More than 50% of patients diagnosed with colorectal cancer (CRC) will develop liver metastases (CRCLM), which is the main cause of death for more than 60% of these patients. The aim of this study was to correlate the clinical and pathological characteristics of the primary CRC and CRCLM, with emphasis in predicting the histological growth pattern of the CRCLM.

Cohort of 73 patients with CRC. Analysis of clinical data and blinded pathological review was performed related with primary tumor and CRCLM features. The analysis was performed in SPSS (version 27) with a significance level of 5%.

A statistically significant association was found between tumor size and metastasis growth pattern (P = .002), with larger tumors giving rise to metastases with a nondesmoplastic growth pattern. Lymphovascular invasion (LVI) was associated with metachronous CRCLM (P = .043). In the absence of LVI, the time required for CRCLM to appear was significantly longer (P = .011). The number of metastases was significantly higher (P = .049) in tumors without LVI when compared to tumors with LVI. There was a statistically significant association between CRC high-grade inflammation and the desmoplastic metastases growth pattern of the CRCLM (P = .017).

The possibility of predicting the CRCLM histological growth pattern resorting to primary CRC characteristics would be useful for proper patient selection for surgery and adapting biological therapies.

Cetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated.

Our study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity.

Through mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo.

Stat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo.

Our study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.

In this study, we aimed to evaluate the cost-effectiveness of S-1 and oxaliplatin (SOX) plus bevacizumab (Bmab group) compared with SOX plus cetuximab (Cmab group) as a first-line treatment for patients with Kirsten rat sarcoma virus (KRAS) wild-type metastatic colorectal cancer (mCRC) in Japan from the perspective of healthcare payers.

A partitioned survival model was developed using data from the randomized phase II Osaka Multicenter Study Group on Colorectal Cancer-1107 study, which included overall survival, progression-free survival, and treatment regimens for the Bmab and Cmab groups. Treatment costs were estimated from the Japanese medical claims database and the National Health Insurance drug price list. The utilities were derived from the literature. Outcomes were reported as incremental cost, incremental quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). The willingness-to-pay (WTP) threshold was set at 7.5 million JPY per QALY. The time horizon of the model was set to 20 years. Sensitivity analyses were conducted to assess the uncertainty of the model for various parameters.

Compared with the Cmab group, the Bmab group had an incremental cost of 911,373 JPY (6,528 USD), an incremental effectiveness of 0.79 QALY, and an ICER of 1,146,745 JPY (8,215 USD) per QALY. One-way sensitivity analysis showed that the cost of progressive disease treatment in the Bmab group had the greatest impact on the ICER. According to the probabilistic sensitivity analysis, the Bmab group had a 94.9% probability of being cost-effective compared with the Cmab group.

Considering a WTP threshold of 7.5 million JPY (approximately 53,700 USD) per QALY, Bmab might be a cost-effective treatment option for patients with KRAS wild-type mCRC in Japan. Further studies on economic evaluations based on personalized drugs and patient selection based on clinical and genetic information are warranted.

Colorectal cancer (CRC) is a common malignant tumor worldwide. Approximately 20%-25% of patients have metastases at the time of initial diagnosis, and nearly half eventually develop metastatic cancer. The standard first- and second-line treatments for unresectable metastatic CRC are full-dose two-/three-agent chemotherapy with or without a combination of molecularly targeted agents. However, many patients are ineligible for intensive therapy due to poor performance status or advanced age. TAS-102 (trifluridine/tipiracil) in combination with bevacizumab may provide a new treatment strategy for patients with advanced CRC who are ineligible for intensive therapy.

We report a case of a 91-year-old woman diagnosed with stage IV adenocarcinoma of the rectosigmoid junction in the presence of multiple metastases. The patient had a history of hypertension, had suffered from deep vein thrombosis of the left lower extremity, and was allergic to several drugs. Genetic testing showed multiple mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), Phosphatidylinositol-4,5-bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA), and Tumor Protein p53 (TP53); microsatellite stability; and a tumor mutational burden of 4.5 Mut/Mb. The patient was diagnosed with stage IV adenocarcinoma of the rectosigmoid junction in May 2020, with a clinical stage of cTxNxM1. Without surgery, the patient received first-line treatment with capecitabine in combination with bevacizumab, which was changed to second-line treatment with TAS-102 in combination with bevacizumab after disease progression, with a progression-free survival of 10 months, achieving a significant survival benefit. Later, due to the patient's poor physical condition, no further medication was administered, and the patient died on 1 September 2022.

TAS-102 in combination with bevacizumab for the treatment of elderly patients with metastatic CRC who are ineligible for intensive therapy is a promising treatment option.

Colorectal cancer (CRC), a global health concern, requires effective treatments. Anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies are used for RAS wild-type and BRAFV600 mutation-negative metastatic CRC (mCRC) but are not indicated for RAS mutant CRC. Evidence suggests CRC patients with sub-clonal RAS/BRAF mutations in tumor tissue may benefit from anti-EGFRs. We assessed the outcomes of patients with sub-clonal RAS/BRAF mutated advanced/mCRC receiving anti-EGFRs using liquid-based GuardantINFORM real-world clinical-genomic analysis.

GuardantINFORM analyzed US patients with advanced CRC with BRAFV600/KRAS/NRAS mutations who received anti-EGFR therapies within 90 days after a Guardant360 test. Primary endpoints were time-to-next treatment (TTNT) and overall survival (OS) (compared across RAS/BRAF mutation clonality cut-offs of 0.3-0.8 using the Cox proportional hazards model).

In GuardantINFORM, 446 patients initiated anti-EGFR therapy within 90 days after the Guardant360 test, and 11%, 9%, and 1% had BRAFV600E, KRAS, or NRAS mutations, respectively; median distribution of RAS/BRAF clonality was 0.84 (IQR, 0.57-1.00). The data show that patients harboring sub-clonal RAS/BRAF mutations benefited from anti-EGFR therapy to a degree similar to patients without RAS/BRAF mutations. For cut-offs of 0.3 to 0.8, sub-clonal RAS/BRAF had similar TTNT to patients without RAS/BRAF mutations, while clonal RAS/BRAF had a significantly shorter TTNT. For cut-offs of 0.3 to 0.7, sub-clonal RAS/BRAF had similar OS to RAS/BRAF mutations not detected, while clonal RAS/BRAF had a significantly shorter OS.

Consistent with tumor tissue biopsy data, patients with CRC harboring sub-clonal RAS/BRAF mutations as assessed by liquid biopsy may derive benefit from anti-EGFR therapy, warranting further investigation.

Hepatic arterial infusion (HAI) chemotherapy, first introduced in the 1980s, has gained recognition as an effective locoregional treatment for colorectal liver metastasis (CRLM). Initially used for unresectable liver metastases, HAI's application has expanded to the adjuvant setting following hepatic resection, with early studies indicating improved hepatic disease-free survival. Recent research demonstrates that combining HAI with modern systemic therapies enhances conversion to resectability and prolongs both recurrence-free and overall survival, even in heavily pretreated patients with diverse RAS mutational statuses. Personalization through approaches like microsatellite instability status and dose modifications further optimize outcomes. However, the complexity of HAI requires expertise across multidisciplinary teams, limiting its widespread adoption to specialized centers. Ongoing clinical trials continue to investigate HAI's role in CRLM management, highlighting its potential to become a cornerstone of liver-directed therapy. We explore how HAI chemotherapy, in combination with personalized medicine, can advance treatment strategies for metastatic colorectal cancer.

Traditionally there has been a nihilistic approach towards patients with pulmonary metastases arising from colorectal cancer. However, emerging evidence highlights the benefit of curative intent treatment. Given the established individual roles of pulmonary metastectomy and CRS/HIPEC in the treatment of colorectal pulmonary and peritoneal metastases, respectively, we decided to combine these modalities and determine whether pulmonary metastases really influence the outcomes of curative intent treatment in CRC patients with peritoneal metastases.

This was a retrospective study of a prospectively maintained database of CRC patients with peritoneal metastases undergoing CRS and HIPEC with curative intent from Jan 1, 2005 to Aug 1, 2018. Patients were divided into two groups of without pulmonary metastases and with pulmonary metastases. Patients were followed up for a median 40.8 months.

Of total 455 patients 19 had pulmonary metastases. The median RFS and OS of all patients was 14.26 months (95 % CI:12.71-16.2) and 56.96 months (95 % CI: 47.73-77.79) respectively. Median RFS and OS of patients with and without pulmonary metastases was 12 & 49.8 months and 14.4 & 57.9 months, respectively. On multivariate analysis, PCI, CC-0 rate, CEA, signet ring histology and retroperitoneal lymph node metastases significantly affected the OS. Presence of pulmonary metastases did not significantly affect the RFS or OS.

There has always been a skepticism in the management CRC with PM and extraperitoneal disease, especially pulmonary metastases with curative intent. Our study demonstrates that CRS and HIPEC improves OS in such patients and pulmonary metastases per se do not influence the outcomes of disease. Nevertheless, further prospective and multi centric studies are required to validate these findings.

The treatment landscape for metastatic colorectal cancer (mCRC) has evolved into a continuum of care with an essential role for biomarkers and molecular subgroups. Treatment guidelines are primarily based on trial results; however, populations and outcomes differ from clinical practice. To support the interpretation of trial results and to assist in tailored patient counseling, we evaluated real-world treatment patterns and outcomes according to RAS/BRAF status. We included all patients diagnosed with BRAFV600E-mutated mCRC in 2015-2020, participating in the Prospective Dutch Colorectal Cancer cohort study, plus a 1:2 random selection of patients with RAS-mutated and double wild-type mCRC. We evaluated differences in administered lines of treatment (LOTs), local treatment, attrition rates, treatment duration, progression-free survival (PFS) and overall survival (OS). 178 BRAFV600E-mutated, 221 RAS-mutated, and 174 double wild-type patients were included. Of BRAFV600E-mutated patients, 26% received ≥3 LOTs, compared to 42% and 47% of the RAS-mutated and double wild-type patients, respectively (p = .002). Local treatment was performed in 25% of BRAFV600E-mutated, 43% of RAS-mutated, and 49% of double wild-type patients (p < .001). Median OS from diagnosis was 15.4, 24.1, and 32.6 months, respectively (p < .001) and loss of prognostic value of RAS/BRAF was observed from the 3rd LOT onwards (p = .17 and p = .54). This paper provides a comprehensive overview of the treatment landscape of mCRC per RAS/BRAF status in daily clinical practice. The observed substantial treatment heterogeneity within and between molecular subgroups underlines the importance of collecting real-world data to address post-trial knowledge gaps and to optimize individualized counseling for all mCRC patients.

Immune checkpoint inhibitors (ICIs) have been approved for treatment of microsatellite instable (MSI-H) metastatic colorectal cancer (mCRC), but factors associated with receipt and efficacy of ICIs in routine clinical practice remain largely unknown.

To identify factors associated with receipt of ICIs and associated survival outcomes among patients with mCRC in routine clinical practice.

This population-based cohort study used deidentified data from a nationwide electronic health record-derived database to include 18 932 patients diagnosed with mCRC between January 2013 and June 2019. Population-based patients were diagnosed with de novo mCRC and had at least 2 documented clinical visits on or after the date of diagnosis. The study analyses were performed between September 2020 and April 2021.

Patients received ICI therapy and/or chemotherapy as part of a systemic treatment for mCRC.

The outcomes were receipt of ICI therapy, overall survival (OS), and time to treatment discontinuation (TTD).

In this cohort study of 18 932 patients diagnosed with mCRC (10 537 [55.7%] male; 546 [2.9%] Asian, 2005 [10.6%] Black or African American, 1674 [8.8%] Hispanic, 12 338 [65.2%] White, 4043 [21.4%] unknown race or ethnicity; median [IQR] age at metastatic diagnosis, 64.6 [55.0-73.3] years), patients with MSI-H tumors had a significantly higher probability of receiving ICIs than those with microsatellite stable (MSS) tumors (odds ratio [OR], 22.66 [95% CI, 17.30-29.73]; P < .001), whereas patients initially diagnosed with synchronous mCRC had significantly lower odds of receiving ICIs than patients with metachronous mCRC (OR, 0.57 [95% CI, 0.45-0.73]; P < .001). Patients with MSI-H tumors who received ICIs as first line of therapy had significantly longer OS than those receiving chemotherapy only (HR, 0.37 [95% CI, 0.25-0.56]; P < .001). Among patients with MSS tumors, ICI-based therapy was associated with significantly longer OS for patients with high albumin level (vs low: HR, 0.28 [95% CI, 0.18-0.45]; P < .001) and antibiotic use (vs nonuse: HR, 0.43 [95% CI, 0.27-0.67]; P < .001), but a significantly shorter OS for patients with synchronous mCRC (vs metachronous: HR, 1.90 [95% CI, 1.24-2.89]; P = .003). In addition, 29 out of 235 patients with MSS tumors (12.3%) experienced durable responses on ICI-based therapy. Similar patterns of associations with TTD were observed.

In this cohort study of patients with mCRC, clinical characteristics were associated with different survival outcomes in patients treated with ICI-based therapy, with important clinical implications for patients with MSS tumors who are generally unresponsive to immunotherapy.

Colorectal cancer (CRC) holds the position of being the third most prevalent cancer and the second primary cause of cancer-related fatalities on a global scale. Approximately 65% of CRC patients survive for 5 years following diagnosis. Metastasis and recurrence frequently occur in half of CRC patients diagnosed at the late stage. This study used bioinformatics analysis to identify key signaling pathways, hub genes, transcription factors, and protein kinases involved in transforming primary CRC with liver metastasis potential. Prognostic markers in CRC were also identified.

The GSE81582 dataset was re-analyzed to identify differentially expressed genes (DEGs) in early CRC compared to non-tumoral tissues. A protein interaction network (PIN) was constructed, revealing significant modules and hub genes. Prognostic markers, transcription factors, and protein kinases were determined. Boxplot and gene set enrichment analyses were performed.

This study identified 1113 DEGs in primary CRC compared to healthy controls. PIN analysis revealed 75 hub genes and 8 significant clusters associated with early CRC. The down-regulation of SUCLG2 and KPNA2 correlated with poor prognosis. SIN3A and CDK6 played crucial roles in early CRC transformation, affecting rRNA processing pathways.

This study demonstrated several pathways, biological processes, and genes mediating the malignant transformation of healthy colorectal tissues to primary CRC and may help the prognosis and treatment of patients with early CRC.

Colorectal cancer (CRC) is a major health problem the world face currently and one of the leading causes of death worldwide. CRC is genetically heterogeneous and multiple genetic aberrations may appear on course of the disease throughout patient's lifetime. Genetic biomarkers such as BRAF, KRAS, and NRAS may provide early precision treatment options that are crucial for patient survival and well-being. The aim of this study was to identify pathogenic mutations in the NRAS gene causing colorectal cancer in the Saudi population. We enrolled 80 CRC tumor tissue samples and performed molecular analyses to establish the mutation spectrum status in the western region of Saudi Arabia. We identified 5 different mutations in 10 patients, 4 of whom were reported previously (G10R, E37K, Q61K, and Q61*) in the literature while we discovered one novel lethal insertion mutation (E49R). A novel identified insertion mutation was present in the third codon of the NRAS gene [c.145 insA (p.Glu49ArgTer85)], causing a frameshift in the amino acid sequence of the protein, and leading to an aberrant and truncated protein of 85 amino acids. Subsequent bioinformatics analysis showed that the mutation was highly deleterious and affected protein function to a greater extent. This identification may further improve the prognosis of CRC and benefit subsequent treatment choices.

Colorectal cancer, being 1 of the most significant malignant tumors globally, poses a substantial risk to human health. Unfortunately, its 5-year survival rate stands at a mere 65%. There remains an urgent need for the development of novel treatments to combat this detrimental malignancy effectively. The Shenmai Injection (SMI) is a Chinese medicine that has been proven to have significant clinical efficacy in the treatment of cardiovascular diseases. This study aimed to examine the impact of SMI on the proliferation, migration, invasion, and angiogenesis of tumor-derived endothelial cells (Td-EC).

Human umbilical vein endothelial cells (HUVEC) induced Td-EC, and HUVEC were treated with conditioned media from the human colorectal carcinoma cells (HCT116). The effects of HCT116 on the proliferation, migration, and invasion of hepatocellular carcinoma cells after treatment of SMI were observed by MTS assay and Transwell techniques. Additionally, an angiogenesis experiment was used to investigate Td-EC tube formation capacity.

SMI had a significant inhibiting effect on the proliferation, migration, and invasion of HCT116. SMI was also able to inhibit the angiogenesis of Td-EC. Notably, SMI did not have any effect on the normal endothelium.

SMI has obvious antiproliferation, migration, infiltration, and neogenesis effects on HCT116.

Patients with metastatic colorectal cancer (mCRC) undergoing systemic treatment often experience toxicities. Although exercise may improve physical fitness and quality of life and counteract treatment toxicity, knowledge in patients with mCRC is limited. The ongoing randomized controlled AMICO trial evaluates the effects of supervised exercise on clinical outcomes. The present qualitative study was a pre-planned part of this trial aiming to capture adherence, satisfaction, and perceived effects of exercise among patients with mCRC.

Patients with mCRC receiving first-line systemic treatment were randomized (1:1:1) to a control group or one of two supervised exercise arms including continuous aerobic exercise with either resistance exercises or high-intensity interval training. Semi-structured interviews with patients in the exercise arms were transcribed verbatim and thematically analyzed. Descriptive data on adherence (exercise logs) and satisfaction (questionnaire) was collected to complement and contextualize the qualitative findings.

Twenty-one patients were interviewed. Median exercise attendance was 67% [IQR 35-91], and the median satisfaction score was 8 [IQR 8-9] out of 10. Patients valued the guidance and knowledge of the physical therapist and expressed interindividual preferences regarding training content. Patients experienced that exercise improved their physical and mental wellbeing and helped them to endure treatment. Perceived exercise barriers were treatment toxicity, physical problems, and hospital appointments. Perceived exercise facilitators included adequate tailoring and internal or external motivation.

Patients with mCRC appreciated exercise during systemic treatment and perceived several beneficial effects, both physically and mentally. Exercise attendance varied and barriers were mainly treatment- and disease-related.

Clinical trial.

NCT04754672. Date of registration: 04-12-2020.

Reduction in skeletal muscle mass during chemotherapy is associated with poor outcomes. This study investigated the impact of changes in the psoas muscle index (PMI) on the prognosis of patients with unresectable colorectal liver metastases (CRLM) undergoing chemotherapy, including subgroup analyses based on the initial treatment response assessment.

We evaluated 47 patients with unresectable CRLM who underwent systematic chemotherapy and assessed changes in PMI to determine their prognosis.

Changes in PMI were significantly associated with the presence or absence of primary tumor resection and the chemotherapeutic responses to first-line chemotherapy. The PMI reduction group was significantly associated with poor prognosis in both overall survival (OS) and progression-free survival (PFS) in patients with CRLM, and in both OS and PFS in the partial response (PR) group at the initial chemotherapy response assessment.

Skeletal muscle loss at chemotherapy initiation was significantly associated with poorer survival in patients with unresectable CRLM. Maintaining muscle mass could serve as a new indicator for identifying patients with a PR at the initial chemotherapy response assessment for prognosis. Personalized interventions should be investigated to determine whether they can improve muscle mass and lead to better clinical outcomes.

Optimal local treatment for pulmonary oligometastases from colorectal cancer (CRC) remains unclear. We aimed to compare the long-term survival outcomes between surgery and stereotactic body radiation therapy (SBRT) as the initial local treatment for CRC pulmonary oligometastases.

We retrospectively reviewed 335 consecutive patients who initially underwent surgery or SBRT for CRC pulmonary metastases from 2011 to 2022, and 251 patients (173 surgery and 78 SBRT) were ultimately included. Freedom from intrathoracic progression (FFIP), progression-free survival (PFS), and overall survival (OS) were compared using stabilized inverse probability of treatment weighting (sIPTW) analysis. In addition, patterns of intrathoracic progression and subsequent treatment were analyzed.

Median follow-up was 61.6 months for surgery and 54.4 months for SBRT. After sIPTW adjustment, significant differences emerged in both FFIP and PFS between surgery and SBRT (FFIP: hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.31-0.79; PFS: HR = 0.56, 95% CI, 0.36-0.87). The 3- and 5-year FFIP rates were 58.6% and 54.8%, respectively, after surgery, and 34.6% and 31.3%, respectively, after SBRT (P = .006). The 3- and 5-year PFS rates were 49.4% and 45.2%, respectively, after surgery, and 28.8% and 26.1%, respectively, after SBRT (P = .010). However, OS was not significantly affected by treatment approach (HR = 0.93, 95% CI, 0.49-1.76). The 3- and 5-year OS rates were 85.9% and 73.1%, respectively, after surgery, and 78.9% and 68.7%, respectively, after SBRT (P = .849). Recurrence at the treated site was more prevalent after SBRT than after surgery (33.3% vs 16.9%), whereas new intrathoracic tumors occurred more frequently after surgery than after SBRT (71.8% vs 43.1%). Both groups chose radiation therapy as the primary local salvage treatment.

Notwithstanding the significant differences in FFIP and PFS between surgery and SBRT, the long-term survival of patients with CRC pulmonary oligometastases did not depend on the initial choice of the local treatment approach.

For patients with refractory metastatic colorectal cancer (mCRC), trifluridine/tipiracil (FTD-TPI) has been associated with a significant improvement in overall survival (OS). However, data are lacking regarding the activity of FTD-TPI in patients with BRAF-mutated mCRC.

This retrospective, multicenter, international cohort included patients with BRAF-mutated mCRC treated with FTD-TPI in a real-life setting in Spain and Italy. Survival analysis was performed using Kaplan-Meier methods and Cox proportional hazard models and according to established prognostic groups: good prognosis characteristics (GPC; < 3 metastatic sites and time from metastases to FTD-TPI ≥ 18 months) and poor prognosis characteristics (PPC; ≥ 3 metastatic sites or time from metastases to FTD-TPI < 18 months).

In the 26 patients included, the median age was 61 years, 13 (50%) were female, and 20 (77%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fourteen (56%) patients had right-sided tumors, six (23%) had microsatellite instability tumors, and thirteen (50%) had liver metastases. Median progression-free survival was 2.3 months (95% CI 2.0-3.2), and median OS (mOS) was 6.6 months (95% CI 4.4-12.0). mOS was 7.6 vs. 4.2 months (HR 1.64, 95% CI 0.65-4.10, p = 0.3) for GPC and PPC patients, respectively. Exploratory analyses identified ECOG as the only feature associated with survival. The most frequent grade 3-4 adverse events were neutropenia (8%), anemia (8%), and asthenia (4%).

Patients with BRAF mutant mCRC achieved modest benefits with FTD-TPI; however, patients with GPC and ECOG 0 achieved longer OS compared with those with PPC or ECOG 1-2, thus warranting further exploration in prospective cohorts.

The efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors in the treatment of advanced colorectal cancer is controversial. This meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors for advanced colorectal cancer.

PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for relevant studies. Outcomes including median progression-free survival (mPFS), median overall survival (mOS), overall response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs) and ≥grade 3 TRAEs were extracted for further analysis. The risk of bias was assessed by subgroup analysis.

12 articles with 566 patients were identified and subjected to meta-analysis. With regard to survival analysis, the pooled mOS and mPFS were 6.66 months (95%CI 4.85-9.16) and 2.92 months (95%CI 2.23-3.83), respectively. In terms of tumor response, the pooled ORR and DCR were 21% (95%CI 6%-41%) and 49% (95%CI 27%-71%), respectively. The pooled AEs rate and ≥ grade 3 AEs rate were 94% (95%CI 86%-99%) and 44% (95%CI 30%-58%).

PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors have shown promising clinical responses in the treatment of colorectal cancer (CRC). Although the incidence of adverse reactions is high, they are generally tolerable.

https://inplasy.com/, identifier INPLASY202480030.

Aim: The main aim of this study was to evaluate the effectiveness of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computerized tomography (PET/CT) parameters in predicting the Kristen rat sarcoma viral oncogene(KRAS) mutation status of patients with colon cancer. Materials and Methods: Between April 2013 and December 2020, 79 patients who were diagnosed with colon cancer by colonoscopy underwent staging 18FDG PET/CT with this diagnosis and met all the inclusion criteria were included in this study. Clinical and prognostic features and also imaging (18FDG PET/CT and magnetic resonance imaging) reports of the patients were collected and analyzed retrospectively. Results: KRAS mutation was seen in 32 of patients (40.5%). No significant difference was observed between KRAS mutant and wild-type patients in terms of clinical features (tumor location, findings regarding metastasis, T stage, and tumor differentiation grade in patients who underwent surgery) and overall survival. Progression-free survival was significantly shorter in KRAS mutant patients (p = 0.018). Primary tumor standardized uptake value (SUVmean) was significantly higher in KRAS mutant cases in the whole group (p = 0.024) and in patients in whom KRAS analysis was performed only in the primary lesion (p = 0.036). The cutoff value for predicting KRAS mutation status was 7.01 g/mL (area under the curve [AUC]: 0.650, confidence interval [CI] 95%, 0.56-0.74). Conclusions: When colon and rectal cancer cases were evaluated separately, the primary tumor SUVmean value was significantly higher in KRAS mutant colon cancer cases. However, its effectiveness in predicting KRAS mutation status was low, similar to other parameters in the literature.

Fruquintinib is a third-line and subsequent targeted therapy for patients with metastatic colorectal cancer (mCRC). Identifying survival predictors after fruquintinib is crucial for optimizing the clinical use of this medication.

We aimed to identify factors influencing the prognosis of patients with mCRC treated with fruquintinib and to leverage these insights to develop a nomogram model for estimating survival rates in this patient population.

Multicenter retrospective observational study.

We collected patient data from January 2019 to October 2023, with one healthcare institution's data serving as the training cohort and the other three hospitals' data serving as the multicenter validation cohort. The nomogram for overall survival was calculated from Cox regression models, and variable selection was screened using the univariate Cox regression analysis with additional variables based on clinical experience. Model performance was measured by the concordance index (C-index), calibration curves, decision curve analyses (DCA), and utility (patient stratification into low-risk vs high-risk groups).

Data were ultimately collected on 240 patients, with 144 patients included in the training cohort and 96 included in the multicenter validation cohort. Predictors included in the nomogram were CA199, body mass index, T stage, the primary site of the tumor, and other metastatic and pathological differentiation. The C-index of the nomogram in the training set and multicenter validation was 0.714 and 0.729, respectively. The models were fully calibrated and their predictions aligned closely with the observed data. DCA curves indicated the promising clinical benefits of the predictive model. Finally, the reliability of the model was also verified through the risk classification using the nomogram.

We constructed a nomogram for mCRC treated with fruquintinib based on six variables that may be used to assist in personalizing the use of the drug.

Colorectal cancer (CRC) ranks second in incidence and third in cancer mortality worldwide. This situation, together with the understanding of the heterogeneity of the disease, has highlighted the need to develop a more individualised approach to its prevention, diagnosis and treatment through personalised medicine. This approach aims to stratify patients according to risk, predict disease progression and determine the most appropriate treatment. It is essential to identify patients who may respond adequately to treatment and those who may be resistant to treatment to avoid unnecessary therapies and minimise adverse side effects. Current research is focused on identifying biomarkers such as specific mutated genes, the type of mutations and molecular profiles critical for the individualisation of CRC diagnosis, prognosis and treatment guidance. In addition, the study of the intestinal microbiota as biomarkers is being incorporated due to the growing scientific evidence supporting its influence on this disease. This article comprehensively addresses the use of current and emerging diagnostic, prognostic and predictive biomarkers in precision medicine against CRC. The effects of host genetics and gut microbiota composition on new approaches to treating this disease are discussed. How the gut microbiota could mitigate the side effects of treatment is reviewed. In addition, strategies to modulate the gut microbiota, such as dietary interventions, antibiotics, and transplantation of faecal microbiota and phages, are discussed to improve CRC prevention and treatment. These findings provide a solid foundation for future research and improving the care of CRC patients.

Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.

Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is an apoptosis inducer that exhibits an ideal therapeutic safety profile with less adverse effects than conventional chemotherapy. However, the occurrence of TRAIL resistance has been reported in various cancers including colorectal cancer (CRC). Substantial efforts have been channelled towards managing TRAIL resistance including identifying molecular targets. Interleukins (ILs) have been recently shown to play critical roles in modulating TRAIL sensitivity in cancer cells.

This study investigated the roles of two ILs, IL-8 and IL⍺, in TRAIL resistance in CRC. TRAIL-resistant HT-29 and TRAIL-sensitive HCT 116 cells, were treated with human recombinant IL-8 and IL-1⍺. The results indicated that treatment with IL-8 (2.5 ng/mL) significantly protected TRAIL-sensitive HCT 116 cells from TRAIL-induced cell death (p < 0.05). However, IL-1⍺ did not play a role in modulating CRC cells' responses to TRAIL. Data from RT-qPCR and Western blotting revealed the molecular regulations of IL-8 on TRAIL decoy receptor genes (OPG) and autophagy-related genes (BECN1 and LC3B) expression. The activation of the phosphoinositide 3-kinase (PI3K) pathway was shown to counteract TRAIL-induced cell death. By inhibiting its activation with wortmannin, the protective role of IL-8 against TRAIL treatment was reversed, suggesting the involvement of the PI3K pathway.

Collectively, findings from this study identified the role of IL-8 and PI3K in modulating CRC cells' sensitivity to TRAIL. Further validation of these two potential molecular targets is warranted to overcome TRAIL resistance in CRC.

Interval cancer (IC) is an important quality indicator in colorectal cancer (CRC) screening. Previously, we found that fecal immunochemical test (FIT) ICs are more common in women, older age, right-sided tumors, and advanced stage. Here, we extended our existing stage IV patient cohort with clinicopathological and molecular characteristics, to identify factors associated with FIT-IC.

Logistic regression models were fit to identify variables associated with the odds of having a stage IV FIT-IC. Multivariate models were corrected for gender, age, and location.

A total of 292 screen-detected (SD) CRCs and 215 FIT-IC CRCs were included. FIT-IC CRC had 5 fold higher odds to be a neuroendocrine (NET) tumor and 2.5 fold higher odds to have lymphovascular invasion. Interestingly, some variables lost significance upon accounting for location. Thus, tumor location is a critical covariate that should always be included when evaluating factors related to FIT-IC.

We identified NETs and lymphovascular invasion as factors associated with increased odds of having a stage IV FIT-IC. Moreover, we highlight the importance of tumor location as a covariate in evaluating FIT-IC related factors. More research across all stages is needed to clarify how these insights might help to optimize the Flemish CRC screening program.

Prior trials validated triplet chemotherapy (Tri-CT) with bevacizumab as first line treatment for metastatic colorectal cancer (mCRC) but real-world data are scarce and practices remain heterogeneous.

To evaluate Tri-CT +/- bevacizumab efficacy and safety, and to identify factors influencing treatment decisions.

The COLOTRIP retrospective study enrolled mCRC patients treated from 2014 to 2019 in 14 French centers.

Of 299 patients (81% PS 0-1, 58% RAS-mutated and 19% BRAF-mutated), 51% received Tri-CT and 49% Tri-CT + bevacizumab. Metastatic disease was classified as resectable (6.5%), potentially resectable (40%), and unresectable (54%). Bevacizumab use was associated with primary tumor location, mutational status and number of metastases. Median overall survival was 33.5 months in the Tri-CT group and 23.9 months in the Tri-CT + bevacizumab group, with median progression-free survival being 14.5 and 11.4 months. After adjusting for initial characteristics, no difference in survival was noted. Around 30% of patients experienced grade ≥3 adverse events.

This study highlights several factors influencing Tri-CT use +/- bevacizumab decision and confirms the real-world good oncological outcomes and tolerability of these regimens in mCRC patients. Our results suggest that Tri-CT alone may by an appropriate option for specific subgroups of patients.

About one third of patients with deficient mismatch repair/microsatellite instability-high metastatic colorectal cancer (dMMR/MSI-H mCRC) experience primary resistance or early progression on immune checkpoint inhibitors (ICI), while others benefit from exceptionally long-lasting responses. In this single-centre retrospective study, we aimed to identify variables associated with improved overall survival (OS) as well as early disease progression.

All dMMR/MSI-H mCRC patients treated with ICI between 2014 and 2022 were included. Baseline patient demographics, tumour characteristics as well response and outcome data were recorded. OS was estimated using the Kaplan-Meier method. Uni- and multivariate cox regression analysis was used to identify parameters associated with improved OS. Clinicopathological factors associated with early progression (≤ 12 months after treatment initiation) were assessed using uni- and multivariate logistic regression analysis.

About 84 ICI-treated dMMR/MSI-H mCRC patients were included. Progressive disease occurred in 37 (44%) patients, but only in 11 (19%) patients with disease control at 12 months. Median OS was 80 months and improved outcome was associated with a lower neutrophile-to-lymphocyte ratio (NLR) (P = .004) and the presence of immune-related adverse events (irAEs) (P = .015). Early progression was associated with poor performance status (P = .036), a higher blood CRP level (P = .033) and absence of irAEs (P = .002).

Disease progression in ICI-treated dMMR/MSI-H mCRC rarely occurs in patients experiencing disease control for at least 12 months. Performance status, presence of immune-related adverse events, CRP levels, CEA levels and NLR can be helpful to identify those patients that may benefit from ICI treatment, guiding clinicians in therapeutic decisions.

Accumulated evidence highlights the biological significance of diverse protein post-translational modifications (PTMs) in tumorigenicity and progression of colorectal cancer (CRC). In this study, ten PTM patterns (ubiquitination, methylation, phosphorylation, glycosylation, acetylation, SUMOylation, citrullination, neddylation, palmitoylation, and ADP-ribosylation) were analyzed for model construction. A post-translational modification index (PTMI) with a 14-gene signature was established. CRC patients with high PTMI had a worse prognosis after validating in nine independent datasets. By incorporating PTMI with clinical features, a nomogram with excellent predictive performance was constructed. Two molecular subtypes of CRC with obvious difference in survival time were identified by unsupervised clustering. Furthermore, PTMI was related to known immunoregulators and key tumor microenvironment components. Low-PTMI patients responded better to fluorouracil-based chemotherapy and immune checkpoint blockade therapy compared to high-PTMI patients, which was validated in multiple independent datasets. However, patients with high PTMI might be sensitive to bevacizumab. In short, we established a novel PTMI model by comprehensively analyzing diverse post-translational modification patterns, which can accurately predict clinical prognosis and treatment response of CRC patients.

Identifying precise biomarkers for colorectal cancer (CRC) detection and management remains challenging. Here, we developed an innovative prognostic model for CRC using cuproptosis-related long non-coding RNAs (lncRNAs).

In this retrospective study, CRC patient transcriptomic and clinical data were sourced from The Cancer Genome Atlas database. Cuproptosis-related lncRNAs were identified and used to develop a prognostic model, which helped categorize patients into high- and low-risk groups. The model was validated through survival analysis, risk curves, independent prognostic analysis, receiver operating characteristic curve analysis, decision curves, and nomograms. In addition, we performed various immune-related analyses. LncRNA expression levels were examined in normal human colorectal epithelial cells (FHC) and CRC cells (HCT-116) using quantitative polymerase chain reaction (qPCR).

Six cuproptosis-related lncRNAs were identified: ZKSCAN2-DT, AL161729.4, AC016394.1, AC007128.2, AL137782.1, and AC099850.3. The prognostic model distinguished between high-/low-risk populations, demonstrating excellent predictive ability for survival outcomes. Immunocorrelation analysis showed significant differences in immune cell infiltration and functions, immune checkpoint expression, and m6A methylation-related genes. The qPCR results showed significant upregulation of ZKSCAN2-DT, AL161729.4, AC016394.1, AC007128.2 in HCT-116 cells, while AL137782.1 and AC099850.3 expression patterns were significantly downregulated.

Cuproptosis-related lncRNAs can potentially serve as reliable diagnostic and prognostic biomarkers for CRC.

Over the years immunotherapy has demonstrably improved the field of cancer treatment. However, achieving long-term survival for colorectal cancer (CRC) patients remains a significant unmet need. Combination immunotherapies incorporating targeted drugs like MEK or multi-kinase inhibitors have offered some palliative benefit. Nevertheless, substantial gaps remain in the current therapeutic armamentarium for CRC. In recent years, there has been a surge of interest in exploring novel treatment strategies, including the application of light-activated drugs in conjunction with optical devices. This approach holds promise for achieving localized and targeted delivery of cytotoxic agents, such as microtubule-targeting drugs, directly to cancerous cells within the colon.

This study aims to establish a machine learning (ML) model for predicting the risk of liver and/or lung metastasis in colorectal cancer (CRC).

Using the National Institutes of Health (NIH)'s Surveillance, Epidemiology, and End Results (SEER) database, a total of 51265 patients with pathological diagnosis of colorectal cancer from 2010 to 2015 were extracted for model development. On this basis, We have established 7 machine learning algorithm models. Evaluate the model based on accuracy, and AUC of receiver operating characteristics (ROC) and explain the relationship between clinical pathological features and target variables based on the best model. We validated the model among 196 colorectal cancer patients in Beijing Electric Power Hospital of Capital Medical University of China to evaluate its performance and universality. Finally, we have developed a network-based calculator using the best model to predict the risk of liver and/or lung metastasis in colorectal cancer patients.

51265 patients were enrolled in the study, of which 7864 (15.3 %) had distant liver and/or lung metastasis. RF had the best predictive ability, In the internal test set, with an accuracy of 0.895, AUC of 0.956, and AUPR of 0.896. In addition, the RF model was evaluated in the external validation set with an accuracy of 0.913, AUC of 0.912, and AUPR of 0.611.

In this study, we constructed an RF algorithm mode to predict the risk of colorectal liver and/or lung metastasis, to assist doctors in making clinical decisions.

The treatment landscape for patients with colon cancer is continuously evolving. Risk-adapted treatment strategies, including neoadjuvant chemotherapy and immunotherapy, are slowly finding their way into clinical practice and guidelines. Radiologists are pivotal in guiding clinicians toward the most optimal treatment for each colon cancer patient. This review provides an overview of recent and upcoming advances in the diagnostic management of colon cancer and the radiologist's role in the multidisciplinary approach to treating colon cancer.

Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab.

15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM).

Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity.

We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.

The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time.

This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed.

Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.

Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial-mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK-Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle-encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM.

TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK-Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.

Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Stage IV colorectal cancer (CRC) often requires multidisciplinary approach. However, multimodal treatment options (receipt of > 1 type of treatment) may not be uniformly delivered across health systems. We characterized the association between center-level cancer center designation and receipt of multimodal treatment and survival.

The Texas Cancer Registry was used to identify patients diagnosed with stage IV CRC from 2004-2017. We identified those who received care at either: a National Cancer Institute-designated (NCI-D), an American College of Surgeons-Commission on Cancer-designated (ACS-D), or an undesignated facility. We used multivariable logistic regression and Cox regression for analysis to assess receipt of one or more treatment modality and 5-year overall survival.

Of 19,355 patients with stage IV CRC, 2955 (15%) received care at an NCI-D facility and 5871 (30%) received multimodal therapy. Both NCI-D (odds ratio [OR] 1.64; 95% confidence interval [CI] 1.49-1.81) and ACS-D (OR 1.37; 95% CI 1.27-1.48) were associated with increased likelihood of multimodal therapy compared with undesignated centers. NCI-D also was associated with significantly improved survival (hazard ratio [HR] 0.74; 95% CI 0.70-0.78), although ACS-D was associated with a modest improvement in survival (HR 0.95; 95% CI 0.92-0.99). Receipt of multimodal therapy was strongly associated with improved survival (HR 0.61; 95% CI 0.59-0.63).

In patients with stage IV CRC, treatment at ACS-D and NCI-D facilities was associated with increased use of multimodality therapy and improved survival. However, only a small proportion of patients have access to these specialized centers, highlighting a need for expanded access to multimodal therapies at other centers.

Patients with both BRAF V600E mutations and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) have poor prognosis. Currently, there are no specifically targeted first-line treatment options indicated for patients with mCRC whose tumors harbor both molecular aberrations. Pembrolizumab is a checkpoint inhibitor approved for the treatment of MSI-H/dMMR mCRC, and the BRAF inhibitor encorafenib, in combination with cetuximab, is approved for previously treated BRAF V600E-mutant mCRC. Combination of pembrolizumab with encorafenib and cetuximab may synergistically enhance antitumor activity in patients with BRAF V600E-mutant, MSI-H/dMMR mCRC. SEAMARK is a randomized phase II study comparing the efficacy of the combination of pembrolizumab with encorafenib and cetuximab versus pembrolizumab alone in patients with previously untreated BRAF V600E-mutant, MSI-H/dMMR mCRC.