Elsevier

Human Pathology

Volume 72, February 2018, Pages 28-34
Human Pathology

In this issue
PD-L1 in breast cancer: comparative analysis of 3 different antibodies

https://doi.org/10.1016/j.humpath.2017.08.010Get rights and content

Highlights

  • There is a differential expression of PD-L1 in breast cancer subtypes.

  • PD-L1 expression is associated with higher tumor grade and ER−, PgR−, TN, and highly proliferative tumors.

  • Dako 22C3, Ventana SP263, and BioCare PD-L1 antibodies exhibited similar performance with high κ values.

Summary

The interaction of programmed cell death-1 and its ligand-1 (PD-L1) serves as a regulatory check against excessive immune response to antigen and autoimmunity. We compared the performance of 3 different PD-L1 antibodies (Ventana SP263, Dako 22C3, and BioCare RbMCAL10 antibodies) in 136 invasive ductal carcinoma specimens including 43 primary, 48 locally metastatic, and 46 distantly metastatic diseases. PD-L1 expression was correlated with clinicopathologic parameters including tumor size, grade, lymphovascular invasion, estrogen receptor, progesterone receptor, HER2, Ki67, molecular type, and triple-negative status. There was excellent agreement between the 3 antibodies, with highly significant κ values (P  .001). PD-L1 expression was more likely to be associated with higher tumor grade and estrogen receptor–negative, progesterone receptor–negative, triple-negative, and highly proliferative tumors (P < .001). When we studied PD-L1 expression at 0, 1%-9%, 10%-49%, and ≥50% cutoff points by the 3 antibodies, there were 20 discordant cases between the antibodies. Sixteen were of inconsequential impact as far as low and high PD-L1 expression. The 4 differences between antibodies did exhibit an interesting pattern of expression, where there was a general agreement between the BioCare and Ventana antibodies with consistently higher PD-L1 expression compared with the Dako antibody. Given the high concordance, it is not surprising that all 3 antibodies demonstrated the same associations with all pathologic and clinical parameters studied. Standardization studies to identify reliable biomarkers that help in patient selection for immune therapy to improve the risk-benefit ratio for these drugs are still needed.

Introduction

Cancers use multiple mechanisms to evade the immune response. Programmed death-1 (PD-1) is an inhibitory signaling receptor on the surface of activated T and B cells [1]. Its ligand programmed cell death ligand-1 (PD-L1) has been reported to be expressed on tumors cells and stromal tumor-infiltrating lymphocytes (TILs). The normal physiological role of this protein is to bind to PD-1 receptors expressed on the surfaces of activated cytotoxic T cells [2]. This PD-1/PD-L1 interaction serves as a regulatory check against excessive immune response to antigen and autoimmunity. Recent data suggest that the PD-1 pathway may be an active immune checkpoint in a variety of cancers. Targeting the PD-1/PD-L1 pathway may prevent inhibitory T-cell signaling and reactivate T cells to mediate tumor cell killing. Recent exciting studies have highlighted the therapeutic potential of agents that target the PD-1/PD-L1 pathway in patients with advanced cancers such as melanoma, non–small cell lung cancer, pancreatic cancer, esophageal cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, and urothelial carcinoma [2], [3], [4]. New classes of drugs either singly or in combination such as pembrolizumab provide cancer patients with a chance for a long-term and durable response [2], [3], [4], [5], [6], [7]. Pembrolizumab is a humanized monoclonal antibody that binds to PD-1. Several recent clinical trials using pembrolizumab highlighted its value as a new option for first-line treatment or in combination for patients with advanced non–small cell lung cancers [5], [6], [7]. Moreover, recent studies have highlighted the potential value of evaluating PD-L1 expression as a predictive marker in breast cancer immunotherapy, particularly for triple-negative (TN) molecular type [8], [9], [10], [11], [12].

The value of PD-L1 detection by immunohistochemistry (IHC) as a valuable marker is confounded by many unresolved issues such as different detecting antibodies, different staining protocols and platforms, and different cutoff points in addition to variable tissue preparations and variable tumors with different characteristics. Some studies have agreed upon PD-L1 expression from low (≥1%-49%) to high (≥50%-100%) as an accepted standard in lung cancer. It is not clear, however, whether cutoffs using frequency of positive cells and/or intensity of PD-L1 expression are of value in predicting the response to immune therapy in other cancers such as breast cancer. Given the concerns surrounding the analytic and clinical validity of PD-L1 testing, it is possible that a negative test result with one antibody might be changed to a positive test result using a different assay and antibody.

The aim of this study is to compare the performance of 3 commercially available PD-L1 antibodies (Dako 22C3, Agilent, Santa Clara, CA, USA, Ventana SP263, Ventana Medical Systems, Roche, Tucson, AZ, USA and BioCare RbM CAL10, Pacheco, CA, USA) in breast cancer.

Section snippets

Patient cohort

This study was approved by the institutional review committee at the University of Kansas Medical Center. A total of 136 specimens including 42 primary breast cancers, 48 metastatic diseases in regional Lymph nodes (LNs) (42 paired to the primary tumors), and 46 nonpaired distant metastases (15 paired to the primary tumors) diagnosed between 2007 and 2016 were examined. The samples were taken from 42 breast core needle biopsy specimens, 48 lymph node core needle biopsy specimens, and 46

Distribution of clinical and histopathologic parameters in breast cancer

Table 2 summarizes the clinicopathologic parameters for the 136 specimens from 90 patients included in our study. Sixty-five percent of the patients were 50 years or older. Forty percent of the specimens were grade II, and 37% were grade III. The remaining 23% were distant metastases with unknown grades of their primary tumors. Sixty-seven percent and 47% of the tumor plus metastatic lesions were ER and PgR positive, respectively. A significant percentage (45%) of this cohort of samples had a

Discussion

At least 5 therapeutic anti–PD-1 or PD-L1 monoclonal antibodies are currently available for evaluating PD-L1 expression in many types of cancer [13], [14], [15], [16], [17], [18]. Unfortunately, each clinical trial evaluating the PD-1/PD-L1 status has elected to use a custom primary antibody along with a specific staining platform and unique scoring criteria, making it very difficult for investigators to accurately compare results correlating staining patterns with treatment selection. This is

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    Disclosures: None of the authors have a conflict of interest of either financial or personal nature that is connected to the submitted manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The contents are solely the responsibility of the authors.

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