Search Results (382)

Colorectal cancer (CRC) remains one of the most lethal malignancies worldwide, with high recurrence rates and limited curative options in metastatic settings. Cancer vaccines represent an emerging immunotherapeutic approach that aims to stimulate robust, tumor-specific immune responses. This review summarizes the current state of CRC vaccine development, including tumor cell-based, dendritic cell-based, peptide-based, nucleic acid-based (DNA and mRNA), and virus-based platforms. We highlight findings from key clinical trials that demonstrate immunogenicity, safety, and preliminary efficacy, with particular attention to combinations with chemotherapy and immune checkpoint inhibitors. Furthermore, we explore critical challenges such as tumor heterogeneity, immunosuppressive tumor microenvironments, and the logistical complexity; in this context, we particularly focus on the current development of personalized cancer vaccines, exploring the newly identified encouraging epitopes and their safety and efficacy in recent trials. The integration of cancer vaccines with in silico modeling, advanced delivery systems such as nanoparticles or AI-guided designs, and microbiome modulation represents a promising avenue for enhancing their clinical utility. Overall, therapeutic and prophylactic cancer vaccines may soon contribute meaningfully to the comprehensive management of CRC, especially in settings of minimal residual disease or early recurrence. Full article

Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair (pMMR) and microsatellite stability (MSS) metastatic colorectal cancer (mCRC). Inhibition of vascular endothelial growth factor (VEGF) or cytotoxic chemotherapy can boost immunogenicity and has the potential to upregulate ICI efficacy. Methods: A comprehensive electronic literature search was conducted up to April 2025 to identify randomized controlled trials comparing cytotoxic chemotherapy plus bevacizumab with or without ICI. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival (OS), objective response rate (ORR), and severe adverse events (AEs: grade 3 or more). A meta-analysis was performed using random-effects models to calculate hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Results: Four studies involving 986 patients (With-ICI group, n = 651; Without-ICI group, n = 335) were included. The meta-analysis demonstrated a significant improvement in PFS in the With-ICI group compared with the Without-ICI group, with an HR of 0.82 (95% CI: 0.70–0.96, p = 0.01) without statistical heterogeneity. No significant improvements were observed between the With- and Without-ICI groups in OS and ORR meta-analyses, but the With-ICI group had a favorable trend in OS. A significant increase in serious AEs was not observed in the With-ICI group. Conclusions: This meta-analysis suggests a potential benefit of adding ICIs to chemotherapy plus bevacizumab in pMMR mCRC; however, the evidence remains preliminary and hypothesis-generating, warranting further investigation in biomarker-driven trials and clarification of long-term outcomes. Full article

Background: The development of brain metastases (BM) is a relatively uncommon but significantly adverse event in the spread of colorectal cancer (CRC). Although management of CRC BM has improved with advances in imaging and systemic therapies, clinical outcomes remain poor. Methods: This retrospective cohort study used the U.S. National Cancer Database to evaluate survival outcomes, treatment patterns, and prognostic factors in CRC patients diagnosed with BM between 2010 and 2020. Patients with isolated brain-only metastases formed the primary analytic cohort, while those with additional extracranial metastases were included for descriptive comparison. Multivariable Cox proportional hazards and logistic regression models were used to assess factors associated with of survival. Proportional hazards assumptions were tested using Schoenfeld residuals. Accelerated failure time models were also employed. Results: From a cohort of 1,040,877 individuals with CRC, 795 had metastatic disease present along with relevant data, of which 296 had isolated BM. Median overall survival (mOS) in BM-only metastatic disease group was 7.82 months (95% CI: 5.82–9.66). The longest survival was observed among patients treated with stereotactic radiosurgery combined with systemic therapy (SRS+Sys), with a median OS of 23.26 months (95% CI: 17.51–41.95) and a 3-year survival rate of 35.8%. In adjusted Cox models, SRS, systemic therapy, and definitive surgery of the primary site were each independently associated with reduced hazard of death. Rectal cancer patients had longer survival than those with colon primaries (mOS: 10.35 vs. 6.08 months). Age, comorbidity burden, and insurance status were not associated with survival in adjusted analyses. Conclusions: SRS+Sys was associated with longer survival compared to other treatment strategies. However, treatment selection is highly dependent on individual clinical factors such as performance status, comorbidities, and disease extent; therefore, these findings must be interpreted with caution Future prospective studies incorporating molecular and biomarker data are warranted to better guide care in this rare and high-risk group. Full article

Background/Objectives: Pembrolizumab demonstrates a high response rate in patients with mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC), with responses often sustained even after treatment cessation. However, the pathological complete response (pCR) rate in clinically responding cases remains unknown. This study aimed to evaluate the relationship between the radiological and pathological responses in patients with dMMR mCRC who responded to pembrolizumab. Methods: This retrospective study included 27 patients with dMMR mCRC treated with pembrolizumab. The radiological response was assessed using RECIST version 1.1 criteria. The pathological response was evaluated in patients who underwent metastasectomy, with pCR defined as the absence of residual cancer cells. Results: The median progression-free survival (PFS) of the cohort was 19 months. Among the 27 patients, 3 achieved clinical complete response (cCR), and 10 had clinical partial response (cPR), resulting in a response rate of 48%. All three patients with cCR maintained their responses without metastasectomy (2-year PFS: 100%). Among patients with cPR, eight maintained their responses, while two experienced progression (2-year PFS: 75%). Five patients with cPR underwent curative-intent metastasectomy, and four of them (80%) achieved pCR. Thus, at least 40% of patients with cPR in this cohort had no residual cancer histologically. Conclusions: Our findings demonstrate the significant discordance between the radiological and pathological responses to pembrolizumab in dMMR mCRC patients, with 80% of those with cPR achieving pCR upon metastasectomy. These observations highlight the need for improved response assessment methods for precision immunotherapy. Full article

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, posing significant treatment challenges, particularly in its metastatic form (mCRC). This review comprehensively examines the pivotal role of RAS mutations, specifically KRAS and NRAS, which are detected in approximately 40–45% of mCRC cases, and their impact on treatment decisions and patient outcomes. We assess the effectiveness of standard treatments within the RAS mutant population, highlighting the challenges and limitations these therapies face. Recent advancements in targeted therapies, particularly the focus on novel agents such as KRAS G12C inhibitors, including sotorasib and adagrasib, have shown promising efficacy in overcoming resistance to conventional treatments. Furthermore, this review discusses future directions, emphasizing the need for research into non-RAS targets to address the complexities of resistance mechanisms and improve therapeutic outcomes. This review aims to provide a detailed overview of the current treatments and innovative approaches, supporting the development of personalized management strategies for patients with mCRC. Full article

Background: Anti-EGFR therapy, combined with chemotherapy, represents the standard therapeutic approach for triple wild-type (KRAS/NRAS and BRAF), left-sided, microsatellite stable (MSS) metastatic colorectal cancer (mCRC). However, acquired resistance develops in approximately 50% of patients. This study evaluated the efficacy of anti-EGFR therapy re-challenge and analyzed circulating tumor DNA (ctDNA) for potential resistance mechanisms. Methods: Eleven patients with triple wild-type, MSS, HER2-negative, left-sided mCRC were included. All patients received Cetuximab with chemotherapy as the first-line treatment, with three patients subsequently receiving Cetuximab re-challenge. Twenty-one plasma samples were collected at baseline and at each response assessment for retrospective ctDNA analysis using next-generation sequencing with a 16-gene panel. Results: Genetic alterations were detected in only 14.2% of ctDNA samples. In one re-challenge patient, the KRAS: c.35G>A mutation appeared during progression. No RAS mutations were identified in four patients who progressed on first-line Cetuximab treatment. Conclusions: This preliminary study suggests that clinically based anti-EGFR re-challenge may benefit selected mCRC patients. The low detection rate of resistance-conferring mutations indicates potential alternative resistance mechanisms beyond RAS pathway alterations. Our findings, while limited by sample size and the retrospective design of ctDNA testing, contribute to the growing evidence supporting anti-EGFR re-challenge strategies in mCRC management. Full article

Background: Colorectal cancer is a significant health concern. Immunotherapy has become a promising approach in colorectal cancer, offering a wider array of therapeutic strategies. This study aims to summarize the current evidence regarding the use of checkpoint inhibitors in metastatic colorectal cancer. Methods: A systematic review of relevant clinical trials and randomized controlled trials (RCTs) assessing checkpoint inhibitors, published between January 2019 and January 2025, was conducted on Medline, Web of Science, and Cochrane. Progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were the primary outcomes. Studies focusing on other types of immunotherapy, non-clinical trials, pre-clinical trials, and study protocols were excluded. Results: 48 studies were included. Checkpoint inhibitors demonstrated significant efficacy in microsatellite instability (MSI) metastatic colorectal cancer (mCRC). In microsatellite stability (MSS) mCRC, immunotherapy was less effective, and combination strategies with chemotherapy or targeted therapies yielded mixed results. Grade ≥ 3 treatment-related adverse events (TRAEs) were common in combination regimens. Conclusion: Immunotherapy has revolutionized MSI mCRC treatment while treating MSS CRC with these molecules remains unconvincing. Combination strategies and novel agents may offer potential but require further research to prove efficacy. Full article

Machine learning (ML) algorithms hold the potential to outperform the selection of patients for immunotherapy (ICIs) compared to previous biomarker studies. We analyzed the predictive performance of ML models and compared them to traditional clinical biomarkers (TCBs) in the field of gastrointestinal (GI) cancers. The study has been registered in PROSPERO (number: CRD42023465917). A systematic search of PubMed was conducted to identify studies applying different ML algorithms to GI cancer patients treated with ICIs using tumor RNA gene expression profiles. The outcomes included were response to immunotherapy (ITR) or survival. Additionally, we compared the ML methodology details and predictive power inherent in the published gene sets using 5-fold cross-validation and logistic regression (LR), on an available well-defined ICI-treated metastatic gastric cancer (GC) cohort (n = 45). A set of standard clinical ICI biomarkers (MLH, MSH, and CD8 genes, plus PMS2 and PD-L1)) and de-novo calculated principal components (PCs) of the original datasets were also included as additional points of comparison. Nine articles were identified as eligible to meet the inclusion criteria. Three were pan-cancer studies, five assessed GC, and one studied colorectal cancer (CRC). Classification and regression models were used to predict ICI efficacy. Next, using LR, we validated the predictive power of applied ML algorithms on RNA signatures, using their reported receiver operating characteristics (ROC) analysis area under the curve (AUC) values on a well-defined ICI-treated gastric cancer (GC) dataset (n = 45). In two cases our method has outperformed the published results (reported/LR comparison: 0.74/0.831, 0.67/0.735). Besides the published studies, we have included two benchmarks: a set of TCBs and using principal components based on the whole dataset (PCA, 99% explained variance, 40 components). Interestingly, a study using a selected gene set (immuno-oncology panel) with AUC = 0.83 was the only one that outperformed the TCB (AUC = 0.8) and the PCA (AUC =0.81) results. Cross-validation of the predictive performance of these genes on the same GC dataset and an investigation of their prognostic role on a collated multi-cohort GC dataset of n = 375 resected, or chemotherapy-treated patients revealed that genes mannose-6-phosphate receptor (M6PR), Indoleamine 2,3-Dioxygenase 1 (IDO1), Neuropilin-1 (NRP1), and MAGEA3 performed similarly, or better than established biomarkers like PD-L1 and MSI. We found an immuno-oncology panel with an AUC = 0.83 that outperformed the clinical benchmark or the PC results. We recommend further investigation and experimental validation in the case of M6PR, IDO1, NRP1, and MAGEA3 expressions based on their strong predictive power in GC ITR. Well-designed studies with larger sample sizes and nonlinear ML models might help improve biomarker selections. Full article

Background: Regorafenib (R) and trifluridine/tipiracil (T) are approved treatments for metastatic colorectal cancer (mCRC) in refractory cases. However, the optimal sequencing of these agents is unknown. The ReTrITA study planned to assess the real-world efficacy of R and T, administered either sequentially or as monotherapy, in a large Italian multicentre population. Methods: This retrospective observational analysis comprised 1156 mCRC patients treated between 2012 and 2023 at 17 Italian cancer centres. Patients were divided into four groups: sequential T/R (n = 261), sequential R/T (n = 155), R monotherapy (n = 313), and T monotherapy (n = 427). The primary objectives were overall survival (OS) and progression-free survival (PFS), with secondary goals being disease control rate, objective response rate, and treatment-related toxicity. Results: The monotherapy cohorts showed no significant difference in OS (R: 5.0 months; T: 5.9 months; p = 0.8371) or PFS (R: 3.2 months; T: 3.3 months; p = 0.6531). Compared to T/R, the sequential R/T group had significantly better outcomes: median OS was 16.6 vs. 12.6 months (HR = 0.67; p = 0.0004), and median PFS was 11.5 vs. 8.5 months (HR = 0.60; p < 0.0001). The survival advantage of R/T was consistent across clinical subgroups. The toxicity profiles were comparable with known safety data, with a lower prevalence of neutropenia reported in the R/T sequence. Conclusions: ReTrITA confirms the efficacy of R and T as monotherapies and provides compelling real-world evidence that the R/T sequence improves survival in refractory mCRC. These findings support a regorafenib-first approach in patients who are eligible, and they emphasise the need for future research into combination strategies and comparisons with newer drugs such as fruquintinib. Full article

Background: Colorectal cancer (CRC) is among the most prevalent and lethal cancers globally, with liver metastasis representing the leading cause of CRC-related mortality. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has recently gained attention due to its overexpression in colorectal tumor tissues and its potential role in driving metastatic progression. This aims to investigate the involvement of PCSK9 in the liver metastatic niche, focusing on its effects on liver sinusoidal endothelial cells (LSECs), key components of the liver microenvironment. Methods: LSECs were stimulated with conditioned media derived from differentiated colorectal cancer cells and cancer stem cells (CSCs), the latter generated by reprogramming SW620 and CT26 cell lines. RNA sequencing was used to profile gene expression in LSECs. PCSK9 mRNA and protein levels were quantified by qPCR and Western blotting, respectively. PCSK9 expression in CRC liver metastases was evaluated by immunofluorescent staining. Results: PCSK9 was detected in both human and murine LSECs and significantly upregulated following exposure to CSC-conditioned media. Immunofluorescent staining confirmed PCSK9 expression in LSECs within CRC liver metastases. Total RNA sequencing revealed that a pre-treatment of LSECs with the PCSK9 inhibitor PF-06446864 prior to CSC stimulation seems to reduce the expression of microRNAs linked to cell migration and proliferation. Functional assays demonstrated that CSC-conditioned media enhanced LSEC proliferation and migration, effects reversed by PCSK9 inhibition. Conclusions: PCSK9 promotes the activation of LSECs in response to colorectal CSCs, contributing to a pro-metastatic phenotype. These findings highlight PCSK9 as a potential therapeutic target in colorectal liver metastasis. Full article

The current treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) involves combined inhibition of BRAF and the epidermal growth factor receptor (EGFR). However, tumour responses are often short-lived due to a rebound in mitogen-activated protein kinase (MAPK) activity. In this study, we combined short-term cell viability assays with long-term regrowth assays following drug removal over a period of three weeks. This allowed assessment of regrowth after therapy discontinuation. We tested the effect of combined BRAF inhibition (encorafenib) and EGFR inhibition (afatinib) on BRAF-V600E mutant CRC patient-derived organoids (PDOs). Combined EGFR/BRAF inhibition initially caused a major reduction in PDO growth capacity in BRAF-V600E mutant PDOs. This was followed by rapid regrowth after drug removal, mirroring clinical outcomes. EGFR inhibition in BRAF-V600E mutant PDOs led to activation of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R). The IGF1R/IR inhibitor linsitinib prevented the rebound in MAPK activity following removal of afatinib and encorafenib, prevented regrowth of CRC PDOs, and improved the anti-tumour response in an in vivo model. PDO regrowth assays allow the identification of pathways driving tumour recurrence. IR/IGF1R-inhibition prevents regrowth following golden standard MAPK pathway-targeted therapy and provides a strategy to improve the treatment of BRAF-V600E mutant CRC Full article

Background: Colorectal cancer (CRC) is a significant global health burden, with liver metastases representing a key prognostic factor. Neoadjuvant chemotherapy (NAC) has improved outcomes in metastatic CRC (mCRC), and tumor regression is commonly assessed using the Rubbia–Brandt classification. The Poultsides classification defines ≥40% fibrosis as an independent prognostic factor, particularly in patients treated with cetuximab (45.71%). However, the predictive value of this threshold remains under debate, warranting further investigation. Methods: This study evaluates the extent of fibrosis (≥40%) induced by NAC plus anti-epidermal growth factor receptor (anti-EGFR) therapy vs. NAC plus anti-vascular endothelial growth factor (anti-VEGF) therapy in mCRC patients. It also examines the prognostic relevance of the Poultsides and Rubbia–Brandt classifications. A total of 108 patients undergoing liver resection for CRC metastases were included. Statistical analyses were performed using SPSS 28.0 version and R software 4.5 version to compare fibrosis rates and survival outcomes. Results: From September 2005 to January 2023, 108 patients were analyzed: 54 received chemotherapy plus anti-EGFR (Cohort 1), and 54 received chemotherapy plus anti-VEGF (Cohort 2). Fibrosis was significantly higher in Cohort 1 (median 40.0%, IQR: 25.4–53.2) than in Cohort 2 (median 20.6%, IQR: 8.07–36.9), p < 0.001. Overall survival was similar between both cohorts (p = 0.96), with a median follow-up of 41.6 months. Conclusions: Anti-EGFR therapy is associated with greater fibrosis than anti-VEGF, despite similar survival outcomes. The Poultsides classification may be a useful prognostic tool for resected liver metastases in mCRC. Full article

Metastatic colorectal cancer (mCRC) remains a major cause of cancer-related mortality worldwide and requires the development of new biomarkers to improve patient management. Traditional markers, such as RAS mutations and microsatellite instability (MSI), have revolutionized therapeutic decisions, but emerging evidence underlines the importance of integrating multi-omics sciences for a deeper understanding of tumor biology and therapeutic resistance. Although these omics technologies hold great promise for the advancement of precision oncology, significant challenges remain. However, the integration of multi-omics data is opening the way to more accurate diagnostics, personalized therapies, and improved outcomes for mCRC patients. This review provides an in-depth description of the various omics sciences and explores their advantages and critical issues. Full article

Surgery is one of the most effective treatment methods for liver metastases developing from primary colorectal cancer (CRC). Despite the widespread application of surgical approaches, recurrence rates remain substantial. Although chemotherapy is frequently employed, the supporting evidence for its efficacy in this context remains inconclusive. In the present study, we aimed to identify potential predictors of post-metastasectomy recurrence by analyzing clinical, pathological, and molecular features of both primary colorectal tumors and their corresponding hepatic metastases. Specifically, we evaluated the expression of epithelial–mesenchymal transition (EMT) markers, cancer stem cell (CSC) markers, and selected oncogenic mRNAs (RAS, mTOR, and CMYC) in tissue samples from 84 patients. RAS and CMYC are well-known proto-oncogenes involved in cell proliferation and survival, while mTOR functions as a central regulator of cell growth and metabolism. Following liver metastasectomy, intra-hepatic recurrence was observed in 40.5% of the cases. Among the molecular markers analyzed, the EMT transcription factor SNAIL—which plays a critical role in cancer cell invasion and metastasis—and mTOR exhibited significantly elevated expression in metastatic lesions from patients who experienced recurrence. While SNAIL expression did not show a clear association with the time to recurrence, increased mTOR expression in metastatic liver tissue was significantly associated with both shorter recurrence-free survival and diminished overall survival (p < 0.001). Results showed that mTOR expression levels could be a clinically relevant predictive indicator of remnant liver recurrence. In patients with liver metastases, the use of mTOR inhibitors may be considered after hepatic metastasectomy. Full article

Sex steroid hormones and systemic iron metabolism are emerging as modulators of colorectal cancer (CRC) development and progression. However, information linking systemic factors to tumor characteristics and epithelial–mesenchymal transition (EMT) is limited, particularly in a sex-specific context. We measured serum levels of sex hormones [testosterone, estradiol, progesterone, Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), Carcinoembryonic antigen (CEA)] and iron-related biomarkers (iron, transferrin, ferritin, % transferrin saturation, ceruloplasmin, and the ceruloplasmin/transferrin ratio) in 82 CRC patients and 31 healthy controls. EMT-related proteins [mediator of ErbB2-driven cell motility 1 (MEMO1), E-cadherin, fibronectin, vimentin, and vinculin] were quantified by Western blotting in tumor and adjacent normal mucosa. Non-parametric tests and Spearman correlations were applied, stratified by sex and corrected for age and anemia where appropriate. Progesterone levels were significantly lower in male CRC patients (median 0.17 ng/mL vs. 0.20 ng/mL, p = 0.04) and higher in female patients (0.17 ng/mL vs. 0.10 ng/mL, p = 0.0077) compared with controls. The iron-related biomarkers indicated a pattern of iron deficiency, including in non-anemic patients, with reduced % transferrin saturation (p < 0.01) and an elevated ceruloplasmin/transferrin ratio (p = 0.02). Correlations were found between iron status, tumor stage, and hormonal levels. Progesterone correlated with EMT protein expression in healthy mucosa (e.g., fibronectin in females: ρ = 0.567, p = 0.014; vimentin in males: ρ = −0.446, p = 0.007), but not in tumor tissue. In the healthy mucosa of male patients, ceruloplasmin/transferrin correlated with MEMO1 (ρ = 0.419, p = 0.04), vinculin (ρ = 0.299, p = 0.041), and vimentin (ρ = 0.394, p = 0.07); transferrin levels inversely correlated with MEMO1 expression (ρ = −0.392, p = 0.032), and vimentin showed a positive correlation with serum iron (ρ = 0.350, p = 0.043). Furthermore, fibronectin expression inversely correlated with iron in the sole tumor tissue of female patients (ρ = −0.366, p = 0.040). These findings support the role of sex hormones and iron metabolism in CRC biology, suggesting that EMT might be accompanied by altered iron uptake and redox remodeling, which can enhance cellular motility and the metastatic potential. Full article