R Cohen1, O Buhard2, P Cervera3, E Hain2, S Dumont9, A Bardier5, J-B Bachet6, J-M Gornet7, D Lopez-Trabada8, S Dumont9, R Kaci10, P Bertheau11, F Renaud12, F Bibeau13, Y Parc14, D Vernerey15, A Duval16, M Svrcek3, Thierry André17. 1. 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. 2. 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. 3. 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. 4. Sorbonne Universités, UPMC Univ Paris 06, France. 5. Surgical Pathology Department, Hôpital Pitié Salpêtrière, Paris, France. 6. Department of Hepato-Gastroenterology, Hôpital Pitié Salpêtrière, Paris, France. 7. Department of Hepato-Gastroenterology, Hôpital Saint-Louis, Paris, France. 8. Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, 184 rue du Faubourg Saint-Antoine, Paris 75012, France. 9. Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France. 10. Department of Pathology, Hôpital Lariboisière, Paris, France. 11. Department of Pathology, Hôpital Saint-Louis, Paris, France. 12. 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. 13. Department of Pathology, Institut du Cancer de Montpellier, Montpellier, France. 14. 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. 15. Methodology and Quality of Life Unit in Oncology (INSERM UMR 1098), Centre Hospital-Universitaire de Besançon, France. 16. 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. 17. 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.
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.
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: Mohamed E Salem; Francesca Battaglin; Richard M Goldberg; Alberto Puccini; Anthony F Shields; David Arguello; W Michael Korn; John L Marshall; Axel Grothey; Heinz-Josef Lenz Journal: Oncologist Date: 2019-12-17
Authors: James E Lapinski; Alok A Khorana; Lisa Rybicki; Canan Firat; Hwajeong Lee; Kathryn Piotti; Eugene H Lewis; Michael McNamara; Vikram Deshpande; Jinru Shia; Deepa T Patil Journal: Virchows Arch Date: 2022-05-06 Impact factor: 4.064