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)

DxS is a personalized medicine company that meets the needs of the pharmaceutical industry for biomarkers and companion diagnostics to support the development and sales of cancer and other therapies. The company provides both biomarker products, which are used predominately during clinical trials, and companion diagnostics, which aid doctors in selecting therapies for patients. Working in partnership with drug companies, DxS offer validated biomarker assays to support drug development and then regulatory approval, by identifying likely responders to drug therapies. DxS have launched the world's first cancer mutation companion diagnostic to support Amgen's Vectibix colorectal cancer therapy. DxS kits detect mutations in oncogenes associated with cancer drug response. TheraScreen is the range of CE-marked diagnostic products for detecting mutations in the EGFR and K-RAS genes. Validated biomarker kits are available for research use for EGFR, RAS, RAF, BCR-ABL and other genes that show a correlation between patient mutation status and drug response.
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PMID:DxS Ltd. 1838 59

Overexpression of VEGF (vascular endothelial growth factor) and EGFR (epidermal growth factor receptor) is detected in malignant tumors, and it is associated with poor prognosis. Bevacizumab is a monoclonal anti-body targeting VEGF, and cetuximab and panitumumab are monoclonal anti-bodies targeting EGFR. In some clinical trials, these drugs brings a survival benefit with acceptable toxicity. In Western, bevacizumab, cetuximab and panitumumab have been already approved for patients with unresectable colorectal cancer, and used in clinical practice. In Japan, bevacizumab was approved in April 2007, cetuximab and panitumumab probably will be approved within several years. It is very important to know their efficacy and safety of these drugs for the clinical practice of Japanese patients.
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PMID:[Molecular target therapy and chemotherapy for advanced colorectal cancer]. 1848 7

In December 2007 the European Medicines Agency (EMEA) approved panitumumab (Vectibix) for the treatment of metastatic colorectal cancer. Panitumumab has a conditional approval as monotherapy for the treatment of patients with EGFR-expressing tumours with non-mutated (wild-type) K-ras genes after failure of standard chemotherapy regimens. This specific subgroup of patients showed a more favourable outcome in a controlled, open-label, randomized phase III study. Patients treated with panitumumab plus best supportive care had a significantly prolonged progression-free survival compared to patients receiving best supportive care alone.
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PMID:[Panitumumab]. 1849 43

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in Western countries. Despite the progress achieved with the introduction of new cytotoxic agents, CRC recurrence rates for patients with resected stage II and/or stage III disease remain higher than 20%. Furthermore, for patients diagnosed with metastatic CRC, the median survival time remains below 2 years and cure is often an elusive goal. These data highlight the need for more-effective systemic therapies. The EGFR is frequently overexpressed in CRC and has been associated with the malignant phenotype. Numerous clinical trials are now investigating the role of EGFR-targeted agents in CRC and have produced some encouraging results. Panitumumab is a fully human IgG(2) monoclonal antibody that in a randomized phase III trial was shown to increase efficacy when added to best supportive care in patients with chemotherapy-refractory metastatic CRC. In phase I-III trials, panitumumab was safe and well tolerated, with most of its adverse effects related to some form of skin toxic effect. Early studies assessing the safety and efficacy of panitumumab alongside chemotherapy have also yielded promising results, and this combination is now being investigated in the first-line and second-line settings in randomized clinical trials.
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PMID:Drug Insight: panitumumab, a human EGFR-targeted monoclonal antibody with promising clinical activity in colorectal cancer. 1850 65

The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive (EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, PI3KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH+ patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH+ patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. PI3KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role in primary resistance. The potential prognostic implication of IGF1R expression merits further evaluation.
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PMID:Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients. 1857 88

During the carcinogenesis of colorectal cancer in about half of the cases K-RAS, while much less frequently B-RAF mutation occur in early adenomas. While K-RAS mutant tumors are more likely present in male patients, B-RAF mutant tumors develop more frequently in females and are independent of the microsatellite status. Colorectal cancers are characterized by EGFR expression; the gene is not mutated, rarely amplified and increased copy number is due to chromosomal polysomy. This phenotype/genotype of colorectal cancer lent support to the introduction of anti-EGFR antibody therapies. For a while positive EGFR expression status of the tumor was the basis of patient selection for these targeted therapies in colorectal cancer. Monotherapies with the two available anti-EGFR antibodies of chemoresistant colorectal cancers resulted in appr. 10% objective response rate, which was independent of the level of EGFR expression. In case of panitumumab it was discovered that the efficacy of this targeted therapy depends on the K-RAS mutant status of the tumors. Furthermore, preliminary data suggest that cetuximab combined with chemotherapy is effective also exclusively in K-RAS wild-type tumors. Based on these data it is safe to say that K-RAS mutant status of colorectal cancer is a negative predictor for EGFR-targeted therapies of colorectal cancer. Accordingly, it is necessary to determine the K-RAS status of colorectal cancer before making therapeutic decisions.
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PMID:[The RAS paradox of the EGFR-targeted therapy in colorectal cancer]. 1864 Aug 95

Oncogenic KRAS mutations are associated with resistance to anti-EGFR therapy in colorectal carcinoma. Since anti-EGFR monoclonal antibodies are employed in clinical practice in advanced colorectal cancer, KRAS mutations have become an important predictor of therapy outcome. Mutational analysis of KRAS was performed on 163 adenocarcinoma samples. Exons 1-3 of KRAS were analyzed using SSCP and sequencing. Fifty seven (35%) carcinomas had missense point mutations in one of codons 12, 13, 59, 61, 117. In accordance with the published data, missense mutations in codons 12 (66%) and 13 (22%) were the most frequent. Mutations in codons 59 and 117 occurred with the same frequency as in codon 61. The only detected insertion occurred in exon 2. 15-bp insertion resulted in tandem duplication of codons 62-66. Presumably, 5 additional amino acids affected switch II conformation and sustained Ras activity due to decreased GTP hydrolysis. We report this unusual new type mutation.
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PMID:KRAS mutation profile in colorectal carcinoma and novel mutation--internal tandem duplication in KRAS. 1866 74

Pharmacological treatment of colorectal cancer has improved survival rates in recent years. Individual genetic variation in genes associated with metabolism and targets of commonly used drugs can be responsible for variability in treatment outcome and toxicity. Diverse study designs have been used and heterogeneous end points evaluated by studies assessing the association of genetic markers with treatment outcome. We conducted this systematic review, including 51 studies, to present a comprehensive overview and draw further conclusions. To facilitate comparison of reported study results, risk estimates for observed genetic variants in 33 key genes are presented using defined reference categories and recalculated risk estimates based on data provided in original publications, where necessary. Overall, evidence indicates associations of the UGT1A1(*) 28 variant genotype with toxicity after irinotecan treatment, mutations in GSTP1-105 with improved treatment outcome and the XPD-751 variant genotype with poor treatment outcome after oxaliplatin treatment, and amplification of the EGFR gene with improved treatment outcome after therapy with monoclonal antibodies. Adequately powered prospective investigations designed specifically for pharmacogenetics are needed.
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PMID:Pharmacogenetics in colorectal cancer: a systematic review. 1868 83

Over the past 10 years, healthcare providers involved in the management of metastatic colorectal cancer (MCRC) have seen an explosion in new agents and their combinations. These developments have resulted in an expansion in the options of care for MCRC patients and in a significant improvement in their overall survival. This article reviews the current role of anti-EGFR monoclonal antibodies in the management of MCRC and the identification of recent markers of response that lead towards treatment individualization.
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PMID:Anti-EGFR monoclonal antibodies in metastatic colorectal cancer: time for an individualized approach? 1875 98

The introduction of modern chemotherapeutic drugs and targeted therapies has substantially changed the treatment of advanced colorectal cancer (aCRC). Thus, median survival of stage IV patients was increased from 6 months under best supportive care to over 2 years if all drugs are administered. Also, new combination therapies may cause irresectable liver metastases to shrink to such an extent that they may be resected (downsizing). Patients who were formerly treated with palliative intent may now be cured. However, not all patients benefit from the new compounds. Very recently, new genetic characteristics were identified as potential molecular biomarkers that may predict response to anti-EGFR therapy, a specific targeted therapy; the marker detected is the mutational status of the oncogene k-ras. Only patients with wild-type k-ras-expressing tumors respond to anti-EGFR antibodies. The integration of biomarker analysis into the clinical routine represents an important step toward customized treatment of cancer patients.
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PMID:[Systemic treatment of advanced colorectal cancer]. 1879 19


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