Effect of Primary Systemic Therapy on PD-1, PD-L1, and PD-L2 mRNA Expression in Advanced Breast Cancer

OBJECTIVE: The association between PD-1, PD-L1, and PD-L2 expression and prognosis has been extensively studied in various cancers but remained controversial in breast cancer. Besides, little is known about the prognostic value of PD-1, PD-L1, and PD-L2 upregulation or downregulation following systemic therapy (chemotherapy and hormonal therapy) in breast cancer. Therefore, we aim to investigate the change of PD-1, PD-L1, and PD-L2 expression in mRNA level after primary systemic therapy in breast cancer patients and its clinical implications. METHODS: Expression of PD-1, PD-L1, and PD-L2 mRNA were measured before-after chemotherapy and hormonal therapy with real-time PCR in 80 advanced breast cancer patients. The correlation between alteration of PD-1, PD-L1, and PD-L2 expression and clinicopathological characteristics as well as overall survival was also statistically analyzed. RESULTS: Chemotherapy and hormonal therapy altered PD-1, PD-L1, and PD-L2 expression in breast cancer with most patients have an increase expression. As much as 57.1%, 62.9% and 60% patients have an increase PD-1, PD-L1, and PD-L2 expression after chemotherapy, while 60%, 60%, and 64% patients have an increase PD-1, PD-L1, and PD-L2 expression after hormonal therapy. Alteration of PD-1, PD-L1, and PD-L2 expression was not correlated with all clinicopathological characteristics. Increase in PD-1, PD-L1, and PD-L2 expression was significantly associated with better OS (p=0.031, p=0.019, and p=0.019 for PD-1, PD-L1, and PD-L2, respectively), which remained significant in multivariate analysis including age, stage, primary systemic therapy, histology grade, subtype and primary tumor histology (HR PD-1 0.5 (95% CI 0.28-0.88) p=0.031; HR PD-L1 0.43 (95% CI 0.24-0.8) p=0.019; HR PD-L2 (95% CI 0.24-0.87) p=0.019). CONCLUSION: Expression of PD-1, PD-L1, and PD-L2 in breast cancer patients is mostly enhanced after chemotherapy and hormonal therapy, and the enhancement is associated with good OS. This result revealed the potential of measuring PD-1, PD-L1, and PD-L2 mRNA expression in predicting clinical outcome.