Detalle Publicación


Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types

Autores: Pare, L. ; Pascual, T.; Segui, E.; Teixido, C.; Gonzalez-Cao, M.; Galvan, P. ; Rodriguez, A.; Gonzalez, B. ; Cuatrecasas, M.; Pineda, E.; Torne, A.; Crespo, G. ; Martín Algarra, Salvador; Perez-Ruiz, E.; Reig, O. ; Viladot, M. ; Font, C.; Adamo, B.; Vidal, M.; Gaba, L.; Munoz, M. ; Victoria, I.; Ruiz, G.; Vinolas, N.; Mellado, B.; Maurel, J.; Garcia-Corbacho, J.; Molina-Vila, M. A. ; Juan, M. ; Llovet, J. M.; Reguart, N.; Arance, A.; Prat, A. (Autor de correspondencia)
Título de la revista: ANNALS OF ONCOLOGY
ISSN: 0923-7534
Volumen: 29
Número: 10
Páginas: 2121 - 2128
Fecha de publicación: 2018
Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.