Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Panitumumab is a fully human IgG2 monoclonal antibody that is highly selective for the epidermal growth factor receptor (EGFR), which is overexpressed in 25-77% of colorectal cancers and is often associated with a poor prognosis. Binding of panitumumab to EGFR reduces cell proliferation and mediator production, and induces apoptosis. In a comparative, phase III trial in adult patients with chemotherapy-refractory metastatic colorectal cancer, intravenous panitumumab 6 mg/kg every 2 weeks plus best supportive care (BSC) improved progression-free survival (PFS) [primary endpoint] and objective tumor response rate to a significantly greater extent than BSC alone. The improvement in PFS produced by panitumumab monotherapy was significantly greater in patients with non-mutated (wild-type) KRAS than in those with mutant KRAS (in whom no benefit from panitumumab was observed). Similarly, all patients experiencing a partial response had wild-type KRAS, while stable disease was achieved by more patients with wild-type KRAS than with mutant KRAS. The predictive value of mutant KRAS for a lack of clinical benefit with panitumumab monotherapy was supported by results from an open-label extension of the phase III study and a large phase II study. Although most patients treated with panitumumab experienced at least one adverse event, the incidence of severe adverse events resulting in discontinuation of treatment was relatively low. The most commonly reported treatment-related adverse events were skin-related toxicities, which reflect the mechanism of action of panitumumab.
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PMID:Panitumumab: in metastatic colorectal cancer with wild-type KRAS. 1899 57

PURPOSE Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. PATIENTS AND METHODS We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. CONCLUSION BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.
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PMID:Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. 1900 46

Regarding the evolution of the treatments of colorectal cancer during the last five years, it appears that numerous questions have to be considered with a strategic point of view. In order to avoid inclusion of a lot of patients in clinical patients, we urgently need the help of biology to give us arguments to choose one treatment or another. The fact that ten years after their approval, we are not able to select responders to oxaliplatin or irinotecan, confirm that this is difficult problem to solve. The contribution of biology to the prescription of drugs commonly used in colorectal cancer is discussed in this paper. There are already situations where the contribution of biology to clinical practice and prescription is not debatable : this is the case for the use of UGT1A1 status determination when using irinotecan and the determination of KRAS status for the prescription of panitumumab (and cetuximab in a few months). This individual adaptation is a dream that becomes reasonable when we look on the recent results concerning EGFR inhibitors, but a lot of work has to be done and it is not sure that biological assessment of the tumour will be able to solve all the problems. For instance, to determine predictive factors of response to angiogenesis inhibitors, it is likely that solutions will come from new techniques of imaging rather than from biology. However, new tools such as proteomics or metabolomics, as well as a better dialogue between clinician and biologist, will allow fast improvements. It must be emphasised that, for the first time in 2008, it is possible to prescribe targeted therapies to a specific "targeted" group of patients with metastatic colorectal cancer.
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PMID:[Is it possible to individualize prescription of medical treatment in colorectal cancer? The clinician point of view]. 1900 22

Several drugs have been developed and demonstrated similar efficacy in colorectal cancer treatment therefore with choice, time comes for decision. The biologist will have to provide the tools allowing to clarify this choice. Among the tools available, those of pharmacogenetics and pharmacogenomics appear most promising and recent examples allow to illustrate their clinical interest. The pharmacogenetics of anti-cancer agents presents a clinical characteristic, which requires to hold into account the genetic variations not only of host cells but also of those of the tumor cells. Among the most conclusive examples one is that of the prediction of severe neutropenia induced by the irinotecan among patients homozygous for * 28 allele of UGT1A1 enzyme which conjugates SN38 active compound of irinotecan, the other one is the presence of a KRAS mutated allele in tumor cell to predict resistance to anti EGFR antibodies in the treatment of colorectal metastatic cancer.
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PMID:[The biological point of view on pharmacogenetics of anticancer agents in colorectal cancer]. 1900 23

The majority of current major advances in the management of main human malignancies including breast, colorectum and head and neck result from the introduction of targeted therapies. An optimal application of targeted therapy needs a knowledge for the tumoral status of the target itself. It is also interesting to dispose of biological informations resulting from the interactions between treatment and target (biological proof of the concept). These informations are at the basis of the conception of new clinical protocols in oncology. In this context the role of molecular biology units is determinant. Examples of concrete applications of this strategy will be detailled particularly for the MINDACT Trial in breast cancer and for the KRAS status in the setting of EGFR targeting therapies in advanced colorectal cancer.
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PMID:[Design of new protocols. Role of molecular biology units?]. 1900 33

The incidence of colorectal carcinoma has increased among patients <40 years of age for unclear reasons. In this study, we describe the clinical, pathologic, and molecular features of colorectal carcinomas that developed in young patients. We compiled a study group of 24 patients <40 years of age with colorectal carcinoma, and 45 patients > or =40 years of age served as controls. Cases were evaluated for clinical risk factors of malignancy and pathologic features predictive of outcome. The tumors were immunohistochemically stained for O6-methylguanine methyltransferase, MLH-1, MSH-2, MSH-6, beta-catenin, chemokine (C-X-C motif) receptor 4, epidermal growth factor receptor, TP53, p16, survivin, and alpha-methylacyl-CoA racemase; assessed for microsatellite instability and mutations in beta-catenin, APC, EGFR, PIK3CA, KRAS, and BRAF; evaluated for micro-RNA expression (miR-21, miR-20a, miR-183, miR-192, miR-145, miR-106a, miR-181b, and miR-203); and examined for evidence of human papillomavirus infection. One study patient each had ulcerative colitis and hereditary nonpolyposis colorectal cancer. Ninety-two percent of tumors from young patients occurred in the distal colon (P=0.006), particularly the rectum (58%, P=0.02), and 75% were stage III or IV. Tumors from young patients showed more frequent lymphovascular (81%, P=0.03) and/or venous (48%, P=0.003) invasion, an infiltrative growth pattern (81%, P=0.03), and alpha-methylacyl-CoA racemase expression (83%, P=0.02) compared with controls. Carcinomas in this group showed significantly increased expression of miR-21, miR-20a, miR-145, miR-181b, and miR-203 (P< or =0.005 for all comparisons with controls). These results indicate that early-onset carcinomas commonly show pathologic features associated with aggressive behavior. Posttranslational regulation of mRNA and subsequent protein expression may be particularly important to the development of colorectal carcinomas in young patients.
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PMID:Clinical, pathologic, and molecular features of early-onset colorectal carcinoma. 1904 96

The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and tumor progression of colorectal cancer (CRC). As a result, the EGFR has evolved as a relevant target in the treatment of metastatic CRC. KRAS serves as a mediator between extracellular ligand binding and intracellular transduction of signals from the EGFR to the nucleus. The presence of activating KRAS mutations has been identified as a potent predictor of resistance to EGFR-directed antibodies such as cetuximab or panitumumab. These agents should therefore be applied only in tumors with a wild-type status of the KRAS gene. Further parameters of resistance are lack of EGFR amplification, PTEN loss or BRAF mutation. However, they are less well studied or associated with less consistent data and therefore require prospective analyses before integration into clinical decision making. Future studies need to identify patterns of single or multiple mutations to further increase the power of patient selection for anti-EGFR therapy. While molecular parameters help to predict treatment efficacy upfront, skin toxicity has been accepted as an independent predictor of response during exposure to anti-EGFR therapy.
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PMID:Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR. 1911 87

Recent retrospective evidence from several randomized studies has established that advanced colorectal cancer patients with tumors harboring a mutation in the KRAS gene do not derive benefit from the administration of epidermal growth factor receptor-directed monoclonal antibodies, such as cetuximab or panitumumab. This represents a paradigm-changing event and will have substantial impact on current and future anticancer drug development. These results add to the economic and ethical considerations involved in the development of novel targeted therapies and should increase our scrutiny of mechanisms of resistance and predictive biomarkers while in earlier developmental stages. In this article we will review the available clinical data, discuss the potential implications for future drug development in colorectal cancer, and provide a comprehensive overview of the technical aspects of KRAS mutation testing. In particular we aimed at enumerating the available procedures for mutation detection and their main characteristics, as well as comparing them from a clinical feasibility standpoint. While the true specificity and sensitivity of these methods have yet to be fully characterized, a better understanding of the differences between tests will be critical so that clinicians and pathologists can fully integrate this testing into the routine care of patients with colorectal cancer.
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PMID:KRAS mutations and sensitivity to epidermal growth factor receptor inhibitors in colorectal cancer: practical application of patient selection. 1912 2

Dysregulated expression of microRNAs (miRNAs) is associated with a variety of diseases, including colorectal cancer. By comparing more than 200 miRNAs in 13 pairs of matched colorectal cancer and normal adjacent tissue samples through qRT-PCR and microarray analysis, we found a widespread disruption of miRNA expression during colorectal tumorigenesis. In particular, among a panel of presumed targets generated by in silico analysis that may interact with these aberrantly expressed miRNAs, KRAS oncogene has been further experimentally validated as the target of miR-143. First, an inverse correlation between KRAS protein and miR-143 in vivo was found. Second, KRAS expression in Lovo cells was significantly abolished by treatment with miR-143 mimic, whereas miR-143 inhibitor increased KRAS protein level. Third, luciferase reporter assay confirmed that miR-143 directly recognize the 3'-untranslated region of KRAS transcripts. Four, Lovo cells treated with miR-143 inhibitor showed a stimulated cell proliferation, whereas miR-143 overexpression had an opposite effect. Finally, inhibition of KRAS expression by miR-143 inhibits constitutive phosphorylation of ERK1/2. Taken together, the present study provides the first evidences that miR-143 is significant in suppressing colorectal cancer cell growth through inhibition of KRAS translation.
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PMID:Role of miR-143 targeting KRAS in colorectal tumorigenesis. 1913 7

Over the past 10 years there has been a significant increase in the armamentarium of agents available for use in the treatment of advanced colorectal cancer (CRC). Among these new agents are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR): cetuximab, a mouse-human chimeric monoclonal antibody, and panitumumab, a fully human monoclonal antibody. Both are approved as monotherapy for the treatment of chemotherapy-refractory advanced CRC. Cetuximab is also indicated for use in combination with irinotecan. Here, we review 10 reports of phase II and III clinical studies of patients treated with panitumumab or cetuximab monotherapy. The clinical trials demonstrate similar efficacy profiles for advanced CRC patients treated with panitumumab and cetuximab monotherapy, with some differences in their adverse event profiles. In addition, the recent results of retrospective tumor KRAS gene mutational analyses in CRC patients treated with anti-EGFR monotherapy are reviewed. Data from the clinical trials reviewed here clearly demonstrate that anti-EGFR monotherapy is an effective treatment modality for patients with chemotherapy-refractory advanced CRC.
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PMID:Anti-epidermal growth factor receptor monotherapy in the treatment of metastatic colorectal cancer: where are we today? 1914 81


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