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Simple Summary: Trifluridine/tipiracil (FTD–TPI) is a therapy for metastatic colorectal cancer after progression on standard treatment. Some patients with colorectal cancer harbor a BRAF gene mutation and may not respond as well to treatment compared to patients without this mutation. We evaluated patients with a BRAF mutated colorectal cancer treated with FTD–TPI as part of routine hospital care. Survival for these patients was 6.6 months, with disease progression after 2.3 months. Patients' functional status (according to a standardized scale "ECOG") stands as the most relevant factor guiding survival outcome; patients with a better status (ECOG 0) survived for longer than patients with poorer status (ECOG 2; 12 months vs. less than 2 months, respectively). Side effects with FTD-TPI were equivalent to those reported for the overall colorectal cancer population. This study suggests that FTD–TPI remains a therapeutic option for selected patients with BRAF mCRC. Background: 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. Methods: 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). Results: 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%). Conclusions: 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. [ABSTRACT FROM AUTHOR]

Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of colorectal cancer has been revolutionized in recent decades by the identification of new targeted agents, particularly for metastatic colorectal cancer when the disease has spread to other sites in the body. Cetuximab targets a specific protein on the surface of the tumor cells. This review highlights the expanding role of this drug in diverse types of metastatic colorectal cancer and describes how cetuximab can be partnered with other anticancer drugs such as immunotherapy (a therapy that activates the immune system) and other agents targeting cell proteins. We also describe promising innovative ongoing clinical trials. The evolving importance of cetuximab in anticancer therapy offers renewed hope in the landscape of personalized treatment for patients with metastatic colorectal cancer. Cetuximab, a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has revolutionized personalized treatment of metastatic colorectal cancer (mCRC) patients. This review highlights the mechanism of action, characteristics, and optimal indications for cetuximab in mCRC. Cetuximab has emerged as a pivotal partner for novel therapies in specific molecular subgroups, including BRAF V600E, KRAS G12C, and HER2-altered mCRC. Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies. Ongoing clinical trials have continued to uncover innovative cetuximab-based treatment strategies, promising a brighter future for mCRC patients. This review provides a comprehensive overview of cetuximab's role and its evolving importance in personalized targeted therapy of mCRC patients, offering valuable insights into the evolving landscape of colorectal cancer treatment. [ABSTRACT FROM AUTHOR]

The journey of metastatic colorectal cancer patients is complex and challenging, requiring coordination and collaboration between multiple healthcare providers. Understanding patients' needs, fears, feelings, concerns, and behaviors is essential for providing individualized patient-centered care. In recent years, mCRC patients have experienced improvements in clinical outcomes, from 16 months of overall survival to 32 months, thanks to research. However, there is still room for improvement, and integrating clinical and translational research into routine practice can help patients benefit from treatments and techniques that would not be an option. In the Journey of mCRC patients, living well with cancer and quality of life becomes a priority given the outcomes of the disease. Patient reported outcomes (PRO) and Patient Reported Outcome Measures (PROMs) are becoming therefore new estimands in Oncology. Patient advocates represent important figures in this process by prioritizing issues and research questions; evaluating research designs and the performance of the research; the analysis and interpretation of data; and how results are disseminated. Multidisciplinary Tumor Boards and shared decision-making is essential for designing treatment strategies for individual patients. Quality of Life is often prioritized only when it comes to refractory advanced disease and end-of-life care, but it has to be integrated from the beginning, as the emotional impact of diagnosis leads to a vulnerable situation where patients' needs and preferences can be easily overseen. First-line treatment will be chosen among more treatment options than subsequent lines, with longer progression-free survival and a bigger impact on the outcomes. Practicing patient-centered care and optimizing first-line treatment for colorectal cancer patients requires a comprehensive understanding of patient experience and treatment outcomes, which can guide clinical practice and inform regulatory decisions for the benefit of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has reshaped the prognosis of several tumor types. In metastatic colorectal cancer, only tumors with microsatellite instability or mismatch repair deficiency achieve profound benefits under immune checkpoint inhibitors. As a result, immunotherapy has moved to the early stage, showing promising results in neoadjuvant settings. However, not all patients respond, and some responses are shortlived, thus highlighting the need for accurate and reliable biomarkers to identify patients who are more likely to achieve clinical benefit, as well as those patients with refractory tumors who will require a different therapeutic approach. Surprisingly, classical biomarkers such as PD-L1 expression or TMB seem to be poorly informative in MSI colorectal cancer. Therefore, the development of novel biomarkers in this population remains an unmet medical need. Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors. In colorectal cancer (CRC), MSI tumors are found in 5% of patients in the metastatic setting and 15% in early-stage disease. Following the impressive clinical activity of immune checkpoint inhibitors in the metastatic setting, associated with deep and long-lasting responses, the development of immune checkpoint inhibitors has expanded to early-stage disease. Several phase II trials have demonstrated a high rate of pathological complete responses, with some patients even spared from surgery. However, in both settings, not all patients respond and some responses are short, emphasizing the importance of the ongoing search for accurate biomarkers. While various biomarkers of response have been evaluated in the context of MSI CRC, including B2M and JAK1/2 mutations, TMB, WNT pathway mutations, and Lynch syndrome, with mixed results, liver metastases have been associated with a lack of activity in such strategies. To improve patient selection and treatment outcomes, further research is required to identify additional biomarkers and refine existing ones. This will allow for the development of personalized treatment approaches and the integration of novel therapeutic strategies for MSI CRC patients with liver metastases. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic colorectal cancer is a complex, prevalent, and life-threatening disease influenced by various factors that affect its progression, evolution, and treatment responses. Tumor heterogeneity, stemming from genetic and non-genetic factors, impacts tumor development and therapy effectiveness. This feature can be assessed by computational analysis of next-generation sequencing to understand spatial tumor evolution and diversity. Analyzing circulating tumor DNA allows the study of temporal heterogeneity by real-time monitoring of tumor changes and treatment response. Different models explain the origins of this heterogeneity, emphasizing complex molecular pathways. This review examines these concepts and focuses on the clinical implications of clonal evolution and tumor heterogeneity. Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease's course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications. [ABSTRACT FROM AUTHOR]

The presence of a BRAF-V600E mutation in metastatic colorectal cancer (mCRC) is observed in approximately 12% of cases and is associated with poor prognosis and aggressive disease. Unlike melanoma, the development of successful BRAF blockade in colorectal cancer has been complex. The phase III BEACON trial made significant progress in the development of BRAF inhibitors by establishing encorafenib-cetuximab as the new standard of care for patients with mCRC who have progressed to one or two previous lines of treatment. Nonetheless, not all patients respond to encorafenib-based combinations, and some responses are short-lived. Identifying new strategies to boost antitumor activity and improve survival is paramount. The development of targeted therapy for BRAF-V600E mCRC starting with BRAF inhibitors as monotherapy through novel combinations with anti-VEGF or anti-PD1 agents to enhance antitumor activity is reviewed, with a particular focus on the development of predictive and prognostic biomarkers. There is a crucial need to better understand tumor biology and develop accurate and reliable biomarkers to enhance the antitumor activity of encorafenib-based combinations. The RNF43 mutation is an accurate and reliable predictive biomarker of response, and combinations that target crosstalk between the MAPK pathway, the immune system, and WNT pathways seem promising. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have reshaped the prognostic of several tumor types, including metastatic colorectal tumors with microsatellite instability (MSI). However, 90-95% of metastatic colorectal tumors are microsatellite stable (MSS) in which immunotherapy has failed to demonstrate meaningful clinical results. MSS colorectal tumors are considered immune-cold tumors. Several factors have been proposed to account for this lack of response to immune checkpoint blockade including low levels of tumor infiltrating lymphocytes, low tumor mutational burden, a high rate of WNT/b-catenin pathway mutations, and liver metastases which have been associated with immunosuppression. However, studies with novel combinations based on immune checkpoint inhibitors are showing promising activity in MSS colorectal cancer. Here, we review the underlying biological facts that preclude immunotherapy activity, and detail the different immune checkpoint inhibitor combinations evaluated, along with novel immune-based therapies, to overcome innate mechanisms of resistance in MSS colorectal cancer. [ABSTRACT FROM AUTHOR]

The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial. [ABSTRACT FROM AUTHOR]

B-type RAF (BRAF) -V600E mutations in metastatic colorectal cancer (mCRC) have been described in up to 12% of the patients. This mutation confers a bad prognostic and poor response with standard chemotherapy. Unlike the scenario for BRAF mutant melanoma, successful BRAF blockade in mCRC has emerged as a complex path, primarily due to the complex underlying biology of mCRC. The BEACON trial has reshaped the therapeutic landscape of BRAF mCRC demonstrating the benefit of the BRAF inhibitor encorafenib in combination with the anti-epidermal growth factor receptor cetuximab. This paper aims to review the main features of BRAF mCRC as well as to review the development of targeted therapy and biomarkers in this specific population. Finally, a deep insight into the underlying biology and molecular classification of BRAF-V600E mCRC has also been performed. The words 'BRAF-V600E mutation', 'colorectal cancer', 'BRAF inhibitors', 'consensus molecular subtypes', 'encorafenib', and 'cetuximab' were used to identify the clinical trials from phase I to phase III related to the development of BRAF inhibitors in this population. A deep search among international meetings (American Society of Clinical Oncology and European Society of Medical Oncology) has been performed to incorporate the last trials presented. BRAF-V600E mCRC is a challenging disease, mostly because of its molecular biology. The BEACON trial has been the most important therapeutic change in the last decade. Nevertheless, new information regarding biomarkers or novel combinations including BRAF inhibitors plus immune checkpoint inhibitors are also promising. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history. [ABSTRACT FROM AUTHOR]

Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (mCRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status, and new biomarkers such as HER2 amplification and NTRK fusions have emerged more recently in refractory CRC, supported by overwhelming clinical relevance. These biomarkers can guide treatment management to improve clinical outcomes in these patients. Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory CRC. Molecular alterations are described for classic and novel biomarkers, and data for completed and ongoing studies with targeted and immunotherapies are presented. Use of targeted therapies based on biomarker testing in CRC has enabled impressive improvements in clinical outcomes in refractory patients. BRAF, MSI, NRAS and KRAS should be tested upfront in all patients given their indisputable therapeutic implications. Other molecular alterations such as HER2 and NTRK are emerging. Testing for these alterations may further improve outcomes for refractory CRC patients. Nonetheless, many key aspects remain to be defined including the optimal timing and technique for testing, the most adequate panel, and whether all patients should be tested for all alterations. [ABSTRACT FROM AUTHOR]

Simple Summary: Given that most patients with MSS mCRC do not respond to immunotherapy agents or do not have durable clinical responses, there is an unmet clinical need to obtain predictors of response to immunotherapy and rational immunotherapy-based combination therapies for this entity. In this review, we present the efforts that have been made to date in the clinical setting to develop immunotherapy-based combinations for MSS mCRC and the rationale that lies behind each strategy. In recent years, deepening knowledge of the complex interactions between the immune system and cancer cells has led to the advent of effective immunotherapies that have revolutionized the therapeutic paradigm of several cancer types. However, colorectal cancer (CRC) is one of the tumor types in which immunotherapy has proven less effective. While there is solid clinical evidence for the therapeutic role of immune checkpoint inhibitors in mismatch repair-deficient (dMMR) and in highly microsatellite instable (MSI-H) metastatic CRC (mCRC), blockade of CTLA-4 or PD-L1/PD-1 as monotherapy has not conferred any major clinical benefit to patients with MMR-proficient (pMMR) or microsatellite stable (MSS) mCRC, reflecting 95% of the CRC population. There thus remains a high unmet medical need for the development of novel immunotherapy approaches for the vast majority of patients with pMMR or MSS/MSI-low (MSI-L) mCRC. Defining the molecular mechanisms for immunogenicity in mCRC and mediating immune resistance in MSS mCRC is needed to develop predictive biomarkers and effective therapeutic combination strategies. Here we review available clinical data from combinatorial therapeutic approaches using immunotherapy-based strategies for MSS mCRC. [ABSTRACT FROM AUTHOR]

Metastatic colorectal cancer (mCRC) currently lacks reliable biomarkers for precision medicine, particularly for chemotherapy-based treatments. This study examines the behavior of 11 CXC chemokines in the blood of 104 mCRC patients undergoing first-line oxaliplatin-based treatment to pinpoint predictive and prognostic markers. Serum samples were collected before treatment, at response evaluation (EVAR), and at disease progression or last follow-up. Chemokines were assessed in all samples using a Luminex® custom panel. CXCL13 levels increased at EVAR in responders, while in non-responders it decreased. Increasing levels of CXCL13 at EVAR, independently correlated with improved progression-free survival (PFS) and overall survival (OS). Nanostring® analysis in primary tumor samples showed CXCL13 gene expression's positive correlation not only with gene profiles related to an immunogenic tumor microenvironment, increased B cells and T cells (mainly CD8+) but also with extended OS. In silico analysis using RNAseq data from liver metastases treated or not with neoadjuvant oxaliplatin-based combinations, and deconvolution analysis using the MCP-counter algorithm, confirmed CXCL13 gene expression's association with increased immune infiltration, improved OS, and Tertiary Lymphoid Structures (TLSs) gene signatures, especially in neoadjuvant-treated patients. CXCL13 analysis in serum from 36 oxaliplatin-treated patients from the METIMMOX study control arm, reported similar findings. In conclusion, the increase of CXCL13 levels in peripheral blood and its association with the formation of TLSs within the metastatic lesions, emerges as a potential biomarker indicative of the therapeutic efficacy in mCRC patients undergoing oxaliplatin-based treatment [Display omitted] • In CRC, Oxalipatin-based combinations often fail due to resistance and/or toxicity. • Lack of biomarkers complicates treatment decision-making.. • We examined serum levels of 11 CXC chemokines in patients on oxaliplatin. • Increased CXCL13 levels correlate with response, prognosis, tumor immunity and TLSs. • CXCL13 may serve as a predictive and prognostic biomarker for treatment efficacy. [ABSTRACT FROM AUTHOR]