Defective Mismatch Repair Status as a Prognostic Biomarker of Disease-Free Survival in Stage III Colon Cancer Patients Treated with Adjuvant FOLFOX Chemotherapy

Zaanan, Aziz; Fléjou, Jean‐François; Émile, Jean-François; Des, Guetz Gaëtan; Cuillière-Dartigues, Peggy; Malka, David; Lecaille, Cédric; Validire, Pierre; Louvet, Christophe; Rougier, Philippe; Gramont, Aimery de; Bonnetain, Franck; Praz, Françoise; Taı̈eb, Julien

doi:10.1158/1078-0432.ccr-11-1048

Cited by 76 publications

(43 citation statements)

References 37 publications

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“…Retrospective analyses of stage III colon cancer patients who received adjuvant FOLFOX suggest that dMMR CRCs maybe sensitive to oxaliplatin (49, 50); however, only limited data from prospective clinical trials evaluating oxaliplatin-based treatment are available (51, 50, 52). …”

Section: Treatmentmentioning

confidence: 99%

Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer

Kawakami

Zaanan

Sinicrope

2015

Curr. Treat. Options in Oncol.

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352

267

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Opinion Statement TNM stage remains the key determinant of patient prognosis after surgical resection of colorectal cancer (CRC), and informs treatment decisions. However, there is considerable stage-independent variability in clinical outcome that is likely due to molecular heterogeneity. This variability underscores the need for robust prognostic and predictive biomarkers to guide therapeutic decision-making including the use of adjuvant chemotherapy. Although the majority of CRCs develop via a chromosomal instability pathway, approximately 12-15% have deficient DNA mismatch repair (dMMR) which is characterized in the tumor by microsatellite instability (MSI). Tumors with the dMMR/MSI develop from a germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), i.e., Lynch syndrome, or more commonly from epigenetic inactivation of MLH1 MMR gene. CRCs with dMMR/MSI status have a distinct phenotype that includes predilection for the proximal colon, poor differentiation, and abundant tumor infiltrating lymphocytes. Consistent data indicate that these tumors have a better stage-adjusted survival compared to proficient MMR or microsatellite stable (MSS) tumors, and may respond differently to 5-fluorouracil-based adjuvant chemotherapy. To increase the identification of dMMR/MSI patients in clinical practice that includes those with Lynch Syndrome, it is recommended that all resected CRCs to be analyzed for MMR status. Available data indicate that patients with stage II dMMR CRCs have an excellent prognosis and do not benefit from 5-FU-based adjuvant chemotherapy which supports their recommended management by surgery alone. In contrast, the benefit of standard adjuvant chemotherapy with the FOLFOX regiment in stage III dMMR CRC patients awaits further study and therefore, all patients should be treated with standard adjuvant FOLFOX.

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Section: Treatmentmentioning

confidence: 99%

Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer

Kawakami

Zaanan

Sinicrope

2015

Curr. Treat. Options in Oncol.

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352

267

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“…To date, only limited data exist in MSI tumors from patients treated with oxaliplatin combined with 5-FU, and predictive information is lacking. A retrospective single-arm study in 5-FU plus oxaliplatin-treated stage III colon cancer patients found that the 3-year DFS rate was significantly higher in patients with deficient vs proficient MMR tumors (58), suggesting that the prognostic impact of MMR status is maintained since oxaliplatin is expected to provide equivalent benefit irrespective of MMR status.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Microsatellite Instability in Colorectal Cancer: Prognostic, Predictive, and Therapeutic Implications

Sinicrope

Sargent

2012

Clinical Cancer Research

235

204

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Microsatellite instability (MSI) is the molecular fingerprint of the deficient mismatch repair (MMR) system that characterizes approximately 15% of colorectal cancers (CRCs). MSI develops due to germline mutations in MMR genes or more commonly, from epigenetic silencing of MLH1 in sporadic tumors that occurs in a background of methylation of CpG islands in gene promoter regions and in tumors that frequently show hotspot mutations in the BRAF oncogene. MSI tumors have distinct phenotypic features and have been consistently associated with a better stage-adjusted prognosis compared to microsatellite stable tumors. MSI negatively predicts response to 5-fluorouracil and may also determine responsiveness to other drugs used in CRC treatment. Recent data expand the molecular heterogeneity of MSI tumors that may contribute to the understanding of differential chemosensitivity. Identifying deficient MMR has important implications for patient management and its exploitation holds promise for improving patient outcomes and for the development of novel therapeutics.

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“…Preclinical data indicate that MSI tumor cells are sensitive to oxaliplatin despite displaying resistance to 5-FU [33]. To date, however, data examining the prognostic/predictive impact of MMR on chemosensitivity to oxaliplatin-based treatment are very limited [34–37]. A preliminary clinical study suggested that the addition of oxaliplatin may reverse the 5-FU resistance for dMMR stage III colon cancer [35].…”

Section: Mmr Status and Clinical Outcome In Stage III Colon Cancermentioning

confidence: 99%

Prognostic Impact of Deficient DNA Mismatch Repair and KRAS and BRAF V600E Mutations in Patients with Lymph-Node-Positive Colon Cancer

Zaanan

Bachet²,

André

et al. 2014

Curr Colorectal Cancer Rep

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While tumor stage remains the key determinant of colorectal cancer (CRC) prognosis and treatment, there is considerable stage-independent variability in clinical outcome. Molecular markers hold promise for explaining variations in clinical behavior, and may identify patient subsets with differential efficacy and survival after adjuvant chemotherapy which is standard of care for patients with lymph node-positive, i.e., stage III, colon cancer. An increased understanding of the molecular evolution and progression of CRC has identified two major pathways of tumorigenesis that are characterized by chromosomal instability or microsatellite instability (MSI). MSI is a consequence of deficient DNA mismatch repair (MMR) that is generally due to epigenetic inactivation of MLH1 in tumors that often carry mutations in oncogenic BRAFV600E. Activating BRAFV600E and KRAS mutations are mutually exclusive and in this article, we review the current status of these mutations and MMR status as prognostic biomarkers in stage III colon cancers.

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Defective Mismatch Repair Status as a Prognostic Biomarker of Disease-Free Survival in Stage III Colon Cancer Patients Treated with Adjuvant FOLFOX Chemotherapy

Cited by 76 publications

References 37 publications

Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer

Microsatellite Instability Testing and Its Role in the Management of Colorectal Cancer

Molecular Pathways: Microsatellite Instability in Colorectal Cancer: Prognostic, Predictive, and Therapeutic Implications

Prognostic Impact of Deficient DNA Mismatch Repair and KRAS and BRAF V600E Mutations in Patients with Lymph-Node-Positive Colon Cancer

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