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. 2018 Oct 1;29(10):2121-2128.
doi: 10.1093/annonc/mdy335.

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

L Paré  1 , T Pascual  1 , E Seguí  1 , C Teixidó  2 , M Gonzalez-Cao  3 , P Galván  1 , A Rodríguez  1 , B González  4 , M Cuatrecasas  4 , E Pineda  1 , A Torné  5 , G Crespo  6 , S Martin-Algarra  7 , E Pérez-Ruiz  8 , Ò Reig  1 , M Viladot  1 , C Font  1 , B Adamo  1 , M Vidal  1 , L Gaba  1 , M Muñoz  1 , I Victoria  1 , G Ruiz  1 , N Viñolas  1 , B Mellado  1 , J Maurel  1 , J Garcia-Corbacho  1 , M Á Molina-Vila  9 , M Juan  10 , J M Llovet  11 , N Reguart  1 , A Arance  1 , A Prat  12
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Free article

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

L Paré et al. Ann Oncol. .
Free article

Abstract

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.

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