The Therapeutic Effectiveness of Neoadjuvant Trastuzumab Plus Chemotherapy for HER2-Positive Breast Cancer Can Be Predicted by Tumor-Infiltrating Lymphocytes and PD-L1 Expression

Abstract

Introduction: Neoadjuvant trastuzumab plus chemotherapy may affect programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes (TILs) in HER2-positive breast cancer. Discordant results were shown on the correlation between PD-L1 expression or TILs and the effectiveness of neoadjuvant therapy in HER2-positive breast cancer patients. This study aimed to clarify the predictive value of PD-L1 expression and TILs in neoadjuvant therapy in patients with HER2-positive breast cancer.

Methods: HER2-positive breast cancer cases receiving neoadjuvant treatment (NAT; n = 155) were retrospectively collected from July 2013 to November 2018. Histopathologic analysis of TILs was performed on hematoxylin and eosin (H&E)-stained sections from pre- and post-NAT specimens. The TIL score as a categorical variable can be divided into high (≥30%) and low (<30%) categories. The expression of PD-L1 was detected by immunohistochemistry, and the percentage of positive membranous staining (at least 1%) in tumor cells (PD-L1+TC) and TILs (PD-L1+TILs) was scored.

Results: In our study, 87 patients received neoadjuvant chemotherapy alone and 68 received neoadjuvant trastuzumab plus chemotherapy. Multivariate logistic regression analysis confirmed that lymph node metastasis, high TILs, and PD-L1+TILs in pre-neoadjuvant therapy specimens were independent predictors of pathological complete response (pCR) in neoadjuvant therapy (p < 0.05, for all). Among all patients, TILs were increased in breast cancer tissues post-neoadjuvant therapy (p < 0.001). Consistent results were found in the subgroup analysis of the trastuzumab plus chemotherapy group and the chemotherapy alone group (p < 0.05, for both). In 116 non-pCR patients, PD-L1+TC was decreased in breast cancer tissues post-neoadjuvant therapy (p = 0.0219). Consistent results were found in 43 non-pCR patients who received neoadjuvant trastuzumab plus chemotherapy (p = 0.0437). However, in 73 non-pCR patients who received neoadjuvant chemotherapy, there was no significant difference in PD-L1+TC expression in pre- and post-neoadjuvant therapy specimens (p = 0.1465). On the other hand, in the general population, the neoadjuvant trastuzumab plus chemotherapy group, and the neoadjuvant chemotherapy group, PD-L1+TILs decreased after treatment (p < 0.05, for both).

Conclusion: Higher TIL counts and PD-L1+TILs in pre-neoadjuvant therapy specimens and lymph node metastasis are independent predictors of pCR in patients with HER2-positive breast cancer treated with neoadjuvant therapy. TIL counts, PD-L1+TC, and PD-L1+TILs changed before and after neoadjuvant trastuzumab plus chemotherapy for HER2-positive breast cancer, which may suggest that, in HER2-positive breast cancer, neoadjuvant trastuzumab plus chemotherapy may stimulate the antitumor immune effect of the host, thereby preventing tumor immune escape.

Keywords: HER2-positive breast cancer; PD-L1; TILs; neoadjuvant trastuzumab plus chemotherapy; therapeutic effect.