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      Association of post-operative CEA with survival and oxaliplatin benefit in patients with stage II colon cancer: a post hoc analysis of the MOSAIC trial

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          Abstract

          Background

          Adjuvant treatment for stage II colon cancer (CC) can be proposed to patients with high-risk disease. Recently, 2.35 ng/mL carcinoembryonic antigen (CEA) was identified as the best cut-off value. This post hoc analysis of the MOSAIC trial assessed post-operative CEA prognostic value for survival outcomes and predictive value for the addition of oxaliplatin to adjuvant treatment.

          Methods

          Prognostic and predictive values of post-operative CEA in patients with stage II CC were evaluated with Kaplan–Meier survival curves and Cox model with interaction terms. Disease-free survival (DFS) and overall survival (OS) were estimated.

          Results

          Among 899 stage II CC patients, post-operative CEA was available in 867 (96.4%); and 434 (48.65%) had a high-risk stage II disease. The 3-year DFS rate was 88.5% and 78.7% in the ≤ 2.35 ng/mL and > 2.35 ng/mL group, respectively ( P = 0.006). Use of oxaliplatin showed survival benefit only in patients with high-risk stage II CC and post-operative CEA > 2.35 ng/ml (interaction term P = 0.09 and 0.03 for DFS and OS).

          Conclusion

          CEA is a strong prognostic factor for DFS and OS in stage II CC. In the MOSAIC trial, only high-risk stage II CC patients with post-operative CEA > 2.35 ng/mL benefited from the addition of oxaliplatin to LV5FU2.

          Trial registration

          NCT00275210 (January 11, 2006).

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          Most cited references6

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          Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study.

          The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation.
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            Detection of free-circulating tumor-associated DNA in plasma of colorectal cancer patients and its association with prognosis.

            Tumor cells are characterized by specific genetic alterations. When such genetic alterations are identified in body fluid including plasma, regardless of the presence of detectable tumor cells, it shows the existence of free-circulating tumor-associated DNA. The objective of our study was to assess the prognostic value of free-circulating tumor-associated DNA in colorectal cancer patients' plasma. The first step of our work was to find common genetic alterations in tumors that would subsequently be used for plasma DNA screening. We focused on KRAS2 mutations in codons 12 and 13 by the mutant allele-specific amplification (MASA) method and p16 hypermethylation by the methylation-specific polymerase chain reaction (MSP) method. Patients with a tumor presenting either alteration were selected for plasma screening; 58 tumors were analyzed for KRAS2 mutations and tested for p16 gene promoter methylation. Survival and recurrence rates were assessed in patients with and without free-circulating tumor-associated DNA alterations in plasma. Of the 58 tumors analyzed, 39 (67%) demonstrated either one or both of the studied genetic alterations. Twenty-two (38%) were mutated at KRAS2, and an identical alteration was detected in 10 (45%) of the 22 corresponding plasma samples. Thirty-one (53%) had p16 gene promoter hypermethylation that could also be detected in the plasma in 21 cases (68%). Among the 39 patients who had one or the other alteration in tumor DNA, 37 had at least one reliable plasma test. In 26 (70%) of the 37 patients, free-circulating tumor-associated DNA was detected in plasma. The 2-year overall survival rate was 48% in the group where free-circulating tumor-associated DNA was detected in plasma and 100% in the one where free-circulating tumor-associated DNA was not detected in plasma (p < 0.03). Among these 37 patients, 25 patients had a stage I, II or III disease. In this subgroup of patients, the 2-year recurrence-free survival rate for the 17 patients with free-circulating tumor-associated DNA detected in plasma was 66%, compared to 100% for the 8 patients without free-circulating tumor-associated DNA detected in plasma (p = 0.044). The presence of free-circulating tumor-associated DNA in plasma seems to be a relevant prognostic marker for patients with colorectal cancer and may be used to identify patients with a high risk of recurrence. Copyright 2002 Wiley-Liss, Inc.
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              Validation of the 12-gene colon cancer recurrence score in NSABP C-07 as a predictor of recurrence in patients with stage II and III colon cancer treated with fluorouracil and leucovorin (FU/LV) and FU/LV plus oxaliplatin.

              Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07.
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                Author and article information

                Contributors
                +33370632175 , dvernerey@chu-besancon.fr
                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                12 July 2019
                13 August 2019
                : 121
                : 4
                : 312-317
                Affiliations
                [1 ]Department of Hepato-Gastroenterology and Gastrointestinal Oncology, Sorbonne Paris-Cité, Paris Descartes University, Hôpital Européen Georges Pompidou, Paris, France
                [2 ]ISNI 0000 0004 0638 9213, GRID grid.411158.8, Methodology and Quality of Life Unit in Oncology, , University Hospital of Besançon, ; Besançon, France
                [3 ]Bourgogne Franche-Comté University, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France
                [4 ]Department of Medical Oncology, Sorbonne University, Hôpital Saint Antoine, Paris, France
                [5 ]Oncology Multidisciplinary Research Group (GERCOR), Paris, France
                [6 ]ISNI 0000000121866389, GRID grid.7429.8, UMR-S 1147, INSERM, ; Paris, France
                [7 ]Unit of Medical Oncology, Clinical Cancer Center, AUSL-IRCCS Reggio Emilia, Reggio Emilia, Italy
                [8 ]ISNI 0000 0001 2348 0746, GRID grid.4989.c, Department of Gastroenterology and Digestive diseases, Hopital Erasme, , Université Libre de Bruxelles, ; Bruxelles, Belgium
                [9 ]GRID grid.7080.f, Vall d’Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, , Universitat Autònoma de Barcelona, ; Barcelona, Spain
                [10 ]ISNI 0000 0000 9910 8169, GRID grid.416098.2, Department of Oncology, , Royal Bournemouth Hospital and Bournemouth University, ; Bournemouth, UK
                [11 ]ISNI 0000 0004 0638 5642, GRID grid.477404.4, Department of Oncology, , Institut Hospitalier Franco-Britannique, ; Levallois-Perret, France
                Article
                521
                10.1038/s41416-019-0521-7
                6738041
                31296923
                1db5e04d-16bc-4611-bde1-e10d90f9032d
                © The Author(s), under exclusive licence to Cancer Research UK 2019

                This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

                History
                : 5 March 2019
                : 12 June 2019
                : 18 June 2019
                Categories
                Article
                Custom metadata
                © Cancer Research UK 2019

                Oncology & Radiotherapy
                colorectal cancer,colon cancer
                Oncology & Radiotherapy
                colorectal cancer, colon cancer

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