RT Journal Article
T1 Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.
A1 Duruisseaux, Michäel
A1 Martinez-Cardus, Anna
A1 Calleja-Cervantes, Maria E
A1 Moran, Sebastian
A1 Castro-de-Moura, Manuel
A1 Davalos, Veronica
A1 Piñeyro, David
A1 Sanchez-Cespedes, Montse
A1 Girard, Nicolas
A1 Brevet, Marie
A1 Giroux-Leprieur, Etienne
A1 Dumenil, Coraline
A1 Pradotto, Monica
A1 Bironzo, Paolo
A1 Capelletto, Enrica
A1 Novello, Silvia
A1 Cortot, Alexis
A1 Copin, Marie-Christine
A1 Karachaliou, Niki
A1 Gonzalez-Cao, Maria
A1 Peralta, Sergio
A1 Montuenga, Luis M
A1 Gil-Bazo, Ignacio
A1 Baraibar, Iosune
A1 Lozano, Maria D
A1 Varela, Mar
A1 Ruffinelli, Jose C
A1 Palmero, Ramon
A1 Nadal, Ernest
A1 Moran, Teresa
A1 Perez, Lidia
A1 Ramos, Immaculada
A1 Xiao, Qingyang
A1 Fernandez, Agustin F
A1 Fraga, Mario F
A1 Gut, Marta
A1 Gut, Ivo
A1 Teixidó, Cristina
A1 Vilariño, Noelia
A1 Prat, Aleix
A1 Reguart, Noemi
A1 Benito, Amparo
A1 Garrido, Pilar
A1 Barragan, Isabel
A1 Emile, Jean-François
A1 Rosell, Rafael
A1 Brambilla, Elisabeth
A1 Esteller, Manel
K1 Programmed Cell Death 1 Receptor
K1 Progression-Free Survival
K1 Proportional Hazards Models
K1 Repressor Proteins
AB Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC. In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival. Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10-4-0·0282; p=0·0067) and overall survival (0·080, 0·017-0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149-0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209-0·802; p=0·0063) and overall survival (0·409, 0·220-0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy. Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies. "Obra Social" La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
PB Elsevier
YR 2018
FD 2018-08-09
LK http://hdl.handle.net/10668/12826
UL http://hdl.handle.net/10668/12826
LA en
NO Duruisseaux M, Martínez-Cardús A, Calleja-Cervantes ME, Moran S, Castro de Moura M, Davalos V, et al. Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis. Lancet Respir Med. 2018 Oct;6(10):771-781
DS RISalud
RD Apr 9, 2025