J Zugazagoitia1, I Ramos2, J M Trigo2, M Palka3, A Gómez-Rueda3, E Jantus-Lewintre4, C Camps5, D Isla6, P Iranzo6, S Ponce-Aix7, R García-Campelo8, M Provencio9, F Franco9, R Bernabé10, O Juan-Vidal11, E Felip12, J de Castro13, J M Sanchez-Torres14, I Faul15, R B Lanman16, P Garrido17, L Paz-Ares18. 1. Medical Oncology Department, Hospital Universitario 12 de Octubre and i+12 Research Institute, Madrid, Spain; Lung Cancer Group, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain. 2. Medical Oncology Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain. 3. Medical Oncology Department, IRYCIS Hospital Universitario Ramón y Cajal, Madrid, Spain. 4. CIBERONC, Madrid, Spain; Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitario de Valencia, Valencia, Spain; Biotechnology Department, Universitat Politècnica de València, Valencia, Spain. 5. CIBERONC, Madrid, Spain; Medical Oncology Department, Hospital General Universitario de Valencia, Valencia, Spain; Medicine Department, Universidad de Valencia, Valencia, Spain. 6. Medical Oncology Department, Hospital Universitario Lozano Blesa, Zaragoza, Spain. 7. Medical Oncology Department, Hospital Universitario 12 de Octubre and i+12 Research Institute, Madrid, Spain; Lung Cancer Group, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain. 8. Medical Oncology Department, Hospital Universitario Da Coruña, A Coruña, Spain. 9. Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain. 10. Medical Oncology Department, Hospital Universitario Vírgen del Rocío, Sevilla, Spain. 11. Medical Oncology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain. 12. Medical Oncology Department, Hospital Universitario Vall d'Hebron, Barcelona, Spain. 13. Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain. 14. Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain. 15. Medical Affairs, Guardant Health, Barcelona, Spain. 16. Medical Affairs, Guardant Health, Redwood City, USA. 17. CIBERONC, Madrid, Spain; Medical Oncology Department, IRYCIS Hospital Universitario Ramón y Cajal, Madrid, Spain. Electronic address: pilargarridol@gmail.com. 18. Medical Oncology Department, Hospital Universitario 12 de Octubre and i+12 Research Institute, Madrid, Spain; Lung Cancer Group, Clinical Research Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain; Complutense University, Madrid, Spain. Electronic address: lpazares@seom.org.
Abstract
BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.
BACKGROUND: Approximately 30% of tumor biopsies from patients with advanced-stage lung adenocarcinomas yield insufficient tissue for successful molecular subtyping. We have analyzed the clinical utility of next-generation sequencing (NGS) of cell-free circulating tumor DNA (ctDNA) in patients with inadequate tumor samples for tissue genotyping. PATIENTS AND METHODS: We conducted the study in a multi-institutional prospective cohort of clinically unselected patients with advanced-stage lung adenocarcinomas with insufficient tissue for EGFR, ALK or ROS1 genotyping across 12 Spanish institutions (n = 93). ctDNA NGS was carried out by Guardant Health (Guardant360, Redwood City, CA), using a hybrid-capture-based 73-gene panel. Variants were deemed actionable if they were part of the OncoKB precision oncology knowledge database and classified in four levels of actionability based on their clinical or preclinical evidence for drug response. RESULTS: Eighty-three out of 93 patients (89%) had detectable levels of ctDNA. Potentially actionable level 1-4 genomic alterations were detected in 53 cases (57%), of which 13 (14%) had level 1-2A alterations (Food and Drug Administration-approved and standard-care biomarkers according to lung cancer guidelines). Frequencies of each genomic alteration in ctDNA were consistent with those observed in unselected pulmonary adenocarcinomas. The majority of the patients (62%), particularly those with actionable alterations (87%), had more than one pathogenic variant in ctDNA. The median turnaround time to genomic results was 13 days. Twelve patients (13%) received genotype-matched therapies based on ctDNA results, deriving the expected clinical benefit. Patients with co-occurring pathogenic alterations had a significantly shorter median overall survival as compared with patients without co-occurring pathogenic alteration (multivariate hazard ratio = 5.35, P = 0.01). CONCLUSION: Digital NGS of ctDNA in lung cancers with insufficient tumor samples for tissue sequencing detects actionable variants that frequently co-occur with other potentially clinically relevant genomic alterations, allowing timely initiation of genotype-matched therapies.
Authors: Rongxue Peng; Rui Zhang; Martin P Horan; Li Zhou; Sze Yee Chai; Nalishia Pillay; Kwang Hong Tay; Tony Badrick; Jinming Li Journal: Oncologist Date: 2019-08-30
Authors: Alessandro Russo; Ana Rita Lopes; Michael G McCusker; Sandra Gimenez Garrigues; Giuseppina R Ricciardi; Katherine E Arensmeyer; Katherine A Scilla; Ranee Mehra; Christian Rolfo Journal: Curr Oncol Rep Date: 2020-04-16 Impact factor: 5.075
Authors: Jordi Remon; Aurelie Swalduz; David Planchard; Sandra Ortiz-Cuaran; Laura Mezquita; Ludovic Lacroix; Cecile Jovelet; Etienne Rouleau; Camille Leonce; Frank De Kievit; Clive Morris; Greg Jones; Kelly Mercier; Karen Howarth; Emma Green; Maurice Pérol; Pierre Saintigny; Benjamin Besse Journal: PLoS One Date: 2020-06-11 Impact factor: 3.240