Miguel-Angel Molina-Vila1, Rolf A Stahel2, Urania Dafni3, Núria Jordana-Ariza1, Ariadna Balada-Bel1, Mónica Garzón-Ibáñez1, Beatriz García-Peláez1, Clara Mayo-de-Las-Casas1, Enriqueta Felip4, Alessandra Curioni Fontecedro5, Oliver Gautschi6, Solange Peters7, Bartomeu Massutí8, Ramon Palmero9, Santiago Ponce Aix10, Enric Carcereny11, Martin Früh12, Miklos Pless13, Sanjay Popat14, Sinead Cuffe15, Paolo Bidoli16, Roswitha Kammler17, Heidi Roschitzki-Voser17, Zoi Tsourti18, Niki Karachaliou19, Rafael Rosell11. 1. Laboratory of Oncology, Pangaea Oncology S.A., Quirón Dexeus University Hospital, Barcelona, Spain. 2. Department of Medical Oncology and Haematology, University Hospital Zurich, Zurich, Switzerland. Electronic address: rolf.stahel@usz.ch. 3. School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece; Frontier Science Foundation-Hellas, Athens, Greece. 4. Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 5. Department of Medical Oncology and Haematology, University Hospital Zurich, Zurich, Switzerland. 6. Medical Oncology, Cantonal Hospital Lucerne, Lucerne, Switzerland; Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland. 7. Département d'Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 8. El Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL Oncologia Médica), Hospital General Universitario de Alicante, Alicante, Spain. 9. Catalan Institute of Oncology, Hospital Duran i Reynals, L'Hospitalet de Llobregat, Catalonia, Spain. 10. Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain. 11. Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Barcelona, Spain. 12. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Oncology and Hematology, Cantonal Hospital St. Gallen, Canton, Switzerland. 13. Swiss Group for Clinical Cancer Research (SAKK), Bern, Switzerland; Medical Oncology, Hospital Winterthur, Winterthur, Switzerland. 14. Lung Unit and The Institute of Cancer Research, Royal Marsden Hospital, London, United Kingdom. 15. Medical Oncology, St. James's Hospital, Dublin, Ireland; Cancer Trials Ireland, Dublin, Ireland. 16. Oncologia Medica, Ospedale San Gerardo, Monza, Italy. 17. European Thoracic Oncology Platform (ETOP) Coordinating Office, Bern, Switzerland. 18. Frontier Science Foundation-Hellas, Athens, Greece. 19. Institute of Oncology Rosell, University Hospital Sagrat Cor, Barcelona, Spain.
Abstract
INTRODUCTION: Longitudinal evaluation of mutations in blood samples was a prespecified secondary objective in the BELIEF trial of erlotinib and bevacizumab in advanced EGFR-positive NSCLC. Here, we report the testing results and explore the correlation of EGFR status in blood with clinical outcomes. METHODS: Blood samples were prospectively collected from patients at baseline, at response evaluation, and at progression and sent to a central laboratory. Circulating free DNA was purified and EGFR mutations were analyzed with a validated real-time quantitative polymerase chain reaction assay. RESULTS: EGFR exon 19/21 mutations were detected in 55 of 91 baseline blood samples (60.4%) and correlated with a significantly worse progression-free survival: 11.4 months (95% confidence interval [CI]: 9.0-14.8 mo) for the patients who were positive versus 22.9 months (95% CI: 9.5-33.9 mo) for those who were negative (log-rank p = 0.0020). Among the 74 samples at response, exon 19/21 mutations were detected only in three samples (4.1%). In contrast, 29 of 58 patients (50.0%) were exon 19/21 positive at progression and showed a significantly worse median overall survival of 21.7 months (95% CI: 17.0-30.9 mo) compared with 37.4 months (95% CI: 22.6-53.1 mo) for those who were negative (log-rank p = 0.011). Blood samples at the three time points were available for 48 patients. Of those, among 14 exon 19/21 EGFR-negative at presentation, 13 (93%) were persistently negative for the sensitizing mutations after progression and the p.T790M could only be detected in the blood of two patients. CONCLUSIONS: Longitudinal testing of EGFR mutations in blood can offer valuable clinical information. In patients of the BELIEF study, detection of EGFR mutations in circulating free DNA at presentation was associated with shorter progression-free survival, whereas positivity at progression correlated with shorter overall survival. Finally, patients negative in blood at presentation were almost invariably negative at relapse.
INTRODUCTION: Longitudinal evaluation of mutations in blood samples was a prespecified secondary objective in the BELIEF trial of erlotinib and bevacizumab in advanced EGFR-positive NSCLC. Here, we report the testing results and explore the correlation of EGFR status in blood with clinical outcomes. METHODS: Blood samples were prospectively collected from patients at baseline, at response evaluation, and at progression and sent to a central laboratory. Circulating free DNA was purified and EGFR mutations were analyzed with a validated real-time quantitative polymerase chain reaction assay. RESULTS:EGFR exon 19/21 mutations were detected in 55 of 91 baseline blood samples (60.4%) and correlated with a significantly worse progression-free survival: 11.4 months (95% confidence interval [CI]: 9.0-14.8 mo) for the patients who were positive versus 22.9 months (95% CI: 9.5-33.9 mo) for those who were negative (log-rank p = 0.0020). Among the 74 samples at response, exon 19/21 mutations were detected only in three samples (4.1%). In contrast, 29 of 58 patients (50.0%) were exon 19/21 positive at progression and showed a significantly worse median overall survival of 21.7 months (95% CI: 17.0-30.9 mo) compared with 37.4 months (95% CI: 22.6-53.1 mo) for those who were negative (log-rank p = 0.011). Blood samples at the three time points were available for 48 patients. Of those, among 14 exon 19/21 EGFR-negative at presentation, 13 (93%) were persistently negative for the sensitizing mutations after progression and the p.T790M could only be detected in the blood of two patients. CONCLUSIONS: Longitudinal testing of EGFR mutations in blood can offer valuable clinical information. In patients of the BELIEF study, detection of EGFR mutations in circulating free DNA at presentation was associated with shorter progression-free survival, whereas positivity at progression correlated with shorter overall survival. Finally, patients negative in blood at presentation were almost invariably negative at relapse.
Authors: Ekaterina S Kuligina; Fedor V Moiseyenko; Albina S Zhabina; Sergey A Belukhin; Tatiana A Laidus; Aleksandr S Martianov; Kirill A Zagorodnev; Tatyana N Sokolova; Svetlana A Chuinyshena; Maxim M Kholmatov; Elizaveta V Artemieva; Ekaterina O Stepanova; Tatiana N Shuginova; Nikita M Volkov; Grigoriy A Yanus; Evgeny N Imyanitov Journal: Int J Clin Oncol Date: 2022-02-16 Impact factor: 3.850