRMT5 contributes to DKK1 expression in CRC and hence CRC chemoresistance. Both in silico and in vitro approaches were used to explore the relationship between PRMT5 and different DKK members. Our data demonstrated that DKK1 expression is significantly upregulated in CRC clinical samples, KRAS-mutated CRC in particular and that the levels of DKK1 positively correlate with PRMT5 activation. Chromatin immunoprecipitation (ChIP) data indicated a possible epigenetic role of PRMT5 in regulating DKK1, possibly through the symmetric dimethylation of H3R8. Knockdown of DKK1 or treatment with the PRMT5 inhibitor CMP5 in combination with doxorubicin yielded a synergistic anti-tumor effect in KRAS mutant, but not KRAS wild-type, CRC cells. These findings suggest that PRMT5 regulates DKK1 expression in CRC and that inhibition of PRMT5 modulates DKK1 expression in such a way that reduces CRC cell growth.

In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework.

Serine/threonine-protein kinase B-raf (BRAF) mutations are found in 8-15% of colorectal cancer patients and identify a subset of tumors with poor outcome in the metastatic setting. We have previously reported that BRAF-mutant human cells display a high rate of protein production, causing proteotoxic stress, and are selectively sensitive to the proteasome inhibitors bortezomib and carfilzomib. In this work, we tested whether carfilzomib could restrain the growth of BRAF-mutant colorectal tumors not only by targeting cancer cells directly, but also by promoting an immune-mediated antitumor response. In human and mouse colorectal cancer cells, carfilzomib triggered robust endoplasmic reticulum stress and autophagy, followed by the emission of immunogenic-damage-associated molecules. Intravenous administration of carfilzomib delayed the growth of BRAF-mutant murine tumors and mobilized the danger-signal proteins calreticulin and high mobility group box 1 (HMGB1). Analyses of drug-treated samples revealed increased intratumor recruitment of activated cytotoxic T cells and natural killers, concomitant with the downregulation of forkhead box protein P3 (Foxp3)+ T-cell surface glycoprotein CD4 (CD4)+ T cells, indicating that carfilzomib promotes reshaping of the immune microenvironment of BRAF-mutant murine colorectal tumors. These results will inform the design of clinical trials in BRAF-mutant colorectal cancer patients.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

The aim to assess treatment failure in patients with stage III colon cancer who underwent radical surgery and was analyzed using the nomogram.

Clinical factors and survival outcomes for stage III colon cancer patients registered in the SEER database from 2018 to 2019 were analyzed, with patients split into training and testing cohorts (7:3 ratio). A total of 360 patients from the First Affiliated Hospital of Longyan served as an external validation cohort. Independent predictors of treatment failure were identified using logistic regression analyses. The nomograms was evaluated by concordance index (C-index), calibration curves, and the area under the curve (AUC), decision curve analysis (DCA) and clinical impact curves (CIC) assessed the clinical utility of nomograms versus TNM staging.

The study included 4,115 patients with stage III colon cancer. Multivariate logistic analysis age, tumor site, pT stage, pN stage, chemotherapy, pretreatment CEA levels, number of harvested lymph nodes, perineural invasion and marital status were identified as independent risk factors for treatment failure. The C-indices for the training and testing sets were 0.853 and 0.841. Validation by ROC and calibration curves confirmed the stability and reliability of the model. DCA showed that the net clinical effect of the histogram was superior to that of the TNM staging system, while CIC highlighted the potentially large clinical impact of the model.

The developed Nomogram provides a powerful and accurate tool for clinicians to assess the risk of treatment failure after radical surgery in patients with stage III colon cancer.

Microsatellite Instability (MSI-H) occurs in approximately 15% of non-metastatic colon cancers, influencing patient outcomes positively compared to microsatellite stable (MSS) cancers. This systematic review focuses on the prognostic significance of KRAS, NRAS, and BRAF mutations within MSI-H colon cancer. Through comprehensive searches in databases like MEDLINE, EMBASE, and others until 1 January 2024, we selected 8 pertinent studies from an initial pool of 1918. These studies, encompassing nine trials and five observational studies involving 13,273 patients, provided insights into disease-free survival (DFS), survival after recurrence, and overall survival. The pooled data suggest that while KRAS and BRAF mutations typically predict poorer outcomes in MSS colorectal cancer, their impact is less pronounced in MSI contexts, with implications varying across different stages of cancer and treatment responses. In particular, adverse effects of these mutations manifest significantly upon recurrence rather than affecting immediate DFS. Our findings confirm the complex interplay between genetic mutations and MSI status, emphasizing the nuanced role of MSI in modifying the prognostic implications of KRAS, NRAS, and BRAF mutations in colon cancer. This review underscores the importance of considering MSI alongside mutational status in the clinical decision-making process, aiming to tailor therapeutic strategies more effectively for colon cancer patients.

Colorectal cancer (CRC) presents with varying prognoses, and identifying factors for predicting metastasis and outcomes is crucial. Perineural invasion (PNI) is a debated prognostic factor for CRC, particularly in stage I-III patients, but its role in guiding adjuvant chemotherapy for node-positive colon cancer remains uncertain.

We conducted a single-center study using data from the Colorectal Section Tumor Registry Database at Chang Gung Memorial Hospital, Taiwan. This prospective study involved 3,327 CRC patients, 1,536 of whom were eligible after application of the exclusion criteria, to investigate the prognostic value of PNI in stage I-III patients and its predictive value for node-positive/negative cancer patients receiving adjuvant chemotherapy. Propensity score matching (PSM) was used to minimize selection bias, and follow-up was performed with standardized procedures.

PNI-positive (PNI+) tumors were associated with higher preoperative CEA levels and more frequent adjuvant chemotherapy. After PSM, PNI + tumors were associated with marginally significantly lower 5-year disease-free survival (DFS) and significantly lower overall survival (OS) rates in stages III CRC. However, no significant differences were observed in stages I and II. Subgroup analysis showed that among PNI + tumors, only poorly differentiated tumors had higher odds of recurrence. PNI did not predict outcomes in node-negative colon cancer. Adjuvant chemotherapy benefited PNI + patients with node-positive but not those with node-negative disease.

Our study indicates that PNI is an independent poor prognostic factor in stage III colon cancer but does not predict outcomes in node-negative disease. Given the potential adverse effects of adjuvant chemotherapy, our findings discourage its use in node-negative colon cancer when PNI is present.

KRAS is a proto-oncogene encoding a small GTPase. Mutations contribute to ∼30% of human solid tumours, including lung adenocarcinoma, pancreatic, and colorectal carcinomas. Most KRAS activating mutations interfere with GTP hydrolysis, essential for its role as a molecular switch, leading to alterations in their molecular environment and oncogenic signalling. However, the precise signalling cascades these mutations affect are poorly understood. Here, APEX2 proximity labelling was used to profile the molecular environment of WT, G12D, G13D, and Q61H-activating KRAS mutants under starvation and stimulation conditions. Through quantitative proteomics, we demonstrate the presence of known KRAS interactors, including ARAF and LZTR1, which are differentially captured by WT and KRAS mutants. Notably, the KRAS mutations G12D, G13D, and Q61H abrogate their association with LZTR1, thereby affecting turnover. Elucidating the implications of LZTR1-mediated regulation of KRAS protein levels in cancer may offer insights into therapeutic strategies targeting KRAS-driven malignancies.

This article is a summary of the French intergroup guidelines regarding the management of non-metastatic colon cancer (CC), revised in November 2022.

These guidelines represent collaborative work of all French medical and surgical societies involved in the management of CC. Recommendations were graded in three categories (A, B, and C) according to the level of evidence found in the literature published up to November 2022.

Initial evaluation of CC is based on clinical examination, colonoscopy, chest-abdomen-pelvis computed tomography (CT) scan, and carcinoembryonic antigen (CEA) assay. CC is usually managed by surgery and adjuvant treatment depending on the pathological findings. The use of adjuvant therapy remains a challenging question in stage II disease. For high-risk stage II CC, adjuvant chemotherapy must be discussed and fluoropyrimidine monotherapy or oxaliplatin-based chemotherapy proposed according to the type and number of poor prognostic features. Oxaliplatin-based chemotherapy (FOLFOX or CAPOX) is the current standard for adjuvant therapy of patients with stage III CC. However, these regimens are associated with significant oxaliplatin-induced neurotoxicity. The results of the recent IDEA study provide evidence that 3 months of treatment with CAPOX is as effective as 6 months of oxaliplatin-based therapy in patients with low-risk stage III CC (T1-3 and N1). A 6-month oxaliplatin-based therapy remains the standard of care for high-risk stage III CC (T4 and/or N2). For patients unfit for oxaliplatin, fluoropyrimidine monotherapy is recommended.

French guidelines for non-metastatic CC management help to offer the best personalized therapeutic strategy in daily clinical practice. Each individual case must be discussed within a multidisciplinary tumor board and then the treatment option decided with the patient.

Cancer represents a significant global public health concern. In recent years, the incidence of cancer has been on the rise worldwide due to various factors, including diet, environment, and an aging population. Simultaneously, advancements in tumor molecular biology and genomics have led to a shift from systemic chemotherapy focused on disease sites and morphopathology towards precise targeted therapy for driver gene mutations. Therefore, we propose a comprehensive review aimed at exploring the research hotspots and directions in the field of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers over the past decade, providing valuable insights for cancer treatment strategies. Specifically, we aim to present an intellectual landscape using data obtained from the Web of Science (WoS) regarding KRAS mutation.

Bibliometrix, VOSviewer, CiteSpace, and HistCite were employed to conduct scientometric analyses on national publications, influential authors, highly cited articles, frequent keywords, etc.

A total of 16,609 publications met the screening criteria and exhibited a consistent annual growth trend overall. Among 102 countries/regions, the United States occupied the vast majority share of the published volume. The journal Oncotarget had the highest circulation among all scientific publications. Moreover, the most seminal articles in this field primarily focus on biology and targeted therapies, with overcoming drug resistance being identified as a future research direction.

The findings of the thematic analysis indicate that KRAS mutation in lung cancer, the prognosis following B-Raf proto-oncogene, serine/threonine kinase (BRAF) or rat sarcoma (RAS) mutations, and anti-epidermal growth factor receptor (EGFR)-related lung cancer are the significant hotspots in the given field. Considering the significant advancements made in direct targeting drugs like sotorasib, it is anticipated that interest in cancers associated with KRAS mutations will remain steadfast.

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. Although the overall incidence of CRC is decreasing, the incidence of young-onset CRC, characterized by a diagnosis of CRC before age 50, is increasing. Outcomes for CRC patients are improving, partly due to comprehensive molecular characterization of tumors and novel therapeutic strategies. Advances in genomic and transcriptomic analyses using blood- and tumor-tissue-based sequencing have facilitated identification of distinct tumor subtypes harboring unique biological characteristics and therapeutic vulnerabilities. These insights have led to the development and incorporation of targeted therapies and immunotherapy in CRC treatment. In this review, we discuss the molecular landscape and key oncogenes/tumor suppressors contributing to CRC tumorigenesis, metastasis, and therapeutic resistance. We also discuss personalized therapeutic strategies for subsets of CRC patients and provide an overview of evolving novel treatments being evaluated in clinical trials.

In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4).

In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations.

In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs.

The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC.

NCT03271047 (09/01/2017).

Most tyrosine kinase inhibitors (TKIs) have failed in clinical trials for metastatic colorectal cancer (mCRC). To leverage the additional lower-affinity targets that most TKIs have, high-dose regimens that trigger efficacy are explored. Here, we studied unprecedented drug exposure-response relationships in vitro using mCRC patient-derived tumour organoids (PDTOs).

We investigated the cytotoxic anti-tumour effect of high-dose, short-term (HDST) TKI treatment on 5 PDTOs. Sunitinib, cediranib and osimertinib were selected based on favourable physicochemical and pharmacokinetic properties. Intra-tumoroid TKI concentrations were measured using a clinically validated LC/MS-MS method. Cell death was determined using an enzyme activity assay, immunofluorescent staining and western blotting.

Most PDTOs tested were sensitive to sunitinib and cediranib, but all to osimertinib. Furthermore, HDST osimertinib treatment effectively blocks organoid growth. This treatment led to markedly elevated intra-tumoroid TKI concentrations, which correlated with PDTO sensitivity. Mechanistically, HDST osimertinib treatment induced apoptosis in treated PDTOs.

Our work provides a better understanding of TKI exposure vs response and can be used to determine patient-specific sensitivity. Additionally, these results may guide both mechanistic elucidation in organotypic translational models and the translation of target drug exposure to clinical dosing strategies. Moreover, HDST osimertinib treatment warrants clinical exploration for mCRC.

Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a "molecule switch" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a "hot" TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a "colder" TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect.

Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial.

Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models.

A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12; p = 0.0091).

In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

Up to one-third of colorectal cancer (CRC) patients experience recurrence after radical surgery, and it is still very difficult to assess and predict the risk of recurrence. Angiogenesis is the key factor of recurrence as metastasis of CRC is closely related to copper metabolism. Expression profiling by microarray from two datasets in Gene Expression Omnibus (GEO) was selected for quality control, genome annotation, normalization, etc. The identified angiogenesis-derived and cuproptosis-related Long non-coding RNAs (lncRNAs) and clinical data were screened and used as predictors to construct a Cox regression model. The stability of the model was evaluated, and a nomogram was drawn. The samples were divided into high-risk and low-risk groups according to the linear prediction of the model, and a Kaplan-Meier survival analysis was performed. In this study, a model was established to predict the postoperative recurrence of colon cancer, which exhibits a high prediction accuracy. Furthermore, the negative correlation between cuproptosis and angiogenesis was validated in colorectal cancer cell lines and the expression of lncRNAs in vitro was examined.