Expression of PD-L1 in Relation to Intrinsic Molecular Subtypes of Breast Cancer in Hainan Free Trade Port, China

Research Article

Expression of PD-L1 in Relation to Intrinsic Molecular Subtypes of Breast Cancer in Hainan Free Trade Port, China

Feng CD¹, Zhang Y², Xu ZP³, Gao BY¹, Wang Y¹, Wang SJ¹ and Xu TF¹*

1Department of Breast Surgery, The First Affiliated Hospital of Hainan Medical University, China

2Department of Internal Medicine, University of Utah, USA

3Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland, Australia

*Corresponding author: Xu TF, Department of Breast Surgery, The First Affiliated Hospital of Hainan Medical University, 31 Longhua Road, Haikou City, Hainan Free Trade Port, China

Received: June 28, 2021; Accepted: July 20, 2021; Published: July 27, 2021


Background: Intrinsic molecular subtype and histological grade are closely related to clinical prognosis in breast cancer. However, their relationship with Programmed Cell Death-Ligand 1 (PD-L1) expression is not very clear, particularly for Hainan Aboriginal patients. Herein, this research aims to reveal the relationship between PD-L1 expression and intrinsic molecular subtypes of breast cancer.

Methods: 225 breast tumor samples from female patients were analyzed for PD-L1 expression using the Immunohistochemistry (IHC) method. The PDL1 expression level was detected by IHC and the relationship between the expression and clinical parameters was analyzed statistically.

Results: Positive staining of PD-L1 was mainly found in the plasma membrane. In all cases, the positive rate was 12.0% (27/225). The PD-L1 expression level was significantly reduced in Luminal A subtype (the corrected ratio OR=0.15, p=0.04) whereas increased in HER2-positive subtype (OR=4.2, p=0.01). PD-L1 was significantly related to HER2-positive subtype (p<0.05) and histological grade 3 (p<0.05). There was statistically significant association between PD-L1 expression and metastasis (p=0.046), but not with the patient’s age, the tumor stage and menstruation (p>0.05). Moreover, there was a significant difference in the frequency of intrinsic subtypes between patients with positive and negative PD-L1 expression (p<0.001) among patients with metastasis.

Conclusions: PD-L1 expression in breast cancer was positively correlated with HER2-positive subtype, higher pathological grade and metastasis of breast cancer, while negatively correlated with Luminal A in female patients in Hainan, China. PD-L1 may be a new independent marker to predict the prognostic factor in HER2-positive subtype breast cancer.

Keywords: PD-L1 expression; Breast cancer; HER2-positive subtype; Histological grade; Immunohistochemistry


PD-1: Programmed Death 1 Protein; PD-L1: Programmed Cell Death-Ligand 1; IHC: Immunohistochemistry; OR: Odds Ratio; TILs: Tumor-Infiltrating Lymphocytes; TNBC: Triple Negative Breast Cancer


Breast cancer is now the most common malignant tumor in global women [1,2] , including Chinese women [3]. With the continuous improvement of diagnosis and comprehensive treatment, most breast cancers are curable. However, the recurrence and distant metastasis of breast cancer are still challenging issues that threaten women’s lives and health.

Breast cancer is a highly heterogeneous malignant tumor. For intrinsic HER2 subtype breast cancer with high malignancy, it is of great scientific significance and clinical value to understand whether immunotherapy can be applied and when is the interfering timing while surgery, chemotherapy combined with targeted therapy, or radiotherapy is performed.

Inhibiting the PD-1/PD-L1 pathway is a promising immunotherapy to enhance the body’s anti-tumor immunity. In recent years, blocking immune checkpoints with antibody drugs, such as Programmed Death 1 Protein (PD-1) and its ligand (PD-L1), has achieved promise results in the treatment of various solid tumors, such as melanoma and lung cancer [4,5]. Targeting the T cell PD-1 has also shown clinical efficacy against cancer.

PD-L1 (also known as CD274 and B7-H1) is a 40kDa transmembrane protein that is expressed on a wide variety of normal tissues, including natural killer cells, macrophages, myeloid dendritic cells, B cells, epithelial cells, and vascular endothelial cells [6]. It is one of the ligands for Programmed Cell Death Protein 1 (PD-1). PD-L1 is a negative costimulatory molecule that binds to its receptor PD-1 on the T cell surface and inhibits the proliferation and activation of CD4+ and CD8+ T cells. As consequence, PD-L1 often leads to immune evasion and promotes the proliferation of tumor cells [7]. Many studies have reported that PD-L1 is highly expressed in tumor-related diseases, and higher PD-L1 expression is often associated with the poor prognosis in breast cancer [8-11]. Clinical trials targeting the PD-1/PD-L1 signaling pathway have achieved very positive results. For example, Opdivo, a PD-1 inhibitor for the treatment of non-small cell lung cancer approved in Japan in July 2014 significantly increased the treatment efficacy [12].

There are some studies reporting expression of PD-L1 in Chinese breast cancer patients [13-15], mainly in mainland China. However, the characteristics of aboriginal Chinese breast cancer patients in Hainan Free Trade Port, a rural island in the south part of China, have not been investigated and reported yet. This study thus aimed to reveal expression of PD-L1 in breast cancer female patients from Hainan Island and its association with clinicopathologic features and the intrinsic molecular subtypes of breast cancer, especially the HER2 subtype and the histological grade of breast cancer.

Materials and Methods

Study design

This retrospective study used an anti-PD-L1 Immunohistochemistry (IHC) antibody optimized for staining of formalin-fixed paraffin-embedded tissue samples of breast cancer patients. The breast cancer tissues were collected from patients enrolled in the First Affiliated Hospital of Hainan Medical University from June 30, 2007 to June 30, 2016 who were aboriginals in Hainan Free Trade Port and did not receive any neoadjuvant chemotherapy or neoendocrine therapy. There were 1830 samples collected initially. Then we performed the random sampling, and a total of 225 cases were included in our study. We randomly selected para-cancerous tissues in 20 cases with the tumor tissue greater than 5cm as the control group. The clinical data of the selected cases were complete, containing patients’ age, tumor stage, lymph node involvement, tumor grade, intrinsic subtype, postoperative chemotherapy regimen, the location of tumor metastasis and metastasis time. The location of metastasis was diagnosed by biopsy, CT or bone scan. All cases were followed up by telephone. The basic clinical data are listed in Table 1.