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Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency

  • R. Cohen
    Correspondence
    Corresponding author: Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France. Fax: +33 (0)1 49 28 23 44.
    Affiliations
    Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    Sorbonne Universités, UPMC Univ Paris 06, France
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  • O. Buhard
    Affiliations
    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
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  • P. Cervera
    Affiliations
    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    Sorbonne Universités, UPMC Univ Paris 06, France

    Department of Pathology, Hôpital Saint-Antoine, APHP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
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  • E. Hain
    Affiliations
    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
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  • S. Dumont
    Affiliations
    Sorbonne Universités, UPMC Univ Paris 06, France
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  • A. Bardier
    Affiliations
    Surgical Pathology Department, Hôpital Pitié Salpêtrière, Paris, France
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  • J.-B. Bachet
    Affiliations
    Department of Hepato-Gastroenterology, Hôpital Pitié Salpêtrière, Paris, France
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  • J.-M. Gornet
    Affiliations
    Department of Hepato-Gastroenterology, Hôpital Saint-Louis, Paris, France
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  • D. Lopez-Trabada
    Affiliations
    Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
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  • S. Dumont
    Affiliations
    Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France
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  • R. Kaci
    Affiliations
    Department of Pathology, Hôpital Lariboisière, Paris, France
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  • P. Bertheau
    Affiliations
    Department of Pathology, Hôpital Saint-Louis, Paris, France
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  • F. Renaud
    Affiliations
    Univ. Lille, UMR-S 1172 – JPARC – Jean-Pierre Aubert Research Center, Lille F-59000, France

    INSERM, UMR-S 1172, Team “Mucins, Epithelial Differentiation and Carcinogenesis”, Lille F-59000, France

    CHU Lille, Institut de Pathologie, Lille F-59000, France
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  • F. Bibeau
    Affiliations
    Department of Pathology, Institut du Cancer de Montpellier, Montpellier, France
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  • Y. Parc
    Affiliations
    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    Sorbonne Universités, UPMC Univ Paris 06, France

    Department of Surgery, Hôpital Saint-Antoine, Paris, France
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  • D. Vernerey
    Affiliations
    Methodology and Quality of Life Unit in Oncology (INSERM UMR 1098), Centre Hospital-Universitaire de Besançon, France
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  • A. Duval
    Affiliations
    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    Sorbonne Universités, UPMC Univ Paris 06, France
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  • Author Footnotes
    1 Equal contribution.
    M. Svrcek
    Footnotes
    1 Equal contribution.
    Affiliations
    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    Sorbonne Universités, UPMC Univ Paris 06, France

    Department of Pathology, Hôpital Saint-Antoine, APHP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France
    Search for articles by this author
  • Author Footnotes
    1 Equal contribution.
    Thierry André
    Footnotes
    1 Equal contribution.
    Affiliations
    Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisee par la Ligue Nationale contre le Cancer, 184 rue du Faubourg Saint-Antoine, Paris 75012, France

    Sorbonne Universités, UPMC Univ Paris 06, France
    Search for articles by this author
  • Author Footnotes
    1 Equal contribution.
Published:October 19, 2017DOI:https://doi.org/10.1016/j.ejca.2017.09.022

      Highlights

      • Metastatic colorectal cancers with sporadic or inherited MMR deficiency display distinct natural histories.
      • A algorithm combining MMR protein expression, BRAF mutation and MLH1 methylation is mandatory to properly determine the mechanism of MMR deficiency.
      • A better characterisation of dMMR CRCs is needed to determine whether therapeutic agents efficacy differs depending on the origin of the MMR deficiency.

      Abstract

      Background

      Patients treated with chemotherapy for microsatellite unstable (MSI) and/or mismatch repair deficient (dMMR) cancer metastatic colorectal cancer (mCRC) exhibit poor prognosis. We aimed to evaluate the relevance of distinguishing sporadic from Lynch syndrome (LS)-like mCRCs.

      Patients and methods

      MSI/dMMR mCRC patients were retrospectively identified in six French hospitals. Tumour samples were screened for MSI, dMMR, RAS/RAF mutations and MLH1 methylation. Sporadic cases were molecularly defined as those displaying MLH1/PMS2 loss of expression with BRAFV600E and/or MLH1 hypermethylation and no MMR germline mutation.

      Results

      Among 129 MSI/dMMR mCRC patients, 81 (63%) were LS-like and 48 (37%) had sporadic tumours; 22% of MLH1/PMS2-negative mCRCs would have been misclassified using an algorithm based on local medical records (age, Amsterdam II criteria, BRAF and MMR statuses when locally tested), compared to a systematical assessment of MMR, BRAF and MLH1 methylation statuses. In univariate analysis, parameters associated with better overall survival were age (P < 0.0001), metastatic resection (P = 0.001) and LS-like mCRC (P = 0.01), but not BRAFV600E. In multivariate analysis, age (hazard ratio (HR) = 3.19, P = 0.01) and metastatic resection (HR = 4.2, P = 0.001) were associated with overall survival, but not LS. LS-like patients were associated with more frequent liver involvement, metastatic resection and better disease-free survival after metastasectomy (HR = 0.28, P = 0.01). Median progression-free survival of first-line chemotherapy was similar between the two groups (4.2 and 4.2 months; P = 0.44).

      Conclusions

      LS-like and sporadic MSI/dMMR mCRCs display distinct natural histories. MMR, BRAF mutation and MLH1 methylation testing should be mandatory to differentiate LS-like and sporadic MSI/dMMR mCRC, to determine in particular whether immune checkpoint inhibitors efficacy differs in these two populations.

      Keywords

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      References

        • Colle R.
        • Cohen R.
        • Cochereau D.
        • Duval A.
        • Lascols O.
        • Lopez-Trabada D.
        • et al.
        Immunotherapy and patients treated for cancer with microsatellite instability.
        Bull Cancer (Paris). 2017; 104: 42-51https://doi.org/10.1016/j.bulcan.2016.11.006
        • Adar T.
        • Rodgers L.H.
        • Shannon K.M.
        • Yoshida M.
        • Ma T.
        • Mattia A.
        • et al.
        A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.
        Mod Pathol. 2017;
        • Newton K.
        • Jorgensen N.M.
        • Wallace A.J.
        • Buchanan D.D.
        • Lalloo F.
        • McMahon R.F.T.
        • et al.
        Tumour MLH1 promoter region methylation testing is an effective prescreen for Lynch Syndrome (HNPCC).
        J Med Genet. 2014; 51: 789-796https://doi.org/10.1136/jmedgenet-2014-102552
        • Parsons M.T.
        • Buchanan D.D.
        • Thompson B.
        • Young J.P.
        • Spurdle A.B.
        Correlation of tumour BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) gene mutation status: a literature review assessing utility of tumour features for MMR variant classification.
        J Med Genet. 2012; 49: 151-157https://doi.org/10.1136/jmedgenet-2011-100714
        • Cunningham J.M.
        • Christensen E.R.
        • Tester D.J.
        • Kim C.-Y.
        • Roche P.C.
        • Burgart L.J.
        • et al.
        Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability.
        Cancer Res. 1998; 58: 3455-3460
        • Sargent D.J.
        • Marsoni S.
        • Monges G.
        • Thibodeau S.N.
        • Labianca R.
        • Hamilton S.R.
        • et al.
        Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer.
        J Clin Oncol. 2010; 28: 3219-3226https://doi.org/10.1200/JCO.2009.27.1825
        • André T.
        • Gramont A de
        • Vernerey D.
        • Chibaudel B.
        • Bonnetain F.
        • Tijeras-Raballand A.
        • et al.
        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.
        J Clin Oncol. 2015; 33: 4176-4187https://doi.org/10.1200/JCO.2015.63.4238
        • Tougeron D.
        • Mouillet G.
        • Trouilloud I.
        • Lecomte T.
        • Coriat R.
        • Aparicio T.
        • et al.
        Efficacy of adjuvant chemotherapy in colon cancer with microsatellite instability: a large multicenter AGEO study.
        J Natl Cancer Inst. 2016; 108: djv438https://doi.org/10.1093/jnci/djv438
        • Sinicrope F.A.
        • Foster N.R.
        • Thibodeau S.N.
        • Marsoni S.
        • Monges G.
        • Labianca R.
        • et al.
        DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy.
        J Natl Cancer Inst. 2011; 103: 863-875https://doi.org/10.1093/jnci/djr153
        • Brueckl W.M.
        • Moesch C.
        • Brabletz T.
        • Koebnick C.
        • Riedel C.
        • Jung A.
        • et al.
        Relationship between microsatellite instability, response and survival in palliative patients with colorectal cancer undergoing first-line chemotherapy.
        Anticancer Res. 2003; 23: 1773-1777
        • Des Guetz G.
        • Mariani P.
        • Cucherousset J.
        • Benamoun M.
        • Lagorce C.
        • Sastre X.
        • et al.
        Microsatellite instability and sensitivity to FOLFOX treatment in metastatic colorectal cancer.
        Anticancer Res. 2007; 27: 2715-2719
        • Tran B.
        • Kopetz S.
        • Tie J.
        • Gibbs P.
        • Jiang Z.-Q.
        • Lieu C.H.
        • et al.
        Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer.
        Cancer. 2011; 117: 4623-4632https://doi.org/10.1002/cncr.26086
        • Koopman M.
        • Kortman G.A.M.
        • Mekenkamp L.
        • Ligtenberg M.J.L.
        • Hoogerbrugge N.
        • Antonini N.F.
        • et al.
        Deficient mismatch repair system in patients with sporadic advanced colorectal cancer.
        Br J Cancer. 2009; 100: 266-273https://doi.org/10.1038/sj.bjc.6604867
        • Fujiyoshi K.
        • Yamamoto G.
        • Takenoya T.
        • Takahashi A.
        • Arai Y.
        • Yamada M.
        • et al.
        Metastatic pattern of stage IV colorectal cancer with high-frequency microsatellite instability as a prognostic factor.
        Anticancer Res. 2017; 37: 239-247
        • Venderbosch S.
        • Nagtegaal I.D.
        • Maughan T.S.
        • Smith C.G.
        • Cheadle J.P.
        • Fisher D.
        • et al.
        Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies.
        Clin Cancer Res. 2014; 20: 5322-5330https://doi.org/10.1158/1078-0432.CCR-14-0332
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • Bartlett B.R.
        • Kemberling H.
        • Eyring A.D.
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520https://doi.org/10.1056/NEJMoa1500596
        • Overman M.J.
        • McDermott R.
        • Leach J.L.
        • Lonardi S.
        • Lenz H.-J.
        • Morse M.A.
        • et al.
        Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
        Lancet Oncol. 2017; 18: 1182-1191https://doi.org/10.1016/S1470-2045(17)30422-9
        • Giardiello F.M.
        • Allen J.I.
        • Axilbund J.E.
        • Boland C.R.
        • Burke C.A.
        • Burt R.W.
        • et al.
        Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US multi-society task force on colorectal cancer.
        Gastroenterology. 2014; 147: 502-526https://doi.org/10.1053/j.gastro.2014.04.001
        • Stoffel E.M.
        • Mangu P.B.
        • Gruber S.B.
        • Hamilton S.R.
        • Kalady M.F.
        • Lau M.W.Y.
        • et al.
        Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk–colorectal cancer: European Society for Medical Oncology clinical practice guidelines.
        J Clin Oncol. 2015; 33: 209-217https://doi.org/10.1200/JCO.2014.58.1322
        • French A.J.
        • Sargent D.J.
        • Burgart L.J.
        • Foster N.R.
        • Kabat B.F.
        • Goldberg R.
        • et al.
        Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer.
        Clin Cancer Res. 2008; 14: 3408-3415https://doi.org/10.1158/1078-0432.CCR-07-1489
        • Taieb J.
        • Zaanan A.
        • Le Malicot K.
        • Julié C.
        • Blons H.
        • Mineur L.
        • et al.
        Prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with leucovorin, fluorouracil, and oxaliplatin with or without cetuximab: a post hoc analysis of the PETACC-8 trial.
        JAMA Oncol. 2016; 2: 643https://doi.org/10.1001/jamaoncol.2015.5225
        • Goldstein J.
        • Tran B.
        • Ensor J.
        • Gibbs P.
        • Wong H.L.
        • Wong S.F.
        • et al.
        Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H).
        Ann Oncol. 2014; 25: 1032-1038https://doi.org/10.1093/annonc/mdu100
        • Roth A.D.
        • Tejpar S.
        • Delorenzi M.
        • Yan P.
        • Fiocca R.
        • Klingbiel D.
        • et al.
        Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial.
        J Clin Oncol. 2010; 28: 466-474https://doi.org/10.1200/JCO.2009.23.3452
        • Popovici V.
        • Budinska E.
        • Tejpar S.
        • Weinrich S.
        • Estrella H.
        • Hodgson G.
        • et al.
        Identification of a poor-prognosis BRAF-mutant–like population of patients with colon cancer.
        J Clin Oncol. 2012; 30: 1288-1295https://doi.org/10.1200/JCO.2011.39.5814
        • Guinney J.
        • Dienstmann R.
        • Wang X.
        • de Reyniès A.
        • Schlicker A.
        • Soneson C.
        • et al.
        The consensus molecular subtypes of colorectal cancer.
        Nat Med. 2015; 21: 1350-1356https://doi.org/10.1038/nm.3967
        • Balmaña J.
        • Balaguer F.
        • Cervantes A.
        • Arnold D.
        Familial risk-colorectal cancer: ESMO clinical practice guidelines.
        Ann Oncol. 2013; 24: vi73-vi80https://doi.org/10.1093/annonc/mdt209
        • Le D.T.
        • Uram J.N.
        • Wang H.
        • Bartlett B.R.
        • Kemberling H.
        • Eyring A.D.
        • et al.
        Programmed death-1 blockade in mismatch repair deficient colorectal cancer.
        J Clin Oncol. 2016; 34 (suppl; abstr 103)