Complete response of metastatic microsatellite-stable BRAF V600E colorectal cancer to first-line oxaliplatin-based chemotherapy and immune checkpoint blockade.

The randomized METIMMOX trial (NCT03388190) examined if patients with previously untreated, unresectable abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC) might benefit from potentially immunogenic, short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade (ICB). Three of 38 patients assigned to this experimental treatment had metastases from BRAF-mutant MSS-CRC, in general a poor-prognostic subgroup explored here. The ≥70-year-old females presented with ascending colon adenocarcinomas with intermediate tumor mutational burden (6.2-11.8 mutations per megabase). All experienced early disappearance of the primary tumor followed by complete response of all overt metastatic disease, resulting in progression-free survival as long as 20-35 months. However, they encountered recurrence at previously unaffected sites and ultimately sanctuary organs, or as intrahepatic tumor evolution reflected in the terminal loss of initially induced T-cell clonality in liver metastases. Yet, the remarkable first-line responses to short-course oxaliplatin-based chemotherapy alternating with ICB may offer a novel therapeutic option to a particularly hard-to-treat MSS-CRC subgroup.

Molecular-targeted therapy for childhood low-grade glial and glioneuronal tumors.

Since the discovery of the association between BRAF mutations and fusions in the development of childhood low-grade gliomas and the subsequent recognition that most childhood low-grade glial and glioneuronal tumors have aberrant signaling through the RAS/RAF/MAP kinase pathway, there has been a dramatic change in how these tumors are conceptualized. Many of the fusions and mutations present in these tumors are associated with molecular targets, which have agents in development or already in clinical use. Various agents, including MEK inhibitors, BRAF inhibitors, MTOR inhibitors and, in small subsets of patients NTRK inhibitors, have been used successfully to treat children with recurrent disease, after failure of conventional approaches such as surgery or chemotherapy. The relative benefits of chemotherapy as compared to molecular-targeted therapy for children with newly diagnosed gliomas and neuroglial tumors are under study. Already the combination of an MEK inhibitor and a BRAF inhibitor has been shown superior to conventional chemotherapy (carboplatin and vincristine) in newly diagnosed children with BRAF-V600E mutated low-grade gliomas and neuroglial tumors. However, the long-term effects of such molecular-targeted treatment are unknown. The potential use of molecular-targeted therapy in early treatment has made it mandatory that the molecular make-up of the majority of low-grade glial and glioneuronal tumors is known before initiation of therapy. The primary exception to this rule is in children with neurofibromatosis type 1 who, by definition, have NF1 loss; however, even in this population, gliomas arising in late childhood and adolescence or those not responding to conventional treatment may be candidates for biopsy, especially before entry on molecular-targeted therapy trials.

Langerhans cell histiocytosis mimicking acute dacryocystitis.

Langerhans cell histiocytosis (LCH) is a myeloid neoplasm characterized by clonal neoplastic proliferation of Langerhans-type dendritic cells associated with an inflammatory infiltrate predominantly composed of lymphocytes and eosinophils. In this article, we present an unusual case of LCH with significant swelling in the left lacrimal sac region in a 3-year-old child, clinically mimicking acute dacryocystitis. Microscopically, it showed intense inflammatory infiltrate and histiocytes with irregular nuclei. The tumor cells were positive for S-100 protein, CD1a, and CD207 (langerin). Molecular study was positive for the V600E/E2/D mutation (EXON 15). This case emphasizes the importance of careful clinical, radiographic, and microscopic evaluation, as some neoplasms may mimic common benign lesions.

Single-Cell Profiling Reveals the Impact of Genetic Alterations on the Differentiation of Inflammation-Induced Murine Colon Tumors.

Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (MinApcΔ716/+) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAFV600E mutation (BRAFF-V600ELgr5tm1(Cre/ERT2)CleMinApcΔ716/+, BLM) or knocking out Msh2 (Msh2LoxP/LoxPVil1-creMinApcΔ716/+, MSH2KO) in the Min model altered colon tumor differentiation. Using single-cell RNA sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single-cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the tumor stem cell population. Interestingly, the tumor stem cell population of BLM tumors had revival colon stem cell characteristics with low WNT signaling and an increase in RevCSC marker gene expression. In contrast, MSH2KO tumors were characterized by an increased tumor stem cell population that had higher WNT signaling activity compared to Min tumors. Furthermore, overall BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we identified additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer.

Toxicities from BRAF and MEK Inhibitors: Strategies to Maximize Therapeutic Success.

PURPOSE OF REVIEW: This report highlights several of the recent therapeutic advancements in the treatment of BRAF-mutant tumors, discusses the most common adverse events observed with BRAF-targeted agents, and suggests strategies to manage and mitigate treatment-related toxicities. RECENT FINDINGS: BRAF and MEK inhibitors represent a significant advancement in the treatment of BRAF-mutated malignancies with data across tumor types demonstrating the anti-tumor efficacy of dual MAPK inhibition. Although these agents have a reasonable toxicity profile, variable side effects across organ systems can develop. The discovery of activating BRAF mutations and subsequent development of BRAF and MEK inhibitors has transformed the treatment algorithms of BRAF-mutant malignancies. With increased application of these targeted regimens, identification and prompt management of their unique adverse events are crucial.

A critical appraisal of the current landscape of resectable BRAF mutated colorectal liver metastases: a systematic review.

BACKGROUND: Patients with surgically resectable BRAF-mutated colorectal liver metastases (CRLM) or limited extrahepatic disease constitute a highly selective subgroup among BRAF-mutated patients, characterized by a more indolent disease biology. This is evident in their suitability for surgical resection. However, initial studies from a decade ago presented a discouraging outlook for these patients, citing early, frequent, multifocal recurrences and a very limited median overall survival (OS) of less than two years. Our objective was to provide an updated, comprehensive, and critically assessed review of the current literature on the prognostic impact of BRAF variants in CRLM, as well as to explore optimal treatment strategies for these patients through a systematic search. METHODS: A systematic literature search of the Medline, Scopus, and CENTRAL databases for studies reporting long-term outcomes of patients with a known BRAF status was performed. RESULTS: A total of 386 unique studies were screened during the study selection process. After applying the exclusion criteria, a total of 18 studies published between 2012 and 2023 were deemed eligible for inclusion. CONCLUSIONS: In contrast to older studies, more recent studies, with larger sample sizes, have revealed that the rate of extrahepatic recurrence is comparable between BRAF-mutated and wild-type patients. Furthermore, they have reported significantly improved survival outcomes, with OS extending up to 52 months. Notably, patients with non-V600E BRAF mutations may even achieve outcomes comparable to those with wild-type BRAF CRLM. Additionally, a few recent studies have compared surgery and systemic therapies, indicating that surgery is associated with improved survival rates, even for patients with the V600E mutation. This challenges the previous belief that BRAF mutations are absolute contraindications to surgical treatment. Surgical denial for technically resectable patients may now be reserved for specific clinical scenarios, such as the presence of a BRAF V600E mutation and concurrent extrahepatic disease.

Analysis of Urinary Iodine Concentration in Differentiated Thyroid Cancer and Breast Cancer Cases.

Iodine intake can affect thyroid and breast cells, and urinary iodine concentration (UIC) is an effective biomarker for iodine intake. OBJECTIVES: This study aimed to analyze the correlation between urinary iodine concentration in differentiated thyroid cancer (DTC) and breast cancer (BC) subjects. METHODS: The study consisted of 80 subjects divided into case (20 DTC and 20 BC subjects) and control (40 subjects). Morning urine or spot urine was used for UIC measurement. RESULTS: In thyroid cancer, UIC median patients and controls were 195.45 ± 133.61 µg/L and 145 ± 39.64 µg/L, respectively, with p =0.33. The UIC median of PTC subjects was significantly higher compared to FTC subjects, 227.12±130.98 µg/L versus 68.75±22.95 µg/L, p=0.00, and papillary thyroid cancer is closely related to a high iodine excretion in urine with contingency coefficient  (c)=0.722. In BC patients, regardless of subtypes, breast cancer subjects showed a significantly lower iodine excretion level. The median of UIC patients and controls were 80.05 ± 38.24 µg/L and 144.25 ± 36.79 µg/L, respectively, p=0.000. CONCLUSIONS: Iodine urine concentrations strongly correlate with the type of DTC histopathology, and in BC subjects, IUC was significantly lower compared to the control.

BRAF mutation in myeloid neoplasm: incidences and clinical outcomes.

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF-mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF-mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.

Response to dabrafenib plus trametinib on a rare BRAF mutation (V600_W604 deletion-insertion R) in an advanced non-small cell lung cancer patient.

Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non-small cell lung cancer (NSCLC), data on its efficacy against uncommon BRAF mutations are still limited due to their rare frequency. We report a case of 70-year-old woman with BRAF V600_W604 deletion-insertion R-positive stage IVA lung adenocarcinoma, who was successfully treated with dabrafenib plus trametinib. Herein, we discuss the oncogenic role of uncommon BRAF mutations and highlight the importance of performing comprehensive genomic profiling on patients without any targetable gene alterations in companion diagnostics.

BRAF Mutations in Patients with Myeloid Neoplasms: A Cancer Center Multigene Next-Generation Sequencing Analysis Experience.

BRAF mutations are rare in myeloid neoplasms and are reported to be associated with poor treatment outcomes. The purpose of our study is to characterize BRAF mutations in myeloid neoplasms using a next-generation sequencing (NGS) panel based on the experiences of a single cancer center. We conducted a retrospective review of patients with myeloid neoplasms who underwent the HopeSeq studies between January 2018 and September 2023. A total of 14 patients with myeloid neoplasms carrying BRAF mutations were included in our cohort. The clinical, pathological, and molecular features of these patients were investigated. Our study indicates that BRAF mutations are rare in myeloid neoplasms, constituting only 0.53% (14/2632) of all myeloid neoplasm cases, with the most common BRAF mutation being BRAF V600E (4/14; 28.6%). Interestingly, we observed that six out of seven patients with acute myeloid leukemia (AML) exhibited AML with monocytic differentiation, and all the patients with AML exhibited an extremely poor prognosis compared to those without BRAF mutations. TET2 (5/14; 35.7%), ASXL1 (4/14; 28.6%), and JAK2 (4/14; 28.6%) were the three most frequently co-mutated genes in these patients. Moreover, we noted concurrent KMT2A gene rearrangement with BRAF mutations in three patients with AML (3/7; 42.9%). Our study suggests that although BRAF mutations are rare in myeloid neoplasms, they play a crucial role in the pathogenesis of specific AML subtypes. Furthermore, RAS pathway alterations, including BRAF mutations, are associated with KMT2A gene rearrangement in AML. However, these findings warrant further validation in larger studies.

TGFß-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.

Activated TGFß signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFß-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFß-responsive, stroma-specific genes to infer TGFß-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFß-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFß-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

Rare metastasis in a patient with BRAF-mutated rectal cancer: choroidal metastasis - case report and literature review.

Purpose: Colorectal cancers are common and have high mortality, and metastasis is common in follow up. Choroidal metastasis is encountered rarely in rectum cancers, and there is no previous case reported from Turkey. We present our patient who developed choroidal metastasis in his cancer follow-up. Case report: A 74-year-old male patient had undergone operation due to the diagnosis of rectum cancer two years ago, and lung (L) metastasis developed in the 4th month after the adjuvant therapy, but he refused to receive treatment and remained out of follow-up. The patient presented with complaints of decreased vision and light flashes in his eye 21 months after the diagnosis. Management and outcome: Ocular examination revealed a choroidal mass and radiologically choroidal and multiple brain metastases were detected. In our case, whole-brain radiotherapy was administered in the treatment since there were also multiple brain metastases. However, as the ECOG (Eastern Cooperative Oncology Group) performance status of the patient was 3-4 after radiotherapy, systemic treatment was not considered appropriate, and the best supportive care was given. The patient died 2 months after the diagnosis of choroidal metastasis. Conclusion: Currently, there are few suggestions in case reports regarding appropriate treatment approaches for the treatment of rectal cancerchoroidal metastases. Multidisciplinary approaches may be effective for local and systemic treatment. Our case highlights a pathological entity with poor prognosis, which is rarely encountered during the course of rectal adenocarcinomas, and it is the first case of choroidal metastasis reported from our country. However, we believe that it will be important to draw attention to the fact that it is the first reported case of choroid metastasis in a rectal cancer patient with a BRAF V600 E mutation, and patients with BRAF V600 E mutation may develop metastasis to atypical areas due to their aggressive biology.

The ERK inhibitor GDC-0994 selectively inhibits growth of BRAF mutant cancer cells.

BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.

Targeted therapy in BRAF mutated aggressive papillary craniopharyngioma: a case report and overview of the literature.

BACKGROUND: Papillary craniopharyngiomas harbor the BRAF V600E mutation, which paves the way for using BRAF inhibitor molecules to treat tumors refractory to standard therapies. Single case reports confirmed the efficacy of targeted therapy. However, most reports were limited by the short follow-up. We describe the long-term course of a patient treated with dual-agent BRAF and MEK inhibitors and review the available literature. CASE REPORT: A 75-year-old male patient had recurrence of a papillary craniopharyngioma after transsphenoidal surgery and Gamma Knife radiosurgery. Review of the pathologic specimen confirmed the presence of the BRAF V600E mutation. Because of the few therapeutic options, we decided to initiate BRAF/MEK inhibitor combined therapy for six months. Rapid reduction of the tumor occurred, but three months after quitting combined medical therapy the tumor recurred. BRAF/MEK inhibitor therapy was resumed and the tumor again showed a marked reduction. The second course was maintained for 20 months and the tumor showed another recurrence within three months, which, again, responded to a third course of targeted therapy. CONCLUSIONS: Our study confirms the excellent response of papillary craniopharyngioma to combined BRAF and MEK inhibitors. However, rapid tumor recurrence is the rule when medical therapy is stopped. Resistance to a second and third course of targeted therapy did not occur, suggesting that tumor mutations affecting the response to drugs seems an uncommon event in papillary craniopharyngioma. The exact role of targeted therapy in the treatment algorithm of papillary craniopharyngiomas has still to be refined.

Genetics-guided therapy in neuroendocrine carcinoma: response to BRAF- and MEK-inhibitors.

Background: Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation. Methods: This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1st, 2018 and December 31st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy. Results: We screened 48 patients diagnosed with NEC between January 1st, 2018 and December 31st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months. Conclusions: BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.

Dabrafenib-trametinib in BRAF V600-mutated non-small-cell lung cancer: a single center real world experience.

Aim: We retrospectively evaluated the effect of dabrafenib/trametinib combination in patients with BRAF-mutated non-small-cell lung cancer (NSCLC) treated in a single center from 2017 to 2022. Patients: The response and safety data of 42 patients (27 treated in first-line and 15 as second/subsequent lines) were analyzed. Results: The objective response was 73.8%, with no differences between patients undergoing first- or second-line. A longer, statistically significant median progression-free survival (PFS) was observed in patients receiving the combination in first-line vs those in the second/subsequent lines (19.9 months [95% CI: 19.7-20] vs 13.1 months [95% CI: 8.6-17.6], respectively; p = 0.012). The median overall survival (OS) was 29.9 months (95% CI: 14.1-45.7) for patients treated with the combination in first-line and 22.4 months (95% CI: 14.6-30.2) for those treated in subsequent lines. The combination was well tolerated. Conclusion: We confirm the efficacy of dabrafenib/trametinib in BRAF-V600-mutated NSCLC.

[Box: see text].

Primary Hepatic Melanoma: A Diagnostic Surprise.

Melanoma is a relatively rare malignancy with a highly aggressive biological behavior. Metastases to other sites, like lymph nodes and liver are common, but primary hepatic melanoma is a rarity with poor survival ranging from months to few years. Diagnosis of primary hepatic melanoma via clinical features and imaging technology is difficult because of its ambiguous features. Here, we present a 26-year-old North Indian woman admitted in the department of gastrointestinal surgery at our tertiary care hospital with the complaint of pain in the abdomen for a month associated with the loss of appetite and subsequent weight loss. The liver function tests were within normal limits and viral markers were negative. The triple-phase computed tomography scan of abdomen showed significant hepatomegaly and two well-defined lesions in both lobes of the liver. Histopathological evaluation was performed on the core liver biopsies submitted from the liver lesions. A malignant tumor with abundant black intracytoplasmic pigment was identified. Immunohistochemistry proved the tumor to be melanoma. The detailed clinical history, laboratory, and radiological investigations were acquired and analyzed to rule out a metastatic lesion of the same. A final diagnosis of primary hepatic melanoma was thus rendered. Primary hepatic melanoma is extremely uncommon and has been rarely reported. Preoperative diagnosis is challenging due to low index of suspicion and nonspecific clinical features. In this case report, we discuss the clinicopathological features of primary hepatic melanoma and review the literature so as to increase the awareness and improve our understanding of the disease.

Tumor Lysis Syndrome in a Patient with BRAFV600E Mutated Colon Cancer Treated with Cetuximab and Encorafenib.

Tumor lysis syndrome (TLS) is a fatal complication associated with chemotherapy. We herein report a case of TLS in a 73-year-old woman with metastatic BRAFV600E mutated colon cancer after she received combined treatment with cetuximab and encorafenib. The serum uric acid, urea nitrogen, and creatinine levels were elevated on day four of the first cycle. The fibrin degradation product (FDP) and D-dimer levels were also high. Diuresis and rasburicase were initiated for TLS, and the laboratory data all normalized on day 8. Thus, the possibility of TLS being induced by targeted drugs in patients with solid tumors, including colorectal cancer, must not be overlooked.

BRAF mutations and survival with surgery for colorectal liver metastases: A systematic review and meta-analysis.

INTRODUCTION: Mutations in the BRAF gene (BRAFmut) are associated with an unfavorable prognosis in patients with metastatic colorectal cancer (CRC). The aim of this meta-analysis was to evaluate the prognosis of colorectal cancer (CRC) patients with liver metastases and the potential benefits of liver resection in patients with BRAFmut CRC. MATERIAL AND METHODS: A systematic search of PubMed, Cochrane Central Controlled Trials, and Embase databases was conducted on May 31, 2023. The inclusion criteria were as follows:1) reporting of outcomes in patients with BRAFmut CRC who underwent surgery for liver metastases and/or comparison of outcomes between those who underwent and those who did not undergo resection; 2) reporting of survival information as hazard ratios (HR); and 3) publication in English. RESULTS: 34 studies were included. Median follow up was 48 months for prognostic BRAF status meta-analysis. BRAFmut status showed a significantly increased risk of mortality (hazard ratio [HR] = 2.56, 95% confidence interval [CI] 2.04-3.22; P < 0.01) and relapse (HR = 1.97, 95% CI 1.44-2.71; P < 0.01). Resection of liver metastases was associated with a survival benefit (median follow up 46 months). The HR for survival was 0.44 (95% confidence interval [CI] 0.33-0.59; P < 0.01) in favor of surgery. CONCLUSIONS: and Relevance: Our analysis indeed confirms that BRAF mutation is associated with poor survival outcomes after liver resection of CRC metastases. However, upon quantitatively assessing the survival benefit of surgical intervention in patients with BRAF-mutated CRC liver metastases, we identified a significant 56% reduction in the risk of death.