| 1. |
- Boman, Caroline, et al.
(författare)
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Discordance of PD-L1 status between primary and metastatic breast cancer : A systematic review and meta-analysis
- 2021
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Ingår i: Cancer Treatment Reviews. - : Elsevier. - 0305-7372 .- 1532-1967. ; 99
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Forskningsöversikt (refereegranskat)abstract
- INTRODUCTION: Programmed cell death ligand 1 (PD-L1) expression is predictive for benefit from immunotherapy in several human malignancies including triple negative breast cancer. Lower positivity rates but a larger relative benefit from atezolizumab has been implied when PD-L1 status is assessed at metastatic sites. We aimed to study the discordance of PD-L1 expression between primary tumor and metastasis in breast cancer due to its potential clinical utility.METHODS: Cochrane Library, Embase, Medline and Web of science were searched for studies reporting on PD-L1 expression in primary and metastatic breast cancer, followed by data extraction. Outcomes included pooled PD-L1 positivity rates in tumor cells, immune cells or both in primary tumor and metastasis, PD-L1 discordance between matched primary tumors and metastasis and direction of discordance.RESULTS: Of 2552 identified entries following de-duplication, 20 studies fulfilled the predefined inclusion criteria. Pooled PD-L1 positivity rate was higher in primary tumors compared to metastasis when assessed in immune cells (51.2% vs 37.1% p < 0.001) and tumor/immune cells (30.1% vs 14.6% p < 0.001), but not in tumor cells (18.7% vs 17.8% p = 0.65). PD-L1 positivity was lowest when assessed in bone metastases (12%) and highest in lymph nodes (60%). Discordance between primary tumors and metastasis was bidirectional, with higher pooled discordance rates when PD-L1 expression was assessed in immune compared to tumor cells (39.5% vs 13.6%, p < 0.001).CONCLUSION: The observed considerable discordance between PD-L1 status in primary and metastatic breast cancer emphasizes the importance of appropriate tissue sampling when selecting patients for immunotherapy.
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| 2. |
- Zerdes, Ioannis, et al.
(författare)
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Discordance of PD-L1 Expression at the Protein and RNA Levels in Early Breast Cancer
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:18
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Despite the increasing use of checkpoint inhibitors for early and metastatic breast cancer, Programmed Death Ligand 1 (PD-L1) remains the only validated albeit imperfect predictive biomarker. Significant discordance in PD-L1 protein expression depending on the antibody used has been demonstrated, while the weak correlation and discordant prognostic information between protein and gene expression underscore its biologic heterogeneity. In this study, we use material from two patient cohorts of early breast cancer and multiple methodologies (immunohistochemistry, RNA fluorescent in situ hybridization, immunofluorescence, bulk gene expression, and multiplex fluorescent immunohistochemistry) to demonstrate the significant discordance in PD-L1 expression among various methods and between different areas of the same tumor, which hints toward the presence of spatial, intratumoral and biological heterogeneity. We aimed to assess if the discrepant prognostic information between Programmed Death Ligand 1 (PD-L1) protein versus mRNA expression in early breast cancer (BC) could be attributed to heterogeneity in its expression. PD-L1 protein and mRNA expression in BC tissue microarrays from two clinical patient cohorts were evaluated (105 patients; cohort 1: untreated; cohort 2: neoadjuvant chemotherapy-treated). Immunohistochemistry (IHC) with SP142, SP263 was performed. PD-L1 mRNA was evaluated using bulk gene expression and RNA-FISH RNAscope, the latter scored in a semi-quantitative manner and combined with immunofluorescence (IF) staining for the simultaneous detection of PD-L1 protein expression. PD-L1 expression was assessed in cores as a whole and in two regions of interest (ROI) from the same core. The cell origin of PD-L1 expression was evaluated using multiplex fluorescent IHC. IHC PD-L1 expression between SP142 and SP263 was concordant in 86.7% of cores (p < 0.001). PD-L1 IF/IHC was weakly correlated with spatial mRNA expression (concordance 54.6-71.2%). PD-L1 was mostly expressed by lymphocytes intra-tumorally, while its stromal expression was mostly observed in macrophages. Our results demonstrate only moderate concordance between the various methods of assessing PD-L1 expression at the protein and mRNA levels, which may be attributed to both analytical performance and spatial heterogeneity.
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| 3. |
- Zerdes, Ioannis, et al.
(författare)
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Interplay between copy number alterations and immune profiles in the early breast cancer Scandinavian Breast Group 2004-1 randomized phase II trial : results from a feasibility study
- 2021
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Ingår i: npj Breast Cancer. - : Springer Nature. - 2374-4677. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Emerging data indicate that genomic alterations can shape immune cell composition in early breast cancer. However, there is a need for complementary imaging and sequencing methods for the quantitative assessment of combined somatic copy number alteration (SCNA) and immune profiling in pathological samples. Here, we tested the feasibility of three approaches-CUTseq, for high-throughput low-input SCNA profiling, multiplexed fluorescent immunohistochemistry (mfIHC) and digital-image analysis (DIA) for quantitative immuno-profiling- in archival formalin-fixed paraffin-embedded (FFPE) tissue samples from patients enrolled in the randomized SBG-2004-1 phase II trial. CUTseq was able to reproducibly identify amplification and deletion events with a resolution of 100 kb using only 6 ng of DNA extracted from FFPE tissue and pooling together 77 samples into the same sequencing library. In the same samples, mfIHC revealed that CD4 + T-cells and CD68 + macrophages were the most abundant immune cells and they mostly expressed PD-L1 and PD-1. Combined analysis showed that the SCNA burden was inversely associated with lymphocytic infiltration. Our results set the basis for further applications of CUTseq, mfIHC and DIA to larger cohorts of early breast cancer patients.
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