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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      Complete response with fluorouracil and irinotecan with a BRAF V600E and EGFR inhibitor in BRAF-mutated metastatic colorectal cancer: a case report

      case-report
      , ,
      OncoTargets and therapy
      Dove Medical Press
      mCRC, BRAFV600E mutation, fluorouracil, vemurafenib, irinotecan, cetuximab

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          Abstract

          Background

          Patients with BRAF (v-Raf murine sarcoma viral oncogene homolog B) V600E-mutated metastatic colorectal cancer (mCRC) have a poor prognosis. The Southwest Oncology Group (SWOG) 1406 study evaluated the efficacy of vemurafenib in combination with irinotecan and cetuximab for simultaneous inhibition of epidermal growth factor receptor (EGFR) and BRAF in patients with BRAF V600E-mutated mCRC. Although the combination achieved higher progression-free survival (PFS) and disease control rates (DCRs), there was no complete response (CR) for the drug combination. In this case report, we report the complete recession of metastasis in a patient treated with irinotecan, cetuximab, vemurafenib, and 5-fluorouracil.

          Case presentation

          A 44-year-old male patient with hepatitis B was diagnosed with right-sided colon adenocarcinoma. He was treated with capecitabine plus oxaliplatin as postoperative adjuvant chemotherapy for eight cycles with a disease-free survival (DFS) of 1 year before the emergence of peritoneal and pelvic metastases. BRAF V600E mutation was positive and chemotherapy included 12 courses of 5-fluorouracil, vemurafenib, irinotecan, and cetuximab. Complete response with recession of metastases was observed.

          Conclusion

          The combination of fluorouracil and irinotecan with a BRAF V600E and EGFR inhibitor may have synergistic action, leading to recession of secondary metastases in patients with BRAF V600E-mutated colorectal cancer.

          Most cited references26

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          CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer.

          Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors.
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            Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial.

            Irinotecan is active against colorectal cancer in patients whose disease is refractory to fluorouracil. We investigated the efficacy of these two agents combined for first-line treatment of metastatic colorectal cancer. 387 patients previously untreated with chemotherapy (other than adjuvant) for advanced colorectal cancer were randomly assigned open-label irinotecan plus fluorouracil and calcium folinate (irinotecan group, n=199) or fluorouracil and calcium folinate alone (no-irinotecan group, n=188). Infusion schedules were once weekly or every 2 weeks, and were chosen by each centre. We assessed response rates and time to progression, and also response duration, survival, and quality of life. Analyses were done on the intention-to-treat population and on evaluable patients. The response rate was significantly higher in patients in the irinotecan group than in those in the no-irinotecan group (49 vs 31%, p<0.001 for evaluable patients, 35 vs 22%, p<0.005 by intention to treat). Time to progression was significantly longer in the irinotecan group than in the no-irinotecan group (median 6.7 vs 4.4 months, p<0.001), and overall survival was higher (median 17.4 vs 14.1 months, p=0.031). Some grade 3 and 4 toxic effects were significantly more frequent in the irinotecan group than in the no-irinotecan group, but effects were predictible, reversible, non-cumulative, and manageable. Irinotecan combined with fluorouracil and calcium folinate was well-tolerated and increased response rate, time to progression, and survival, with a later deterioration in quality of life. This combination should be considered as a reference first-line treatment for metastatic colorectal cancer.
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              American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy.

              An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO), offers timely clinical direction to ASCO's oncologists following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab (see Note). Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with monoclonal antibodies directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy. Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status. Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                OncoTargets and Therapy
                OncoTargets and therapy
                Dove Medical Press
                1178-6930
                2019
                08 January 2019
                : 12
                : 443-447
                Affiliations
                Department of Medical Oncology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China, doctorzangys@ 123456gmail.com
                Author notes
                Correspondence: Yuan-Sheng Zang, Department of Medical Oncology, Changzheng Hospital, Second Military Medical University, No 415, Fengyang Road, Shanghai 200003, China, Tel +86 138 1658 4620, Fax +86 021 6654 0109 8039, Email doctorzangys@ 123456gmail.com
                [*]

                These authors contributed equally to this work

                Article
                ott-12-443
                10.2147/OTT.S180845
                6329477
                30662270
                3524a39b-e52e-4c76-b075-7f39cfad5d71
                © 2019 Wang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                History
                Categories
                Case Report

                Oncology & Radiotherapy
                mcrc,brafv600e mutation,fluorouracil,vemurafenib,irinotecan,cetuximab
                Oncology & Radiotherapy
                mcrc, brafv600e mutation, fluorouracil, vemurafenib, irinotecan, cetuximab

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