High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC
| Autor: | Joan Frigola, Caterina Carbonell, Patricia Iranzo, Nuria Pardo, Ana Callejo, Susana Cedres, Alex Martinez-Marti, Alejandro Navarro, Mireia Soleda, Jose Jimenez, Javier Hernandez-Losa, Ana Vivancos, Enriqueta Felip, Ramon Amat |
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| Přispěvatelé: | Institut Català de la Salut, [Frigola J, Carbonell C, Soleda M, Amat R] Thoracic Cancers Translational Genomics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Clinical Research Department, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Irazno P, Pardo N, Callejo A, Cedres S, Martinez-Marti A, Navarro A] Clinical Research Department, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Jimenez J] Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Hernandez-Losa J] Servei de Patologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Vivancos A] Cancer Genomics Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Felip E] Thoracic Cancers Translational Genomics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Clinical Research Department, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Chromosome Aberrations Male Cancer Research Lung Neoplasms Pathological Conditions Signs and Symptoms::Pathologic Processes::Chromosome Aberrations [DISEASES] Immunology Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] Adenocarcinoma of Lung Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma Bronchogenic::Carcinoma Non-Small-Cell Lung [DISEASES] neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES] Other subheadings::Other subheadings::/drug therapy [Other subheadings] Survival Analysis afecciones patológicas signos y síntomas::procesos patológicos::aberraciones cromosómicas [ENFERMEDADES] Anomalies cromosòmiques Oncology Carcinoma Non-Small-Cell Lung Molecular Medicine Immunology and Allergy Humans Pulmons - Càncer - Tractament |
| Zdroj: | Scientia |
| ISSN: | 2051-1426 |
| Popis: | Immunotherapy; Lung neoplasms; Tumor biomarkers Immunoteràpia; Càncer de pulmó; Biomarcadors tumorals Inmunoterapia; Cáncer de pulmón; Biomarcadores tumorales Background Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit from this type of treatment, and thus several molecular biomarkers of benefit have been explored. The value of somatic copy number alterations (SCNAs) burden remains elusive. Patients and methods We assembled a cohort of 109 patients with NSCLC treated with ICIs and available tumor samples. We performed shallow whole-genome sequencing on 89 patients to determine genome-wide SCNAs and targeted gene expression analysis on 63 patients to study immune infiltration. We analyzed SCNAs burden in different ways (ie, the fraction of the genome altered or number of events) and studied their association with ICIs benefit based on survival analysis. We correlated SCNAs burden and immune infiltration on 35 patients of our cohort and on patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA). Results High SCNAs burden, computed in diverse ways, is negatively associated with ICIs progression-free survival (PFS), with the fraction of the genome altered (FGA) by arm and chromosome events showing the strongest association with PFS (p=0.002) (n=77). Nevertheless, we found differences in SCNAs across some clinicopathological features (sample site origin). A multivariate analysis adjusted for relevant characteristics showed that the FGA of arm and chromosome alterations was strongly associated with PFS (HR=2.21, p=3.3 x 10−5). Finally, we confirmed that SCNAs burden negatively correlates with tumor immune infiltration (n=35), although this correlation was not found for the males studied. Similar results were observed in the TCGA cohort. Conclusions SCNAs burden is a potential biomarker of benefit to ICIs in patients with NSCLC, although there appear to be some nuances worth consideration. Further studies will be needed to establish its role as a biomarker of benefit to ICIs. This work was supported by Merck Healthcare KGaA, Darmstadt, Germany (Grant for Oncology Innovation to the Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain), Fundación Cientifica Asociación Española Contra el Cancer-AECC (grant number GCB14142170 to EF); the Catalan Government/AGAUR (2017–SGR–1738 to EF). Merck Healthcare KGaA reviewed the manuscript for medical accuracy only before journal submission. |
| Databáze: | OpenAIRE |
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