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

Sigurjonsdottir, Gudbjörg LU ; De Marchi, Tommaso LU ; Ehinger, Anna LU orcid ; Hartman, Johan ; Ullén, Susann LU ; Leandersson, Karin LU orcid ; Bosch, Ana LU ; Staaf, Johan LU orcid ; Killander, Fredrika LU and Niméus, Emma LU (2024) In Breast Cancer Research and Treatment
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 regard to PD-L1 gene expression, prognostic value, tumor infiltrating lymphocytes (TILs), and TNBC molecular subtypes. Material & methods: PD-L1 was scored in a tissue microarray with the SP142 (immune cell (IC) score) and the 22C3 (combined positive score; CPS) IHC assays and TIL abundance evaluated in whole slides in a population-based cohort of 237 early-stage TNBC patients. Survival analysis was performed and RNA sequencing... (More)

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 regard to PD-L1 gene expression, prognostic value, tumor infiltrating lymphocytes (TILs), and TNBC molecular subtypes. Material & methods: PD-L1 was scored in a tissue microarray with the SP142 (immune cell (IC) score) and the 22C3 (combined positive score; CPS) IHC assays and TIL abundance evaluated in whole slides 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 toward improved outcome. Tumors with intermediate PD-L1 IHC expression also had intermediate PD-L1 (CD274) gene expression (mRNA). Patients who 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. The Swedish Cancerome Analysis Network – Breast (SCAN-B) study was retrospectively registered 2nd Dec 2014 at ClinicalTrials.gov; ID NCT02306096.

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publishing date
type
Contribution to journal
publication status
epub
subject
keywords
22C3, Gene expression, PD-L1, SP142, Triple-negative breast cancer, Tumor infiltrating lymphocytes
in
Breast Cancer Research and Treatment
publisher
Springer
external identifiers
  • pmid:39656429
  • scopus:85212069382
ISSN
0167-6806
DOI
10.1007/s10549-024-07561-x
language
English
LU publication?
yes
id
ece5b807-606b-4b7c-9cfb-6b0a28f2ce87
date added to LUP
2025-01-30 14:11:13
date last changed
2025-01-31 03:03:46
@article{ece5b807-606b-4b7c-9cfb-6b0a28f2ce87,
  abstract     = {{<p>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 regard to PD-L1 gene expression, prognostic value, tumor infiltrating lymphocytes (TILs), and TNBC molecular subtypes. Material &amp; methods: PD-L1 was scored in a tissue microarray with the SP142 (immune cell (IC) score) and the 22C3 (combined positive score; CPS) IHC assays and TIL abundance evaluated in whole slides 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 &gt; 0%, &lt; 1%; CPS &gt; 0, &lt; 1) showed a trend toward improved outcome. Tumors with intermediate PD-L1 IHC expression also had intermediate PD-L1 (CD274) gene expression (mRNA). Patients who were both low in TILs (&lt; 30%) and PD-L1 (IC &lt; 1%; CPS &lt; 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 &lt; 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. The Swedish Cancerome Analysis Network – Breast (SCAN-B) study was retrospectively registered 2nd Dec 2014 at ClinicalTrials.gov; ID NCT02306096.</p>}},
  author       = {{Sigurjonsdottir, Gudbjörg and De Marchi, Tommaso and Ehinger, Anna and Hartman, Johan and Ullén, Susann and Leandersson, Karin and Bosch, Ana and Staaf, Johan and Killander, Fredrika and Niméus, Emma}},
  issn         = {{0167-6806}},
  keywords     = {{22C3; Gene expression; PD-L1; SP142; Triple-negative breast cancer; Tumor infiltrating lymphocytes}},
  language     = {{eng}},
  publisher    = {{Springer}},
  series       = {{Breast Cancer Research and Treatment}},
  title        = {{Evaluation of alternative prognostic thresholds for SP142 and 22C3 immunohistochemical PD-L1 expression in triple-negative breast cancer : results from a population-based cohort}},
  url          = {{http://dx.doi.org/10.1007/s10549-024-07561-x}},
  doi          = {{10.1007/s10549-024-07561-x}},
  year         = {{2024}},
}