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Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency.
Eur J Cancer. 2017 11; 86:266-274.EJ

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.

Authors+Show 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. Electronic address: romain.cohen@aphp.fr.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.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.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.Surgical Pathology Department, Hôpital Pitié Salpêtrière, Paris, France.Department of Hepato-Gastroenterology, Hôpital Pitié Salpêtrière, Paris, France.Department of Hepato-Gastroenterology, Hôpital Saint-Louis, Paris, France.Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France.Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.Department of Pathology, Hôpital Lariboisière, Paris, France.Department of Pathology, Hôpital Saint-Louis, Paris, France.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.Department of Pathology, Institut du Cancer de Montpellier, Montpellier, 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; Department of Surgery, Hôpital Saint-Antoine, Paris, France.Methodology and Quality of Life Unit in Oncology (INSERM UMR 1098), Centre Hospital-Universitaire de Besançon, 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.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.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.

Pub Type(s)

Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29055842

Citation

Cohen, R, et al. "Clinical and Molecular Characterisation of Hereditary and Sporadic Metastatic Colorectal Cancers Harbouring Microsatellite instability/DNA Mismatch Repair Deficiency." European Journal of Cancer (Oxford, England : 1990), vol. 86, 2017, pp. 266-274.
Cohen R, Buhard O, Cervera P, et al. Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency. Eur J Cancer. 2017;86:266-274.
Cohen, R., Buhard, O., Cervera, P., Hain, E., Dumont, S., Bardier, A., Bachet, J. B., Gornet, J. M., Lopez-Trabada, D., Dumont, S., Kaci, R., Bertheau, P., Renaud, F., Bibeau, F., Parc, Y., Vernerey, D., Duval, A., Svrcek, M., & André, T. (2017). Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency. European Journal of Cancer (Oxford, England : 1990), 86, 266-274. https://doi.org/10.1016/j.ejca.2017.09.022
Cohen R, et al. Clinical and Molecular Characterisation of Hereditary and Sporadic Metastatic Colorectal Cancers Harbouring Microsatellite instability/DNA Mismatch Repair Deficiency. Eur J Cancer. 2017;86:266-274. PubMed PMID: 29055842.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical and molecular characterisation of hereditary and sporadic metastatic colorectal cancers harbouring microsatellite instability/DNA mismatch repair deficiency. AU - Cohen,R, AU - Buhard,O, AU - Cervera,P, AU - Hain,E, AU - Dumont,S, AU - Bardier,A, AU - Bachet,J-B, AU - Gornet,J-M, AU - Lopez-Trabada,D, AU - Dumont,S, AU - Kaci,R, AU - Bertheau,P, AU - Renaud,F, AU - Bibeau,F, AU - Parc,Y, AU - Vernerey,D, AU - Duval,A, AU - Svrcek,M, AU - André,Thierry, Y1 - 2017/10/19/ PY - 2017/07/04/received PY - 2017/09/05/revised PY - 2017/09/14/accepted PY - 2017/10/23/pubmed PY - 2017/11/29/medline PY - 2017/10/23/entrez KW - BRAF mutation KW - Colorectal cancer KW - Immunotherapy KW - Lynch syndrome KW - Microsatellite instability KW - Mismatch repair SP - 266 EP - 274 JF - European journal of cancer (Oxford, England : 1990) JO - Eur J Cancer VL - 86 N2 - 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. SN - 1879-0852 UR - https://www.unboundmedicine.com/medline/citation/29055842/Clinical_and_molecular_characterisation_of_hereditary_and_sporadic_metastatic_colorectal_cancers_harbouring_microsatellite_instability/DNA_mismatch_repair_deficiency_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0959-8049(17)31303-5 DB - PRIME DP - Unbound Medicine ER -