Guillaume Herbreteau1, Alexandra Langlais2, Laurent Greillier3, Clarisse Audigier-Valette4, Lionel Uwer5, José Hureaux6, Denis Moro-Sibilot7, Florian Guisier8, Delphine Carmier9, Jeannick Madelaine10, Josiane Otto11, Pierre-Jean Souquet12, Valérie Gounant13, Patrick Merle14, Olivier Molinier15, Aldo Renault16, Audrey Rabeau17, Franck Morin2, Marc G Denis18, Jean-Louis Pujol19. 1. Department of Biochemistry, Nantes University Hospital, 9 quai Moncousu, 44093 Nantes, France. 2. IFCT Intergroupe Francophone de Cancérologie Thoracique, 10 Rue de la Grange Batelière, 75009 Paris, France. 3. Department of Multidisciplinary Oncology and Therapeutic Innovations, Assistance Publique-Hôpitaux de Marseille, Aix Marseille University, 13015 Marseille, France. 4. Department of Thoracic Oncology, 54 Rue Henri Sainte Claire Deville, CHITS CH Sainte Musse, 83000 Toulon, France. 5. Institut de Cancérologie de Lorraine Alexis Vautrin, 6 Avenue de Bourgogne, 54519 Vandoeuvre-les-Nancy, France. 6. Pôle Hippocrate, Angers University Hospital, 49933 Angers, France. 7. Thoracic Oncology Unit, CHU Grenoble Alpes, 38700 Grenoble, France. 8. Department of Pneumology, Thoracic Oncology and Respiratory Intensive Care, Rouen University Hospital, 76000 Rouen, France. 9. Service de Pneumologie CHRU Hôpitaux de Tours, Hôpital Bretonneau, 2 Boulevard Tonnellé, 37000 Tours, France. 10. Service de Pneumologie, CHU Caen Normandie, Av de La Côte de Nacre, 14000 Caen, France. 11. Pôle Médecine, Centre Antoine Lacassagne, 33 Avenue de Valombrose, 06100 Nice, France. 12. Service de Pneumologie Aiguë Spécialisée et Cancérologie Thoracique, Centre Hospitalier Lyon Sud, 165 Chemin du Grand Revoyet, 69310 Pierre-Benite, France. 13. Department of Thoracic Oncology, Bichat Claude Bernard Hospital, 75018 Paris, France. 14. Service de Pneumologie, 58 Rue Montalembert, CHU G Montpied, 63000 Clermont Ferrand, France. 15. Service de Pneumologie, Centre Hospitalier, 194 Avenue Rubillard, 72037 Le Mans, France. 16. Service de Pneumologie, Centre Hospitalier, 4 Boulevard Hauterive, 64000 Pau, France. 17. Service de Pneumologie, Centre Hospitalier, Université Paul Sabatier, 31300 Toulouse, France. 18. Department of Biochemistry, Nantes University Hospital, 9 Quai Moncousu, 44093 Nantes, France. 19. Department of Thoracic Oncology, Montpellier Regional University Hospital, 34090 Montpellier, France.
Abstract
BACKGROUND: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. METHODS: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. RESULTS: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49; 65.3%) and RB1 (25/49; 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. CONCLUSION: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.
BACKGROUND: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. METHODS: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. RESULTS: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49; 65.3%) and RB1 (25/49; 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. CONCLUSION: ctDNA is strongly associated with the prognosis of SCLCpatients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.
Authors: Daniel J Renouf; Jonathan M Loree; Jennifer J Knox; James T Topham; Petr Kavan; Derek Jonker; Stephen Welch; Felix Couture; Frederic Lemay; Mustapha Tehfe; Mohammed Harb; Nathalie Aucoin; Yoo-Joung Ko; Patricia A Tang; Ravi Ramjeesingh; Brandon M Meyers; Christina A Kim; Pan Du; Shidong Jia; David F Schaeffer; Sharlene Gill; Dongsheng Tu; Chris J O'Callaghan Journal: Nat Commun Date: 2022-08-26 Impact factor: 17.694