Eribulin Promotes Antitumor Immune Responses in Patients with Locally Advanced or Metastatic Breast Cancer

• Published in: Anticancer research 2018-05, Vol.38 (5), p.2929-2938
• Main Authors: Goto, Wataru, Kashiwagi, Shinichiro, Asano, Yuka, Takada, Koji, Morisaki, Tamami, Fujita, Hisakazu, Takashima, Tsutomu, Ohsawa, Masahiko, Hirakawa, Kosei, Ohira, Masaichi
• Format: Article
• Language: English
• Subjects: Antitumor activity; Apoptosis; Biological effects; Breast cancer; Cancer; CD8 antigen; Conversion; E-cadherin; Failure analysis; Forkhead protein; Foxp3 protein; Immune response; Immune system; Immunohistochemistry; Immunoregulation; Lymphocytes; Mesenchyme; Metastases; Metastasis; Patients; PD-1 protein; PD-L1 protein; Proteins; Rank tests; Tumor-infiltrating lymphocytes; Tumors
• ISSN: 0250-7005; 1791-7530
• DOI: 10.21873/anticanres.12541

Several proteins involved in immune regulation and the relationship among these, the tumor microenvironment, and clinical outcomes of eribulin treatment were evaluated in advanced or metastatic breast cancer patients. This retrospective cohort study comprised 52 eribulin-treated locally advanced or metastatic breast cancer patients. Cancer tissue samples were obtained before and after treatment in 10 patients. Immunohistochemistry was performed to determine programmed death (PD)-1, CD8, and forkhead box P3 (FOXP3) expression by stromal tumor-infiltrating lymphocytes, and PD-ligand (L1) and PD-L2 expression by cancer cells. Of the 10 patients, 5 were responders (partial response) and 5 were non-responders (stable disease, 2; progressive disease, 3) to eribulin. PD-1, PD-L2, and FOXP3 expression became negative in 5 patients, PD-L1 expression became negative in 6 patients, and CD8 expression became positive in 3 patients after treatment. The response to eribulin was significantly associated with PD-L1 and FOXP3 negative conversion (p=0.024 and 0.004, respectively). The change in E-cadherin expression (positive or negative) was also correlated with the changes in PD-L1 and FOXP3 (p=0.024 and 0.004, respectively). Kaplan-Meier analysis with log-rank tests revealed that progression-free survival and time-to-treatment failure were significantly longer in patients with PD-L1 and FOXP3 negative conversion (p=0.012 and 0.001; p=0.049 and 0.018, respectively). The efficacy of eribulin may be attributed to its biological effects on the immune system (reduction of PD-L1 and FOXP3 expression) through epithelial-mesenchymal transition suppression, and vascular remodeling and improvement of the tumor microenvironment.