J B Bachet1, O Bouché2, J Taieb3, O Dubreuil4, M L Garcia5, A Meurisse6, C Normand7, J M Gornet8, P Artru9, S Louafi10, F Bonnetain6, A Thirot-Bidault11, I Baumgaertner12, R Coriat13, D Tougeron14, T Lecomte15, F Mary16, T Aparicio17, L Marthey18, V Taly7, H Blons19, D Vernerey6, P Laurent-Puig20. 1. Sorbonne Universités, UPMC Université, Paris; Université Sorbonne Paris Cité, INSERM UMR-S1147 MEPPOT, CNRS SNC5014, Centre Universitaire des Saints-Pères, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris; Department of Hepato-Gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris; AGEO (Association des Gastroentérologues Oncologues), Paris. 2. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Hepato-Gastroenterology, Hôpital Robert Debré, Reims. 3. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Digestive Oncology, Hôpital Européen Georges Pompidou, Paris. 4. Department of Hepato-Gastroenterology, Groupe Hospitalier Pitié Salpêtrière, Paris; AGEO (Association des Gastroentérologues Oncologues), Paris. 5. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Oncology, Hôpital Saint-Antoine, Paris. 6. Department of Methodology and Quality of Life in Oncology, INSERM UMR 1098, Hôpital Universitaire de Besancon, Besancon. 7. Université Sorbonne Paris Cité, INSERM UMR-S1147 MEPPOT, CNRS SNC5014, Centre Universitaire des Saints-Pères, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris. 8. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Hôpital Saint-Louis, Paris. 9. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Hôpital Privé Jean Mermoz, Lyon. 10. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes; Department of Gastroenterology, Groupe Hospitalier Nord Essonne, Longjumeau. 11. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Hôpital Kremlin Bicêtre, Le Kremlin-Bicêtre. 12. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Oncology, Hôpital Henri Mondor, Créteil. 13. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Hôpital Cochin, Paris. 14. AGEO (Association des Gastroentérologues Oncologues), Paris; Depatment of Gastroenterology, Centre Hospitalo-Universitaire de Poitiers, Poitiers. 15. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Centre Hospitalo-Universitaire de Tours, Tours. 16. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Hôpital Avicenne, Bobigny. 17. AGEO (Association des Gastroentérologues Oncologues), Paris; Department of Gastroenterology, Hôpital Saint-Louis, Paris; Department of Gastroenterology, Hôpital Avicenne, Bobigny. 18. AGEO (Association des Gastroentérologues Oncologues), Paris; Depatment of Gastroenterology, Hôpital Antoine Béclère, Clamart. 19. Université Sorbonne Paris Cité, INSERM UMR-S1147 MEPPOT, CNRS SNC5014, Centre Universitaire des Saints-Pères, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris; Department of Biochemistry, Hôpital Européen Georges Pompidou, Paris, France. 20. Université Sorbonne Paris Cité, INSERM UMR-S1147 MEPPOT, CNRS SNC5014, Centre Universitaire des Saints-Pères, Equipe Labellisée Ligue Nationale Contre le Cancer, Paris. Electronic address: pierre.laurent-puig@parisdescartes.fr.
Abstract
Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration: Clinicaltrials.gov, NCT02502656.
Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration: Clinicaltrials.gov, NCT02502656.
Authors: Jeanne Tie; Joshua D Cohen; Serigne N Lo; Yuxuan Wang; Lu Li; Michael Christie; Margaret Lee; Rachel Wong; Suzanne Kosmider; Iain Skinner; Hui Li Wong; Belinda Lee; Matthew E Burge; Desmond Yip; Christos S Karapetis; Timothy J Price; Niall C Tebbutt; Andrew M Haydon; Janine Ptak; Mary J Schaeffer; Natalie Silliman; Lisa Dobbyn; Maria Popoli; Cristian Tomasetti; Nickolas Papadopoulos; Kenneth W Kinzler; Bert Vogelstein; Peter Gibbs Journal: Int J Cancer Date: 2020-10-06 Impact factor: 7.396