Abstract
Immune checkpoint inhibitors (ICI) have demonstrated efficacy in the treatment of solid cancers. However, there is no unified predictive biomarker available for ICIs. We aimed to compare the prognostic impact of using three PD-L1 antibodies (SP142, SP263, and 22C3) for immunohistochemical (IHC) analysis. We retrospectively investigated tumor tissues derived from 316 breast cancer cases, by constructing tissue microarrays and by performing IHC staining. The immune-cell expression rate (for SP142 and SP263) and combined proportional score (for 22C3) were evaluated, and survival outcomes were analyzed. Prediction models were developed, and values of Harrel’s c-index and areas under curves were calculated to compare the discriminatory power. Negative PD-L1 expression based on the 22C3-IHC assay was determined to be an independent prognostic marker for recurrence-free survival (RFS, P = 0.0337) and distant metastasis-free survival (DMFS, P = 0.0131). However, PD-L1 expression based on SP142- and SP263-IHC assays did not reveal a prognostic impact. Among the three antibodies, adding PD-L1 expression data obtained via 22C3-IHC assay to the null model led to a significant improvement in the discriminatory power of RFS and DMFS. We suggest that PD-L1 expression based on the 22C3-IHC assay is a superior prognostic marker than that based on SP142- and SP263-IHC assays.
Highlights
Abbreviations areas under the curve (AUC) Area under curve confidence intervals (CI) Confidence interval combined positive score (CPS) Combined positive score distant metastasis-free survival (DMFS) Distant metastasis-free survival estrogen receptor (ER) Estrogen receptor human epidermal growth factor receptor-2 (HER2) Human epidermal growth factor receptor-2 histological grade (HG) Histological grade hazard ratio (HR) Hazard ratio immune cell (IC) Immune cell integrated discrimination improvement (IDI) Integrated discrimination improvement IHC Immunohistochemical institutional review board (IRB) Institutional review board lympho-vascular invasion (LVI) Lympho-vascular invasion net reclassification index (NRI) Net reclassification index PD-1 Programmed cell death proteins 1
Negative programmed death ligand 1 (PD-L1) expression based on the 22C3-IHC assay was significantly associated with decreased recurrence-free survival (RFS) [Fig. 3a; hazard ratio (HR) 2.537, 95% confidence intervals (CI) 1.188–5.421, P = 0.0337] and distant metastasis-free survival (DMFS) (Fig. 4a; HR 2.867, 95% CI 1.247–6.589, P = 0.0131, log rank test)
In the univariate Cox proportional hazard model, age and positive PD-L1 expression based on the 22C3-IHC assays were found to be significant prognostic factors for RFS (Table 2, HR 0.207 95%, CI 0.050–0.855, P = 0.0295)
Summary
Abbreviations AUC Area under curve CI Confidence interval CPS Combined positive score DMFS Distant metastasis-free survival ER Estrogen receptor HER2 Human epidermal growth factor receptor-2 HG Histological grade HR Hazard ratio IC Immune cell IDI Integrated discrimination improvement IHC Immunohistochemical IRB Institutional review board LVI Lympho-vascular invasion NRI Net reclassification index PD-1 Programmed cell death proteins 1. PD-L1 Programmed death ligand 1 PR Progesterone receptor RFS Recurrence-free survival SISH Silver in situ hybridization TIL Tumor-infiltrating lymphocytes TMA Tissue microarray TNBC Triple-negative breast cancer. PD-L1 can be expressed in both tumor and immune cells. Diagnostic factors used to predict survival outcomes include the expression profiles of the tumor micro-environment and PD-L1/co-inhibitory p roteins[12,13]. This study aimed to perform a comprehensive, retrospective evaluation of PD-L1 expression based on IHC assays with three PD-L1 antibodies (SP142, SP263, and 22C3) in tumors of patients with breast cancer. We investigated PD-L1 expression in tumor samples and compared survival outcomes predicted by using PD-L1 expression data obtained using each PD-L1 antibody
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