Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis

Abstract

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.

Prognostic Role of PD-L1 Expression in Invasive Breast Cancer: A Systematic Review and Meta-Analysis

“…The exact mechanism between tumor and immune microenvironment remains undetermined, but new biomarkers such as CD8 and FOXP3 may contribute to the stratification of patients and a better understanding of these survival curves [ 48 ]. Another important point involves the heterogeneity of tumor PD-L1 expression and its metastatic sites, whether in axillary lymph nodes [ 49 ] or distant metastases [ 28 , 50 ]. Women with PD-L1-negative primary breast tumors who developed metastatic disease with PD-L1 expression seem to improve their prognosis, which favors the inclusion of this variable in new studies [ 28 , 50 ].…”

Enhancer RNA SLIT2 Inhibits Bone Metastasis of Breast Cancer Through Regulating P38 MAPK/c-Fos Signaling Pathway

“…BRCA is one of the most common cancers and is the primary cause of cancer death in women (24). When BRCA spreads beyond the breast, one of the most common places is the bones (25). Bone metastases occur in roughly 70% of women and are often the first symptom that the BRCA has relapsed, and finding and treating bone metastases early on can be critical in preventing problems later (26).…”

Discordance of PD-L1 Expression at the Protein and RNA Levels in Early Breast Cancer

“…This is of paramount importance since increased heterogeneity in the expression of a therapeutic target such as HER2 [41] and PD-L1 could signify a lower response rate to targeted therapies. Previous reports on PD-L1 heterogeneity have focused on the intra-patient temporal expression of PD-L1 protein between primary tumors and metastatic sites, demonstrating a differential expression pattern and correlation with outcome [9,[42][43][44]. Of note, a recent study reported substantial heterogeneity of PD-L1 expression between different areas of the same tissue in TNBC patients, especially for small tumor samples [45].…”

“…Potential causes for the reported inconsistency include assay performance [6]; a potentially lesser role of immunoediting at the primary tumor compared with the distant metastasis, further supported by the lower PD-L1 positivity rates at metastasis compared to primary tumor [9] and the fact that PD-L1 positivity at the metastasis carried potentially stronger predictive information in the IMPassion130 trial [7]; and heterogeneity of PD-L1 expression. In support of the latter, we have previously demonstrated that PD-1/PD-L1 expression is associated with discrepant prognostic values depending on the level of expression, mRNA, or protein [10,11].…”