RESUMO
INTRODUCTION: The mitogen-activated protein kinase (MAPK) signalling network aberrations in metastatic colorectal cancer (mCRC) generate intrinsic dynamic effects and temporal variations that are crucial but often overlooked in clinical trial populations. Here, we investigate the time-varying impact of MAPK pathway mutation genotype on each treatment line's contribution to the overall clinical course. METHODS: The PROMETEO study focused on mCRC patients undergoing second-line treatment at 20 hospitals. We evaluated genotypes and employed flexible models to analyse the dynamic effect of each mutation. RESULTS: We examined data derived from 1160 patients. The effects of KRAS G12C or G12V, and BRAF V600E are clearly time-varying, with unexpected consequences such as the deleterious effect of BRAF V600E vs other genotypes dissipating over time when subjects receive antiangiogenics, or KRAS G12V and G12C showing increasing aggressiveness over time. Thus, contrary to expectations, the 12-month survival rate from the second line for those who survived >6 months was 49.9% (95% CI, 32.7-67.3) for KRAS G12C and 59% (95% CI, 38.5-80.6) for BRAF V600E. CONCLUSIONS: The dynamic perspective is essential for understanding the behaviour of tumours with specific genotypes, especially from the second line onward. This may be relevant in patient monitoring and treatment decision-making, particularly in cases with distinct mutations.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Mutação , Neoplasias do Colo/genética , Progressão da DoençaRESUMO
The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.
Assuntos
Neoplasias Colorretais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Terapia de Alvo Molecular , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Animais , Transdução de Sinais/efeitos dos fármacosRESUMO
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.
Assuntos
Neoplasias Colorretais , Neoplasias Pulmonares , Humanos , Cetuximab , Panitumumabe , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Tremor , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , MutaçãoRESUMO
Colorectal cancer (CRC) is a prevalent disease worldwide, with more than 50% of patients developing metastases to the liver. Five-year overall survival remains modest among patients with metastatic CRC (mCRC) treated with conventional therapies however, liver transplantation in a highly selected population can improve clinical outcomes with an impressive 5-year overall survival of 83%. Despite liver transplantation appearing to be a promising therapeutical option for well-selected patients with mCRC with the liver-limited disease, these data come from small monocentric trials which included a heterogeneous population. Currently, several clinical trials are evaluating liver transplantation in this scenario, aiming for a more accurate patient selection by integrating liquid biopsy, tissue profiling, and nuclear medicine to the already known clinical biomarkers that eventually may lead to a survival improvement. In this paper, the clinical outcomes and inclusion criteria from the most relevant clinical trials and clinical series involving liver transplantation in patients with liver-limited disease colorectal cancer are reviewed as well as the trials currently recruiting.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Hepáticas , Transplante de Fígado , Neoplasias Retais , Humanos , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológicoRESUMO
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.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Humanos , Antígeno B7-H1/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Reparo de Erro de Pareamento de DNA , Receptor de Morte Celular Programada 1/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , Repetições de Microssatélites , Instabilidade de Microssatélites , Imunoterapia , Microambiente Tumoral/genéticaRESUMO
OPINION STATEMENT: The heterogenous nature of colorectal cancer (CRC) renders it a major clinical challenge. Increasing genomic understanding of CRC has improved our knowledge of this heterogeneity and the main cancer drivers, with significant improvements in clinical outcomes. Comprehensive molecular characterization has allowed clinicians a more precise range of treatment options based on biomarker selection. Furthermore, this deep molecular understanding likely extends therapeutic options to a larger number of patients. The biological associations of consensus molecular subtypes (CMS) with clinical outcomes in localized CRC have been validated in retrospective clinical trials. The prognostic role of CMS has also been confirmed in the metastatic setting, with CMS2 having the best prognosis, whereas CMS1 tumors are associated with a higher risk of progression and death after chemotherapy. Similarly, according to mesenchymal features and immunosuppressive molecules, CMS1 responds to immunotherapy, whereas CMS4 has a poorer prognosis, suggesting that a CMS1 signature could identify patients who may benefit from immune checkpoint inhibitors regardless of microsatellite instability (MSI) status. The main goal of these comprehensive analyses is to switch from "one marker-one drug" to "multi-marker drug combinations" allowing oncologists to give "the right drug to the right patient." Despite the revealing data from transcriptomic analyses, the high rate of intra-tumoral heterogeneity across the different CMS subgroups limits its incorporation as a predictive biomarker. In clinical practice, when feasible, comprehensive genomic tests should be performed to identify potentially targetable alterations, particularly in RAS/BRAF wild-type, MSI, and right-sided tumors. Furthermore, CMS has not only been associated with clinical outcomes and specific tumor and patient phenotypes but also with specific microbiome patterns. Future steps will include the integration of clinical features, genomics, transcriptomics, and microbiota to select the most accurate biomarkers to identify optimal treatments, improving individual clinical outcomes. In summary, CMS is context specific, identifies a level of heterogeneity beyond standard genomic biomarkers, and offers a means of maximizing personalized therapy.
Assuntos
Neoplasias Colorretais/classificação , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/metabolismo , Disbiose/genética , Microbioma Gastrointestinal , Perfilação da Expressão Gênica , Humanos , Instabilidade de Microssatélites , Terapia de Alvo Molecular , Mutação , Seleção de Pacientes , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Receptor ErbB-2/genética , Transcriptoma , Proteínas ras/genéticaRESUMO
WHAT IS KNOWN AND OBJECTIVE: Cancer is one of the most important causes of morbidity and mortality worldwide. Pro-, pre- and symbiotics can modulate host metabolism and gut microbiota and potentially help prevent cancer and modulate the adverse effects (AEs) of treatments. Numerous studies on this role for pro-, pre- and symbiotics have reported inconsistent results. The purpose of this review was to examine current scientific evidence from randomized controlled trials (RCTs) on the effects of pro-, pre- and symbiotics on the incidence of complications and AEs, especially diarrhoea, in cancer management. METHODS: A systematic literature search was implemented in MEDLINE using the MeSH terms "probiotics", "prebiotics", "symbiotics" and "neoplasms", according to PRISMA guidelines. Reference lists were also handsearched to identify additional eligible RCTs. Three reviewers independently assessed the eligibility of each RCT. Of 714 retrieved abstracts, 22 articles with 2287 participants were included in the analysis. RESULTS AND DISCUSSION: The most studied bacteriotherapies were probiotics and symbiotics, in 10 and 7 studies, respectively. Both Lactobacillus and Bifidobacterium strains were used in 18 studies, while Lactobacillus and Bifidobacterium strains were individually used in 9 and 2 studies, respectively. Diarrhoea incidence rates were 3.2%-39.1% in intervention groups and 6.7%-60.9% in control groups, while infection incidence rates were 11.1%-22.7% in intervention groups and 17.3%-28.7% in control groups. WHAT IS NEW AND CONCLUSIONS: Pro-, pre- and symbiotics may potentially be efficacious in reducing complications associated with chemotherapy, radiotherapy and surgery in patients with cancer.
Assuntos
Neoplasias/tratamento farmacológico , Prebióticos/administração & dosagem , Probióticos/administração & dosagem , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Colorectal cancer (CRC) is a complex and genetically heterogeneous disease presenting a specific metastatic pattern, with the liver being the most common site of metastasis. Around 20%-25% of patients with CRC will develop exclusively hepatic metastatic disease throughout their disease history. With its specific characteristics and therapeutic options, liver-limited disease (LLD) should be considered as a specific entity. The identification of these patients is particularly relevant in view of the growing interest in liver transplantation in selected patients with advanced CRC. Identifying why some patients will develop only LLD remains a challenge, mainly because of a lack of a systemic understanding of this complex and interlinked phenomenon given that cancer has traditionally been investigated according to distinct physiological compartments. Recently, multidisciplinary efforts and new diagnostic tools have made it possible to study some of these complex issues in greater depth and may help identify targets and specific treatment strategies to benefit these patients. In this review we analyze the underlying biology and available tools to help clinicians better understand this increasingly common and specific disease.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Transplante de FígadoRESUMO
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.
RESUMO
INTRODUCTION: The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time. AREAS COVERED: This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed. EXPERT OPINION: Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.
Assuntos
Antineoplásicos , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Terapia de Alvo Molecular , Medicina de Precisão , Transdução de Sinais , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Seleção de Pacientes , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidoresRESUMO
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/ß-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.
RESUMO
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.
RESUMO
INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.
Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Sulfonamidas , Inibidores de Proteínas Quinases , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Cetuximab/efeitos adversos , Cetuximab/genéticaRESUMO
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.
RESUMO
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.
RESUMO
The COVID19 pandemic has affected the spectrum of cancer care worldwide. Early onset colorectal cancer (EOCRC) is defined as diagnosis below the age of 50. Patients with EOCRC faced multiple challenges during the COVID19 pandemic and in some institutions it jeopardized cancer diagnosis and care delivery. Our study aims to identify the clinicopathological features and outcomes of patients with EOCRC in our Centre during the first wave of the pandemic in comparison with the same period in 2019 and 2021. Patients with EOCRC visited for the first time at Vall d'Hebron University Hospital in Spain from the 1st March to 31st August of 2019, 2020 and 2021 were included in the analysis. 177 patients with EOCRC were visited for the first time between 2019 and 2021, of which 90 patients met the inclusion criteria (2019: 30 patients, 2020: 29 patients, 2021: 31 patients). Neither differences in frequency nor in stage at diagnosis or at first visit during the given periods were observed. Of note, indication of systemic therapy in the adjuvant or metastatic setting was not altered. Days to treatment initiation and enrollment in clinical trials in this subpopulation was not affected due to the COVID-19 outbreak.
RESUMO
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.
RESUMO
INTRODUCTION: Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (CRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF, and MSI status, and over the last few years, several promising new biomarkers have also been identified. Circulating tumor DNA has reshaped the prognosis of localized CRC. These genomic findings can guide treatment management to improve clinical outcomes. AREAS COVERED: Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory and metastatic CRC. In the localized stage, all clinical trials involving new approaches such as liquid biopsy or neoadjuvant immunotherapy are also discussed. Molecular alterations and targeted agents are described, and data from completed and ongoing studies with targeted therapy and immunotherapies are presented. EXPERT OPINION: The implementation of liquid biopsies in the localized CRC setting has reshaped management of this disease. The expanded use of biomarkers to guide CRC patients' treatment has revealed a level of complexity arising from interactions between different biomarkers. Prevalence of most established targetable biomarkers is low; however, the number of identified biomarkers in CRC is increasing. Thus, metastatic CRC may ultimately be considered an umbrella diagnosis encompassing numerous rare disease subtypes.
Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Biomarcadores Tumorais/genética , Ensaios Clínicos como Assunto , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
INTRODUCTION: The introduction of monoclonal antibodies to the chemotherapy backbone treatment has challenged the paradigm of metastatic colorectal cancer (mCRC) treatment. Their mechanism of action and pharmacokinetics are complex but important to understand in order to improve patient selection and treatment outcomes for mCRC population. AREAS COVERED: This review examines the scientific data, pharmacodynamics, and pharmacokinetics of approved monoclonal antibodies used to treat mCRC patients, including agents targeting signaling via VEGFR (bevacizumab and ramucirumab), EGFR (cetuximab and panitumumab), HER2/3 target therapy, and immunotherapy agents such as pembrolizumab or nivolumab. Efficacy and mechanism of action of bispecific antibodies are also covered. EXPERT OPINION: mCRC is a heterogeneous disease and the optimal selection and sequence of treatments is challenging. Monoclonal antibodies have complex pharmacokinetics and pharmacodynamics, with important interactions between them. The arrival of bioequivalent molecules to the market increases the need for the characterization of pharmacokinetics and pharmacodynamics of classic monoclonal antibodies to reach bioequivalent novel molecules.