Molecular Approaches to Metastatic Colorectal Cancer: Better Diagnosis - Better Treatment?
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ABSTRACT:
SUBMITTER: Seufferlein T
PROVIDER: S-EPMC6738174 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
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Project description:Colorectal cancer (CRC) represents 10% of all cancer types, making it the third leading cause of cancer-related deaths globally. Metastasis is the primary factor causing mortality in CRC patients. Approximately 22% of CRC-related deaths have metastasis present at diagnosis, with approximately 70% of these cases recurring. Recently, with the application of novel targeted drugs, targeted therapy has become the first-line option for individualized and comprehensive treatment of CRC. The management of these patients remains a significant medical challenge. The most prevalent targeted therapies for CRC in clinical practice focus on anti-vascular endothelial growth factor and its receptor, epidermal growth factor receptor (EGFR), and multi-target kinase inhibitors. In the wake of advancements in precision diagnosis and widespread adoption of second-generation sequencing (NGS) technology, rare targets such as BRAF V600E mutation, KRAS mutation, HER2 overexpression/amplification, and MSI-H/dMMR in metastatic colorectal cancer (mCRC) are increasingly being discovered. Simultaneously, new therapeutic drugs targeting these mutations are being actively investigated. This article reviews the progress in clinical research for developing targeted therapeutics for CRC, in light of advances in precision medicine and discovery of new molecular target drugs.
| S-EPMC10622804 | biostudies-literature
Project description:BackgroundMetastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients.MethodsA review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications.ResultsRAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research.ConclusionSeveral molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.
| S-EPMC7281737 | biostudies-literature
Project description:Over the past years, colorectal cancer (CRC) was subtyped according to its molecular and genetic characteristics, allowing the development of therapeutic strategies, based on predictive biomarkers. Biomarkers such as microsatellite instability (MSI), RAS and BRAF mutations, HER2 amplification or NTRK fusions represent major tools for personalized therapeutic strategies. Moreover, the routine implementation of molecular predictive tests provides new perspectives and challenges for the therapeutic management of CRC patients, such as liquid biopsies and the reintroduction of anti-EGFR monoclonal antibodies. In this review, we summarize the current landscape of targeted therapies for metastatic CRC patients, with a focus on new developments for EGFR blockade and emerging biomarkers (MSI, HER2, NTRK).
| S-EPMC7563268 | biostudies-literature
Project description:The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.
| S-EPMC7579731 | biostudies-literature
Project description:Over the last 20 years, median survival for patients with metastatic colorectal cancer (CRC) has remarkably improved from about 12 to over 30 months, mainly because of the development of new agents and patient selection using predictive biomarkers. However, the identification of the most effective treatment for an individual patient is still a challenge. Molecular profiling of CRC has made great progress, but it is limited by tumor heterogeneity and absence of driver mutation. However, RAS, BRAF, and microsatellite instability are validated biomarker recommended by NCCN and ESMO. In this review, we discuss recent advances and future developments.
| S-EPMC5705494 | biostudies-literature
Project description: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.
| S-EPMC7383645 | biostudies-literature
Project description:In our recent publication [1], we have explored at the molecular level the consequences of reovirus administration to patients with KRAS mutated colorectal cancer (CRC). This was the first reported study where transcriptome assay was performed on KRAS mutated CRC patients receiving reovirus (pelareorep) therapy. Using peripheral mononuclear cells as a tumor surrogate, we have identified several hundred genes that were significantly altered in a transcriptome assay of patients receiving pelareorep serving as their own controls (pre and post reovirus administration) and compared to untreated controls [2]. We focused primarily on 884 immune related genes and published the data for genes with significance probability of 0.001 (1 in thousand for a perfect random occurrence). Samples were collected at 48 hours, day 8 and day 15 post reovirus administration and compared for dynamic gene expression alterations over time. Using PBMC we also performed flow cytometry, cytokine ELISA, immunohistochemistry, and determination of the expression level of CRC specific microRNA miR-29a-3p. Our data supports the therapeutic competence of reovirus and identifies the four major ways by which it exerts its antitumor effects.
| S-EPMC7793569 | biostudies-literature
Project description:Colorectal cancer is the third most common cancer in the US. In recent decades, an improved understanding of the role of the angiogenesis pathway in colorectal cancer has led to advancements in treatment. Bevacizumab has been shown to improve the progression-free survival and overall survival when combined with cytotoxic chemotherapy in patients with metastatic colorectal cancer, and at present is the only antiangiogenesis agent approved for the treatment of this cancer. Aflibercept is a novel angiogenesis-targeting agent, and has demonstrated efficacy in treating metastatic colorectal cancer in a recent randomized Phase III trial. Here we review the role of angiogenesis in the tumorigenesis of colorectal cancer, strategies for targeting angiogenesis, and the clinical development of aflibercept.
| S-EPMC3256978 | biostudies-other
Project description:BackgroundRAS assessment is mandatory for therapy decision in metastatic colorectal cancer (mCRC) patients. This determination is based on tumor tissue, however, genotyping of circulating tumor (ct)DNA offers clear advantages as a minimally invasive method that represents tumor heterogeneity. Our study aims to evaluate the use of ctDNA as an alternative for determining baseline RAS status and subsequent monitoring of RAS mutations during therapy as a component of routine clinical practice.Patients and methodsRAS mutational status in plasma was evaluated in mCRC patients by OncoBEAM™ RAS CRC assay. Concordance of results in plasma and tissue was retrospectively evaluated. RAS mutations were also prospectively monitored in longitudinal plasma samples from selected patients.ResultsAnalysis of RAS in tissue and plasma samples from 115 mCRC patients showed a 93% overall agreement. Plasma/tissue RAS discrepancies were mainly explained by spatial and temporal tumor heterogeneity. Analysis of clinico-pathological features showed that the site of metastasis (i.e. peritoneal, lung), the histology of the tumor (i.e. mucinous) and administration of treatment previous to blood collection negatively impacted the detection of RAS in ctDNA. In patients with baseline mutant RAS tumors treated with chemotherapy/antiangiogenic, longitudinal analysis of RAS ctDNA mirrored response to treatment, being an early predictor of response. In patients RAS wt, longitudinal monitoring of RAS ctDNA revealed that OncoBEAM was useful to detect emergence of RAS mutations during anti-EGFR treatment.ConclusionThe high overall agreement in RAS mutational assessment between plasma and tissue supports blood-based testing with OncoBEAM™ as a viable alternative for genotyping RAS of mCRC patients in routine clinical practice. Our study describes practical clinico-pathological specifications to optimize RAS ctDNA determination. Moreover, OncoBEAM™ is useful to monitor RAS in patients undergoing systemic therapy to detect resistance and evaluate the efficacy of particular treatments.
| S-EPMC5834035 | biostudies-literature
Project description:The objective of this article is to group together various management strategies and to highlight the recent treatment modifications that attempt to target the multimodal etiological factors involved in cancer cachexia. The contemporary role of nursing fraternity in psychosocial and nutritional assessment of cancer patients is briefly discussed. Cachexia is a syndrome of metabolic disturbance, characterized by the inflammation and loss of muscle with or without loss of adipose tissue. In cancer cachexia, a multifaceted condition, patients suffer from loss of body weight that leads to a negative impact on the quality of life and survival of the patients. The main cancers associated with cachexia are that of pancreas, stomach, lung, esophagus, liver, and that of bowel. The changes include increased proteolysis, lipolysis, insulin resistance, high energy expenditure, and reduced intake of food, all leading to impaired response to different treatments. There is no standardized treatment for cancer cachexia that can stabilize or reverse this complex metabolic disorder at present. The mainstay of cancer cachexia therapy remains to be sufficient nutritional supplements with on-going efforts to explore the drugs that target heightened catabolic processes and complex inflammation. There is a need to develop a multimodal treatment approach combining pharmacology, exercise program, and nutritional support to target anorexia and the severe metabolic changes encountered in cancer cachexia.
| S-EPMC8420916 | biostudies-literature