Evaluation of alternative prognostic thresholds for SP142 and 22C3 immunohistochemical PD-L1 expression in triple-negative breast cancer: results from a population-based cohort

Author:

Sigurjonsdottir Gudbjörg1,De Marchi Tommaso1,Ehinger Anna1,Hartman Johan2,Ullén Susann3,Leandersson Karin4,Bosch Ana1,Staaf Johan1,Killander Fredrika1,Niméus Emma1

Affiliation:

1. Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden

2. Department of Oncology and Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden

3. Clinical Studies Sweden, Skåne University Hospital, Lund, Sweden

4. Cancer Immunology, Department of Translational Medicine, Clinical Research Center, Lund University, Malmö, Sweden

Abstract

Abstract

Background Immune checkpoint inhibitors are now a part of the treatment arsenal for triple-negative breast cancer (TNBC) but refinement of PD-L1 as a prognostic and predictive biomarker is a clinical priority. We aimed to evaluate the relevance of novel PD-L1 immunohistochemical (IHC) thresholds in TNBC with regards to PD-L1 gene expression, prognostic value, tumor infiltrating lymphocytes (TILs) and TNBC molecular subtypes. Material & Methods We evaluated PD-L1 on a tissue microarray with the SP142 (immune cell (IC) score) and the 22C3 (combined positive score; CPS) IHC assays and evaluated abundance of TILs in a population-based cohort of 237 early-stage TNBC patients. Survival analysis was performed and RNA sequencing data employed for molecular profiling. Results As expected, PD-L1 positivity (IC ≥1% and/or CPS ≥1) was significantly associated with better prognosis compared to zero PD-L1 expression. Importantly however, also patients with intermediate expression (IC >0%, <1%; CPS >0, <1) showed a trend towards improved outcome. Tumors with intermediate PD-L1 IHC expression also had intermediate PD-L1 (CD274) gene expression (mRNA). Patients that were both low in TILs (<30%) and PD-L1 (IC <1%; CPS <1), tended to have the poorest prognosis. PD-L1 positive tumors clustered significantly more often as Immunomodulatory-high and Basal-Like 1-high TNBC molecular subtypes and were enriched in immune response and cell cycle/proliferation signaling pathways. PD-L1-zero tumors on the other hand were enriched in cell growth, differentiation and metastatic potential pathways and clustered more prevalently as Luminal-Androgen-Receptor-high and Mesenchymal-high. PD-L1-intermediate tumors categorized with neither PD-L1-positive nor PD-L1-zero tumors on the hierarchical clustering level, consigning them as a unique subgroup. Conclusion With both SP142 and 22C3, we identified an intermediate IHC PD-L1 group within TNBCs that was supported on the molecular level. Any PD-L1 IHC expression, even though it is <1, tended to have positive prognostic impact. We suggest that the generally accepted threshold of PD-L1 IHC positivity in TNBC should be investigated further. Trial Registration The Swedish Cancerome Analysis Network – Breast (SCAN-B) study was retrospectively registered 2nd Dec 2014 at ClinicalTrials.gov; ID NCT02306096.

Publisher

Research Square Platform LLC

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