Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown survival benefits in select patients with peritoneal metastases (PM) from colorectal cancer (CRC). Molecular alterations, particularly RAS/BRAF mutations and Microsatellite Instability (MSI), play crucial roles in prognostic stratification and treatment planning, influencing both disease-free survival (DFS) and overall survival (OS). This scoping review evaluates the prognostic role of MSI and RAS/BRAF mutations in patients with PM-CRC treated with CRS-HIPEC.

A literature search was conducted across several databases to identify papers published between 2000 and September 2024. We selected 18 publications that considered DFS and OS as primary or secondary outcomes in patients with RAS/BRAF mutations and MSI following CRS-HIPEC treatment. Studies involving appendiceal cancer, peritoneal disease from non-CRC, pediatric patients, or subjects not treated with CRS-HIPEC were excluded.

Most studies suggest that RAS and BRAF mutations have a negative influence on survival outcomes. While inconsistencies exist, RAS mutations are generally associated with worse DFS. Specific KRAS subtypes such as KRASMUT2 or KRAS G12V and the BRAF V600 variant correlate with poorer prognosis. MSI status appears to attenuate the adverse effects of RAS/BRAF mutations on survival, although conflicting data persist.

RAS and BRAF mutations correlate with poorer outcomes in PM-CRC, underscoring the need for mutation-informed strategies to refine HIPEC and systemic therapies. Recognizing subtypes may improve patient selection for CRS-HIPEC, optimizing both local disease control and long-term survival. Future research should incorporate these molecular profiles to enhance therapeutic decision-making and better address this challenging condition.

Nearly one-quarter of colorectal cancer (CRC) cases present with de novo metastatic disease (stage IV) at diagnosis. Some metastatic sites confer poorer prognosis, and emerging data suggests that individuals from certain racial and ethnic populations may be at higher risk for de novo metastases.

We identified 181,083 CRC cases aged 20-84 between 2010 and 2020 in the Surveillance, Epidemiology, and End Results database. Two outcomes were analyzed: metastatic site (liver, lung, bone, brain) and metastatic pattern (liver only, lung only, liver and lung, other). We used logistic and multinomial logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) to examine the associations between race and ethnicity and metastatic site and metastatic pattern, respectively, among early-onset (age < 50), screen-eligible (age 50-74), and elderly populations (age 75-84).

43,054 de novo metastatic CRC cases were identified over the 10-year period. Liver was the most common metastatic site (80%). Non-Hispanic Black patients had higher odds of synchronous lung and liver metastases compared to non-Hispanic White (NHW) patients (early-onset patients: OR: 1.29, 95% CI 1.03-1.61; screen-eligible patients: OR:1.42, 95% CI 1.29-1.55; elderly patients: OR:1.66, 95% CI 1.34-2.05). Early-onset American Indian/Alaska Native patients were over twice as likely to present with lung metastases (OR: 2.10, 95% CI 1.11-3.98) compared to NHW patients.

Presentation and patterns of de novo metastatic CRC differed across populations and age groups. Characterizing de novo metastatic CRC provides a unique opportunity to study cancer spread in treatment-naïve individuals and to identify patients at greater risk of metastases associated with poorer prognosis.

Resistance to radiation therapy is a common challenge in the field of oncology. Cancer cells with an increased ability to effectively repair DNA or cells with higher levels of antioxidants are more resistant to radiation. As cancer cells rely on these traits for survival, they may offer vulnerabilities that could be exploited.

In the current study, rectal cancer organoids that showed different responses to radiation treatment were identified. RNA sequencing was used to compare radioresistant and radiosensitive organoids. In vitro combination drug screens were performed. The selection of drugs was guided by the RNA sequencing results.

Radioresistant organoids exhibited superior transcriptional adaptability and activated more DNA repair pathways when irradiated. Additionally, radioresistant organoids displayed enhanced antioxidant metabolism, including pathways related to the detoxification of reactive oxygen species and the synthesis of glutathione. Combinatorial drug screens identified the combination of RRx-001 (an inducer of oxidative stress) with GCLC inhibitor BSO as a highly effective and synergistic drug combination in killing radioresistant organoids. CRISPR-CAS-mediated knockout of GCLC sensitised organoids to RRx-001.

Combining RRx-001 with the inhibition of GCLC may be a promising alternative treatment strategy in radioresistant rectal cancer.

Mismatch repair deficiency leads to high mutation rates and microsatellite instability (MSI-H), associated with immune infiltration and responsiveness to immunotherapies. In early stages, MSI-H tumors generally have a better prognosis and lower metastatic potential than microsatellite-stable (MSS) tumors, especially in colorectal cancer. However, in advanced stages, MSI-H tumors lose this survival advantage for reasons that remain unclear. We developed a syngeneic mouse model of MSI cancer by knocking out the MMR gene Msh2 in the metastatic 4T1 breast cancer cell line. This model mirrored genomic features of MSI-H cancers and showed reduction in metastatic incidence compared to their MSS counterparts. In MSI-H tumors, we observed an enrichment of immune gene-signatures that negatively correlated with metastasis incidence. A hybrid epithelial-mesenchymal signature, related to aggressiveness was detected only in metastatic MSI-H tumors. Interestingly, we identified immature myeloid cells at primary and metastatic sites in MSI-H tumor-bearing mice, suggesting that MMR deficiency elicits specific immune responses beyond T-cell activation.

Aim: As intrinsic resistance - often driven by concurrent genomic alterations in tumor suppressor genes or oncogenes - remains a major challenge in oncology, this work aimed to comprehensively analyze BRAF somatic alterations across cancer types and identify new potential therapeutic strategies to overcome drug resistance. Methods: We conducted an extensive analysis of genomics, transcriptomics, and clinical data retrieved from public repositories, including cBioPortal. Our comprehensive analysis examined BRAF alterations [point mutations, structural variants (SVs) and copy number alteration] in more than 217,000 tumor samples across 120 distinct tumor types from primary and metastatic sites in both adult and pediatric cohorts, focusing on mutual exclusivity and co-occurrence of mutations in other oncogenes or tumor suppressors. The work also explores the association of BRAF somatic alterations with survival, clinical and molecular features. Results: Analysis of mutation frequencies across cancer types revealed that BRAFV600E represents approximately 90% of all BRAF alterations. While melanoma and thyroid carcinoma show the highest prevalence of BRAF mutations, followed by colorectal and non-small cell lung cancer in terms of absolute number of patients harboring BRAF mutations worldwide, notably high mutation frequencies were identified in rare malignancies, including hairy-cell leukemia, ganglioglioma, and serous borderline ovarian tumors. The comprehensive analysis of genomic profiling data across these tumors uncovered distinct patterns of co-occurring and mutually exclusive alterations in oncogenes and tumor suppressor genes, illuminating resistance mechanisms and suggesting novel therapeutic combinations. Conclusion: Comprehensive genomic profiling is critical for optimizing targeted therapy and overcoming drug resistance in BRAF-mutated cancers. The identification of co-occurring alterations provides opportunities for rational combination therapies, emphasizing the importance of detailed mutation profiling in developing effective treatment strategies across diverse cancer types.

BRAF-mutated colorectal cancer correlates with poor prognosis and limited response to standard treatments. Combining immune checkpoint inhibitors with BRAF/MEK inhibitors shows promise against BRAF-mutant melanoma in both preclinical and clinical trials. Therefore, we hypothesized that the treatment would be effective against BRAF-mutant colorectal cancer. In this study, we assessed the efficacy of combining immune checkpoint inhibitors with BRAF and/or MEK inhibitors in BRAF-mutant colorectal cancers. We treated BRAF V600E colorectal cancer cells HT-29 and SNU-1235 with encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) and assessed the degrees of MAPK inhibition, JAK/STAT inhibition, cell viability, apoptosis, and the expression of antigen presenting machinery. We also inoculated HT-29 cells into mice and treated them with an immune checkpoint inhibitor (durvalumab), encorafenib, and binimetinib for 4 weeks. We found that treatment with BRAF inhibitor, MEK inhibitor, or their combination led to significant tumor growth reduction, along with the MAPK and JAK/STAT pathway inhibition, antigen presenting machinery induction, and cytotoxic T cell activation. Our study demonstrates the potential effectiveness of combining immune checkpoint inhibitors with BRAF or MEK inhibitors for BRAF-mutated colorectal cancers.

The BRAF-mutation is a poor prognostic factor in colorectal cancer (CRC). There is a need for real-world data in low-middle-income countries regarding clinical characteristics, outcomes, and treatment strategies. This study aims to describe progression-free survival (PFS) and in the first- and second-line setting and sequences of treatment regimens.

We retrospectively analyze patients from ten oncology centers in Argentina, diagnosed with BRAFV600E-mutated advanced CRC between January 2014 and July 2023.

A total of 161 patients with metastatic CRC and BRAFV600E-mutation. The median age was 58.5 (IQR 47-69), and 21.7% were MMR-deficient (dMMR). Of these patients, 93.8% received first-line treatment. With a median follow-up of 23 months (95% CI 16.5-33.4 months), the median PFS was 9 months (95% CI 7.4-10.5 months). The most common regimen in first line setting was doublet chemotherapy plus anti-VEGF for 49% of the patients. Twenty-six percent of the patients received BRAF inhibitors in the second-line setting, with a median PFS of 5.2 months (95% CI 4.9-NR); the overall response rate (ORR) was 10.5%.

This study represents, to the best of our knowledge, the largest published real-world cohort of BRAFV600E-mutated CRC in Latin America. The heterogeneity of the treatments reflects the existence of barriers to access to high-cost drugs in our country. Cooperative efforts are needed to understand the particular characteristics of this subgroup of patients.

Radiotherapy (RT) is an essential treatment for colorectal cancer (CRC), yet the factors influencing radiosensitivity remain unclear. In the quest to enhance the therapeutic efficacy in CRC, the interplay between genetic mutations and RT sensitivity has emerged as a pivotal yet enigmatic area.

We harness the fidelity of patient-derived organoids (PDOs) to dissect the molecular landscape of radiosensitivity, with a particular emphasis on BRAFV600E mutations. To further investigate, a cohort of 9 BRAFV600E-mutant and 10 BRAF wild-type PDOs is constructed to systematically assess the radiobiological traits of BRAFV600E-mutant CRC, including morphology, cell viability, and DNA damage, while also evaluating their responses to chemotherapy and chemoradiotherapy.

Our systematic investigation unveils a profound correlation between BRAFV600E mutation status and radioresistance, which is validated by clinical treatment responses. Intriguingly, BRAFV600E-mutant PDOs exhibit reduced sensitivity to conventional chemotherapy, yet demonstrate an enhanced response to combined chemoradiotherapy, characterized by increased apoptosis. The results are validated through in vivo analyses using patient-derived organoid xenograft mouse models and aligned with patient clinical outcomes.

This study outlines the distinct radiobiological profile of BRAFV600E-mutant CRC, underscoring the critical role of radiotherapy in comprehensive treatment strategies. This work not only advances our molecular understanding of CRC but also paves the way for precision medicine, offering valuable insights for therapeutic decision-making in the clinical management of BRAFV600E-mutant CRC.

Impact of BRAF V600E mutations (BRAFV600E), a poor prognostic factor in metastatic colorectal cancer, is lacking in non-CRC gastrointestinal (GI) cancers including pancreatic (PDAC), gastric/gastroesophageal (GEA), hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). Due to tumor-agnostic approvals for patients with BRAFV600E, understanding the frequency and impact of BRAF alterations across non-CRC GI cancers is essential for clinical decision-making.

Patients with PDAC, GEA, HCC, or CCA who had cell-free DNA detected on Guardant360 (Guardant Health) from 2020 to 2023 were queried. Prevalence of characterized BRAF genomic alterations (GA) was calculated; GAs were grouped by class (Class I/II/III). The Chi-squared test assessed differences between cancer types. A subset of patients had outcomes analysis using GuardantINFORM, a real-world clinicogenomic database, to derive real-world overall survival (rwOS).

Of 32 480 included patients, BRAF GAs were identified in 4.4%; 19% were BRAFV600E (0.81% prevalence overall). CCA had the highest rate of BRAF GAs and BRAFV600E (P < .01); HCC and GEA had the highest rates of BRAF class II/III alterations. There were no significant differences in rwOS by alteration class or cancer type; numeric differences were observed by alteration class. Few patients were treated with BRAF inhibitors (2.2%). Prevalence of co-occurring alterations was unique by cancer type.

Frequency of BRAF GAs, including BRAFV600E, in non-CRC GI cancers detected by liquid biopsy is similar to tissue-based rates and can be reliably used to assess BRAF status. BRAF GAs have mixed prognostic implications on survival for patients with non-CRC GI malignancies that warrant further exploration.

Detection of the BRAF V600E mutation has important genetic, prognostic, and therapeutic implications for patients with metastatic colorectal cancer (mCRC), identifying a subgroup of patients who derive modest benefit from standard treatments and have extremely poor prognosis. The evolution of molecular profiling and the implementation of next generation sequencing in the evaluation of a patient with BRAF-mutated mCRC has currently led to the discovery of actionable alterations. Targeting multiple pathways of resistance in BRAF-mutated mCRC may be the most efficacious route. Then, over a short period of time, the treatment landscape BRAF-mutated mCRC patients has shifted dramatically. Finally, novel treatment strategies are available. This review will discuss on currently approved treatments for BRAF V600E mutated mCRC and will try and portray the changing landscape in this setting in the era of targeted molecular therapy.

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, 2.443; 95% confidence interval (CI): 1.403-4.253; 99.8% CI: 1.019-5.855; one-sided P = 0.0008). Median duration of response was 13.9 versus 11.1 months. At this first interim analysis of overall survival, the hazard ratio was 0.47 (95% CI: 0.318-0.691; repeated CI: 0.166-1.322). Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 .

Immunotherapy is an effective treatment for BRAF V600E-mutant colorectal cancer, but currently, only a few benefit from it. Therefore, exploring new immunotherapy strategies is essential.

We obtained RNA sequencing data and clinical information of colorectal cancer patients from the TCGA and GEO databases. The impact of the BRAF V600E mutation on tumor microenvironment characteristics, gene expression, and signaling pathways was evaluated using bioinformatics approaches. Weighted gene co-expression network analysis (WGCNA) were used to identify core genes associated with T cell dysfunction. Consensus clustering was applied for subtype construction. Least Absolute Shrinkage and Selection Operator (LASSO) and Random Forest (RF) algorithms were employed to filter potential immunotherapy targets.

We found that BRAF V600E mutation has a complex impact on the immune profile of colorectal cancer. It increases immune cell infiltration and activates immune-related signaling pathways, yet it also severely restricts T cell function. We subsequently identified 39 core genes associated with T cell dysfunction and constructed subtypes of BRAF V600E colorectal cancer based on their expression profiles. Significant heterogeneity was observed between these subtypes in immune signaling pathway activity, immune infiltration patterns, immune phenotype scores, and mechanisms of resistance to immunotherapy. Ultimately, using machine learning algorithms and bioinformatics validation, we identified IDO1 as a potential immunotherapy targets for BRAF V600E-mutant colorectal cancer.

This study constructed novel T cell dysfunction molecular subtypes for BRAF V600E-mutant colorectal cancer and identified IDO1 as a potential immunotherapy target, providing a new strategy for immunotherapy.

Appendiceal Adenocarcinoma (AA) is a rare gastrointestinal cancer with no FDA-approved targeted therapies. Here, we retrospectively compare BRAF-mutant AA and colorectal cancer (CRC). BRAF mutation is rare in AA (3%). Unlike CRC, BRAFV600E AA is not associated with poor prognosis, female sex, microsatellite instability, mucinous histology, or poor differentiation. In both cancers, BRAFV600E but not atypical BRAF mutations are mutually exclusive with other Ras-activating mutations. BRAFV600E + EGFR inhibition shows efficacy in BRAFV600E AA (disease control rate = 80%, median progression-free survival = 7.1 months).

The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.

BRAF p.V600E exon 15 hotspot mutation can identify a molecular subgroup of metastatic colorectal cancer (mCRC) patients exhibiting poor prognosis under the conventional chemotherapy regimen. Recently, the chemotherapy-free combination of encorafenib and cetuximab has been approved as the standard of care for previously treated BRAF p.V600E mCRC patients, and genomic testing for BRAF mutations at the time of mCRC diagnosis is currently recommended. In clinical practice, BRAF mutation testing strategies are dramatically impacted by a lack of harmonization and standardization, both in the pre-analytical and analytical phases, which can result in BRAF-mutated patients not receiving the most appropriate therapy at recurrence. This paper proposes nine statements providing practical and concise advice on BRAF mutation testing in CRC, derived from collegial discussion and analysis of a multidisciplinary team of experts, including referral Italian oncologists and pathologists. The statements overview pivotal aspects implied in the detection, treatment and management of BRAF-mutated patients and have been drafted to represent a valuable tool for healthcare professionals committed to mCRC patient management. In addition, they represent a platform for implementing diagnostic-therapeutic workflows that can adapt to the variability of local resources while respecting the high-quality standards required by modern precision oncology.

Brain metastasis leads to poor outcomes and CNS injury, significantly reducing quality of life and survival rates. Advances in understanding the tumor immune microenvironment have revealed the promise of immunotherapies, which, alongside surgery, chemotherapy, and radiation, offer improved survival for some patients. However, resistance to immunotherapy remains a critical challenge. This review explores the immune landscape of brain metastases, current therapies, clinical trials, and the need for personalized, biomarker-driven approaches to optimize outcomes.

Manatū Hauora, the Ministry of Health of New Zealand (NZ), published minimum standards for molecular testing of colorectal cancers (CRCs) in June 2018. These included mismatch repair (MMR) testing at diagnosis and BRAFV600E mutation analysis on newly diagnosed stage IV CRCs. This study aimed to determine the proportion of patients with CRC in the South Island of NZ with metastatic deficient mismatch repair (dMMR) CRC, the proportion of metastatic CRCs and dMMR CRCs that have a BRAFV600E mutation, and audit testing for BRAF mutations and appropriate referral to genetics services.

People from the South Island with histologically diagnosed colorectal adenocarcinoma between July 1, 2018, and June 30, 2019, were identified by the National Cancer Registry. Data points extracted from the electronic medical record included staging, MMR status, BRAF mutation testing, and genetics referral.

A total of 845 patients met the inclusion criteria; 166 of 845 (19.6%) had dMMR CRC, and of these 130 (78%) had BRAF mutation, 256 patients developed metastatic disease by data cut-off, 20 (7.8%) had dMMR, and 41 (22.2%) had BRAF mutation. When indicated, 275 of 330 (83.3%) were tested for BRAF mutation and 32 of 45 (71.1%) referred to genetics. Compared with other populations, South Island CRC patients had higher rates of dMMR and BRAF mutation.

Less than 10% of patients (n = 20) had metastatic dMMR CRC. These patients could be considered candidates for immune checkpoint inhibitor therapy, a small number that would not significantly burden the NZ health system if funded. The vast majority of dMMR CRC was sporadic. Rates of testing could be improved.

The optimal second-line systemic treatment for metastatic colorectal cancer (mCRC) is inconclusive.

We searched PubMed, Web of Science, EMBASE, and Cochrane Library for RCTs comparing second-line systemic treatments for mCRC from the inception of each database up to February 3, 2024. Markov Chain Monte Carlo (MCMC) technique was used in this network meta-analysis (NMA) to generate the direct and indirect comparison results among multiple treatments in progression-free survival (PFS), overall response rate (ORR), overall survival (OS), complete response (CR), partial response (PR), grade 3 and above adverse events (Grade ≥ 3AE), and any adverse events (Any AE). The surface under the cumulative ranking curve (SUCRA) was adopted to evaluate the probability of each treatment being the optimum intervention. Subgroup analyses were performed based on the RAS gene status.

A total of 47 randomized controlled trials were included, involving 16,925 patients and 44 second-line systemic treatments. In improving OS, FOLFOX + Bevacizumab + Erlotinib exhibited significant superiority (SUCRA:92.7%). In improving PFS, Irinotecan + CMAB009 (SUCRA:86.4%) had advantages over other treatments. FOLFIRI + Trebananib (SUCRA:88.1%) had a significant advantage in improving ORR. Among multiple second-line treatments, the SUCRA values of FOLFOX + Bevacizumab in PFS, OS, ORR, and PR were 83.4%, 74.0%, 81.1%, and 86.1%, respectively, and the safety was not significantly different from other interventions. Subgroup analyses showed that FOLFIRI + Bevacizumab + panitumumab ranked among the top in survival outcomes in the RAS-mutant population (OS SUCRA: 87.9%; PFS SUCRA: 70.2%); whereas in the RAS-wild-type population, FOLFIRI + Bevacizumab significantly improved survival outcomes (OS SUCRA: 73.2%; PFS SUCRA: 65.1%).

For most people, FOLFOX + Bevacizumab may be the best second-line systemic treatment regimen for mCRC. For RAS-mutant populations, FOLFIRI + Bevacizumab + Panitumumab is recommended. However, the therapeutic effect may be affected by the patient's physiological state, and clinicians should apply it based on actual conditions.

Colorectal cancers (CRC) with BRAF V600E mutation exhibit limited chemotherapy response and a poor prognosis. Safety and efficacy of the VIC (Vemurafenib/Irinotecan/Cetuximab) regimen in the first-line setting for patients with BRAF V600E-mutated CRC remain undetermined.

In the prospective cohort study, the untreated, BRAF V600E-mutated, unresectable or metastatic CRC patients were enrolled. The VIC regimen and bevacizumab plus chemotherapy were compared in the first-line setting. The objective response rate (ORR), disease control rate (DCR), conversion resection rate, progression-free survival (PFS), and overall survival (OS) were evaluated.

In the intent-to-treat analysis, 38 patients received VIC regimen and 40 received bevacizumab plus chemotherapy. The ORR and DCR in the VIC group were significantly higher than in the bevacizumab-therapy group (ORR: 63.2% vs. 37.5%, P = .025; DCR: 94.7% vs. 75.0%, P = .019). The VIC regimen significantly outperformed bevacizumab plus chemotherapy in both PFS (11.9 vs. 7.7 months; hazard ratio [HR] = 0.51, 95% CI, 0.30-0.87; P = .010) and OS (25.3 vs. 14.6 months; HR = 0.43, 95% CI, 0.22-0.82; P = .011). In the VIC group, the conversion resection rate for liver metastases was 34.8% (8 of 23 patients), and for unresectable local CRC it was 54.5% (6 of 11 patients). The adverse events rates of Grade 3 to 4 were 34.2% and 32.5% for the VIC regimen and bevacizumab plus chemotherapy respectively.

Among Asian patients with BRAF V600E-mutated CRC, the VIC regimen showed favorable outcomes compared to bevacizumab plus chemotherapy in terms of tumor response and oncological survival, with a tolerable and manageable toxicity profile in the first-line setting.

Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.

Colorectal cancer (CRC) remains a significant global health burden, necessitating a thorough understanding of prognostic and predictive factors to enhance patient outcomes. This systematic review aims to comprehensively evaluate prognostic and predictive determinants in CRC, encompassing both traditional and emerging biomarkers. A systematic search of major electronic databases was conducted to identify relevant studies published from 1995 up to 2024. Eligible articles were critically appraised, and data extraction was performed according to predefined criteria. The prognostic determinants examined included clinicopathological features such as tumor stage, grade, and lymph node involvement, as well as molecular biomarkers including RAS, BRAF, and MSI status. Predictive determinants encompassed biomarkers influencing response to targeted therapies and immunotherapy, such as HER2 and Immunoscore. The review also explores novel prognostic and predictive markers, including tumor microenvironment characteristics and liquid biopsy-based biomarkers. Synthesizing evidence from diverse studies, this review provides insights into the prognostic and predictive landscape of CRC, highlighting the potential clinical implications of identified determinants. Understanding the multifaceted nature of prognostic and predictive factors in CRC is imperative for the advancement of personalized treatment strategies and improvement of patient outcomes.

Patients with BRAF 600E mutated mCRC are associated with specific clinicopathological features and poor prognosis. The relative efficacy of first-line FOLFOXIRI triplet chemotherapy or doublet chemotherapy combined with bevacizumab in patients with BRAF 600E mutated mCRC remains controversial.

BRAF V600E-mutated mCRC patients from 3 institutions were included. The clinicopathological characteristics of the enrolled patients were analyzed. Overall survival (OS) of patients was divided into 4 fractions, including 0-25%, 25-50%, 50-75%,75-100% by quartile method. Patients with OS ranging from 0 to 25% were defined as the poor prognosis group, and patients with OS ranging from 75 to 100% were defined as the good prognosis group. A propensity score matching (PSM) analysis was performed to balance the baseline characteristics of patients treated with doublet chemotherapy and triplet chemotherapy combined with bevacizumab. Survival and tumor response of the two regimens were evaluated.

A total of 125 patients with BRAF V600E-mutated mCRC were enrolled. The median OS of BRAF V600E-mutated mCRC was 14.9 months and the median PFS of first-line therapy was 6.1 months. According to the multivariate analysis and the difference in baseline characteristics between the poor prognosis group and the good prognosis group, poor differentiation and liver metastasis were negative independent prognostic factors for OS in patientsx with BRAF V600E-mutated mCRC. Patients treated with first-line triplets had a longer OS than those treated with doublets both before PSM (17.4 months vs. 13.4 months, p = 0.022) and after PSM (17.4 months vs. 10.4 months, p = 0.004). There was no significant benefit between triplet-drug group and doublet-drug group for PFS, ORR and DCR. Subgroup analysis showed that patients in the triplet-drug group had a better prognosis with the following favorable factors: age ≤ 60 years old, PS score of 0-1, liver metastases and multiple organ metastases.

The overall prognosis of BRAF V600E mutant mCRC patients is poor. Poor differentiation and liver metastases were negative independent prognostic factors for OS. First-line triplet-drug therapy was associated with better OS, especially in patients with good physical condition and high tumor burden.

Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated with a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.

Patients with right-sided metastatic colon carcinoma have a significantly worse prognosis than those with left-sided colorectal cancer (CRC), regardless of treatment. The aim of the prospective IVOPAK II study was to implement an interdisciplinary guideline-conform personalized CRC palliative therapy of metastatic colorectal carcinoma and to improve the overall survival (OS) by multidisciplinary approach via secondary metastatic resection. We present the efficacy data of first-line treatment and the benefit of interdisciplinary collaboration of right-sided metastatic colon carcinoma patients: n  = 25. RAS mutation: n  = 20 (80%): received systemic first-line treatment: FOLFIRI plus bevacizumab. All-RAS-wildtype: n  = 5 (20%): received systemic first-line treatment: FOLFIRI plus cetuximab. Last date evaluation: 31 January 2024. Median age: 59.6 years (range 42-71), men/women: 14/11. Eastern Cooperative Oncology Group (ECOG) index: 0/1/2 : 11/10/4. Evaluable for response: n  = 25. Complete response: n  = 0, partial response: n  = 14 (56%), stable disease: n  = 8 (32%), progressive disease: n  = 3 (12%), early tumor shrinkage: n  = 13 (52%), estimates progression-free survival: 13 months (95% CI 8-17 months), estimated OS: 48 months (95% CI 25-71 months), median follow-up: 26 months (1-61 months), no evidence of disease: n  = 4 (16%). A chemotherapy doublette regimen with FOLFIRI plus a biological as first-line treatment shows promising efficacy and secondary metastatic resection after interdisciplinary discussion was associated with a survival benefit in right-sided metastatic colon carcinoma.

Immune checkpoint inhibitors (ICIs) are the guideline endorsed first choice for patients with deficient mismatch repair or microsatellite instability high (dMMR/MSI-H) mCRC, however a significant proportion experience primary or secondary resistance. BRAF V600E mutated (BRAFm) and dMMR/MSI-H mCRC can be treated with BRAF + EGFR inhibitors but specific data on the efficacy after progression to ICIs are missing.

We collected consecutive patients with BRAFm dMMR/MSI-H mCRC treated from 2017 to 2024 with a combination of BRAFi+EGFRi+/-MEKi, after disease progression on ICIs. A control cohort of BRAFm pMMR/MSS mCRC patients treated with encorafenib+cetuximab+/-binimetinib from 2nd line was used.

dMMR/MSI-H (n = 50) BRAFm mCRC patients were more often > 70-year-old, with right-sided primary tumors, without liver but more lymphnode metastases than pMMR/MSS (n = 170). They were treated more frequently beyond 2nd line and 45 % were primary progressors to ICIs. Lower ORR (18 % versus 32 %, p = 0.09) and DCR (60 % versus 73 %, p = 0.11) was seen without reaching significance in dMMR/MSI-H as compared to pMMR/MSS patients. After a median follow-up of 14.04 months, no differences in PFS (median 5.13 versus 4.50 months, HR 0.83, 95 %CI: 0.57-1.20, p = 0.31) and OS (median 10.75 versus 9.11 months, HR 0.89, 95 %CI: 0.59-1.32, p = 0.55) were observed.

Our results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.

Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a multimodal therapeutic option for the management of peritoneal metastases (PM). Treatment outcomes for patients with colorectal cancer (CRC) PM undergoing CRS+HIPEC with microsatellite instability (MSI) remain unknown. We examined the patient characteristics and outcomes in patients with MSI CRC after CRS+HIPEC.

This was a retrospective cohort study of a prospectively maintained database of all patients with CRC PM undergoing CRS+HIPEC (2010-2020). Categorical and continuous variables were analyzed using the chi-square test and independent samples t test, respectively. Survival was evaluated with the Kaplan-Meier analysis.

There were 324 patients diagnosed as having CRC PM undergoing CRS+HIPEC (MSI, n = 23; microsatellite stable [MSS], n = 301). There was no statistically significant difference in patient demographics, tumor characteristics, or perioperative factors between the 2 groups. There was a trend toward improved survival in the MSI group with a median overall survival (OS) of 96.7 month compared with patients with MSS disease (median OS, 51.4 months; P = .10). Patients with MSI demonstrated median progression-free survival (PFS) 8.5 months compared with 11.4 months in the MSS cohort (P = .28).

Patients with CRC PM, regardless of MSI or MSS status, demonstrate similar OS and PFS after CRS+HIPEC. MSI status should not change a patient's candidacy for CRS+HIPEC.

Palliative systemic therapy alternated with electrostatic precipitation oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (ePIPAC) has never been prospectively investigated in patients with unresectable colorectal peritoneal metastases (CPM). The CRC-PIPAC-II study aimed to assess safety, feasibility and efficacy of such bidirectional therapy.

This two-center, single-arm, phase II trial enrolled chemotherapy-naïve patients to undergo three treatment cycles, consisting of systemic therapy (CAPOX, FOLFOX, FOLFIRI, or FOLFOXIRI, all with bevacizumab) and oxaliplatin-based ePIPAC (92 mg/m2) with intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2). Primary outcome were major treatment-related adverse events. Secondary outcomes included minor events, tumor response, progression-free survival (PFS) and overall survival (OS).

Twenty patients completed 52 treatment cycles. Fifteen major events occurred in 7 patients (35 %): 5 events (33 %) related to systemic therapy; 5 (33 %) related to ePIPAC; and 5 (33 %) were biochemical events. No treatment-related deaths occurred. All patients experienced minor events, mostly abdominal pain, nausea and peripheral sensory neuropathy. After treatment, radiological, pathological, cytological, and biochemical response was observed in 0 %, 88 %, 38 %, and 31 % of patients respectively. Curative surgery was achieved in one patient. Median PFS was 10.0 months (95 % confidence interval [CI] 8.0-13.0) and median OS was 17.5 months (95 % CI 13.0-not reached).

Combining palliative systemic therapy with oxaliplatin-based ePIPAC in patients with unresectable CPM was feasible and showed an acceptable safety profile. Treatment-induced response and survival are promising, yet further research is required to determine the additional value of ePIPAC to systemic therapy.

BRAFV600E-mutant metastatic colorectal cancer represents a distinct molecular phenotype known for its aggressive biological behavior, resistance to standard therapies, and poor survival rates. Improved understanding of the biology of the BRAF oncogene has led to the development of targeted therapies that have paved the way for a paradigm shift in managing this disease. However, despite significant recent advancements, responses to targeted therapies are short-lived, and several challenges remain. In this review, we discuss how progress in treating BRAFV600E-mutant metastatic colorectal cancer has been made through a better understanding of its unique biological and clinical features. We provide an overview of the evidence to support current treatment approaches and discuss critical areas of need and future research strategies that hold the potential to refine clinical practice further. We also discuss some challenging aspects of managing this disease, particularly the complexity of acquired resistance mechanisms that develop under the selective pressure of targeted therapies and rational strategies being investigated to overcome them.

Colorectal cancer (CRC) patients with peritoneal metastasis (CRC-PM) have a worse prognosis than those with liver and lung metastases. Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is an effective locoregional treatment for CRC-PM. To date, the prognostic analysis of CRS/HIPEC mostly focuses on clinical and pathological characteristics; however, genetic characteristics, such as RAS/BRAF mutation status, are not sufficient. This study aimed to systematically assess the correlation between RAS/BRAF status and PM risk, as well as the prognostic efficacy of CRS/HIPEC for CRC.

This study was written in accordance with the 2020 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We searched PubMed, EMBASE, and the Cochrane library with the following keywords: "Peritoneal Neoplasms," "raf Kinases" and "ras Proteins". The fixed-effects model and inverse variance method were used for analysis. Odds ratios (OR) and 95 % confidence intervals (CI) were used to reflect the risk of PM associated with RAS/BRAF mutations. Hazard ratios (HR) and 95 % CI were used to evaluate the effects of RAS/BRAF mutations on the prognosis of CRS/HIPEC.

Eighteen articles included 5567 patients. In the risk analysis of PM, patients with BRAF mutation were more likely to have PM than those with wild-type BRAF (OR = 2.28, 95 % CI = 1.73-3.01, P < 0.001, I2 = 0 %). In contrast, there was no significant difference in the effect of RAS mutation and wild-type on PM of CRC (OR = 1.28, 95 % CI = 0.99-1.66, P = .06, I2 = 0 %). In a prognostic analysis of CRS/HIPEC, RAS mutation predicted poor overall survival (HR = 1.68, 95 % CI = 1.39-2.02, P < 0.001, I2 = 1 %) and disease-free survival (HR = 1.61, 95 % CI = 1.34-1.94, P < 0.001, I2 = 42 %). The results for BRAF mutation was consistent with the prognostic impact of RAS mutation's overall survival (HR = 2.57, 95 % CI = 1.93-3.44, P < 0.001, I2 = 0 %) and disease-free survival (HR = 1.90, 95 % CI = 1.40-2.56, P < 0.001, I2 = 82 %).

BRAF mutation, rather than RAS mutation, was a high-risk factor for CRC-PM. And both BRAF and RAS mutations negatively affected the prognosis of CRS/HIPEC in CRC-PM patients. Our results could provide suggestions for the selection of comprehensive treatment for CRC-PM with RAS/BRAF mutations.

Primary tumor (PT) sidedness is an established prognostic marker in metastatic colorectal cancer (mCRC) and has a predictive impact on the efficacy of anti-epidermal growth factor receptor (anti-EGFR) antibody [monoclonal antibody (mAb)] in patients with RAS wild-type mCRC. This investigation focuses on patients with BRAFV600E-mutated (BRAFmt) mCRC and examines the efficacy of anti-EGFR mAbs in relation to primary tumor sidedness (PTS).

This pooled analysis was carried out using individual patient data from five randomized studies in the first-line setting of mCRC. The population of interest was limited to patients with BRAFmt mCRC and known PTS. For analysis, treatment was stratified into two groups: those treated with anti-EGFR mAbs and those without. Dichotomous variables, such as overall response rate and objective response rate (ORR), were compared using chi-square or Fisher's exact test. Time-to-event endpoints [progression-free survival (PFS) and overall survival (OS)] were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. An interaction test was carried out via Cox regression.

A total of 102 patients with BRAFmt mCRC were identified. The type of targeted therapy (anti-EGFR-based versus non-anti-EGFR) did not significantly impact the outcome. However, in patients with left-sided primary tumors, anti-EGFR mAb-based treatment, compared with non-anti-EGFR, was associated with a higher ORR (58% versus 34%; P < 0.01), trended toward improved PFS [hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.34-1.13; P = 0.12], and demonstrated prolonged OS (HR 0.38; 95% CI 0.20-0.72; P < 0.01). In patients with right-sided primary tumors, anti-EGFR-based therapy had no effect on ORR (33% versus 36%; P > 0.99), induced inferior PFS (HR 1.97; 95% CI 1.12-3.47; P = 0.02), and trended toward a worse OS (HR 1.76; 95% CI 0.99-3.13; P = 0.05).

This analysis suggests that PTS has predictive value for the efficacy of anti-EGFR mAb in the first-line treatment of BRAFmt mCRC.

Triplet chemotherapy plus cetuximab showed promising results in phase II trials in unsystematically selected RAS population. We evaluated FOLFIRINOX+cetuximab efficacy as first-line treatment in extended RAS wild-type metastatic colorectal cancer (mCRC) patients.

We retrospectively analyzed patients treated with FOLFIRINOX+cetuximab, using data from clinical trials and real-life practice. Extended mutation analysis was performed when RAS/BRAF status was unavailable. The primary endpoint was progression-free survival (PFS).

Seventy patients (61.4 % male, median age 58.7 years) were analyzed. Eighty percent had left-sided mCRC and 97.1 % had liver metastases. Median PFS and overall survival (OS) were 13.3 and 48.5 months, respectively. The objective response rate was 85.7 %, with 20 % complete response. Primary tumor location did not affect OS and PFS. BRAF wild-type patients (n = 65) had longer PFS (13.3 vs. 6.0 months; p = 0.005) and OS (50.1 vs. 21.2 months; p = 0.007) than BRAF mutated patients (n = 5, including four BRAFV600E). Median OS was significantly longer in resected patients (n = 39, 55.1 vs. 30.7 months; p = 0.030). Main toxicities were diarrhea (31.4 %) and neutropenia (21.4 %).

FOLFIRINOX+cetuximab provides good PFS, high response rate and prolonged disease control in initially unresectable extended RAS wild-type mCRC. This combination is particularly interesting for selected patients with liver-limited disease eligible to secondary resection.