47P - Correlation of clinical, genetic and transcriptomic traits with PD-L1 positivity in TNBC patients

Background

Compared with other breast cancer subtypes, TNBC is characterised by higher tumour mutational burden, elevated levels of PD-L1 expression and increased levels of immune cell infiltration. Predictors of immunotherapy response are not yet fully elucidated with several responders harbouring both PD-L1- and TMB-low tumours. We investigated the clinical and molecular traits associated with PD-L1 expression in TNBC patients with the aim to uncover distinct signatures that may impact on PD-L1 status and could potentially explain divergent responses to ICIs.

Methods

We performed WES, RNAseq and IHC using FFPE blocks from primary tumour resections derived from 196 treatment-naïve TNBC patients. Slides were stained with the anti- PD-L1 clone 22C3 and scored using a cut-off of CPS>=10 for PD-L1-high samples. DGE analysis was conducted between PD-L1-high and -low cases. The read count matrix was normalized using the median of ratios via DESeq2. A generalized linear model identified DEGs, followed by pathway analysis using over-representation analysis with KEGG pathways. Additionally, GSEA was employed to evaluate specific gene sets within the expression data.

Results

Almost one fourth of TNBC patients were PD-L1-high. The most frequent mutations in both groups involved TP53, PIK3CA, BRCA1, RB1 and PTEN genes with PIK3CA mutations almost exclusively encountered in PD-L1-high tumours. In PD-L1-high tumours, most DEGs (n=1708) were downregulated, including cell adhesion and collagen-related genes, while the up-regulated genes (n=481) included HLA isotypes, IFN-gamma, JAK2 and STAT1. Most DEGs were involved in the neuroactive ligand-receptor interactions, calcium, cAMP and cell adhesion signalling pathways. Immune, chemokine and JAK-STAT signalling pathways were positively enriched in PD-L1-high tumours.

Conclusions

This integrative analysis of clinical, genetic, transcriptomic and immunohistochemical data revealed differences in mutational signatures and gene expression patterns between PD-L1-high and -low TNBC tumours.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

A. Semertzidou, O. Arqués, Z. Lai: A.E. Storti, M. Heininen-Brown, S. Willis, B. Nuttall, M. Scaltriti, R. Stewart: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca. S. Hassanieh, E.M. Wigmore: Financial Interests, Institutional, Full or part-time Employment, Shareholder: AstraZeneca. E. De Bruin: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. H. Angell: Financial Interests, Institutional, Advisory Board: AstraZeneca.