Microenvironment-related predictive markers of the therapeutic effectiveness of eribulin in patients with locally advanced or metastatic breast cancer: pilot study

Background. Triple negative breast cancer has no specific treatment sites for chemotherapy and is unfavorable in terms of prognosis. One of the drugs widely used in this cohort of patients is eribulin, which in addition to its antimitotic effect has an effect on the tumor microenvironment. The search for biological criteria that will allow predicting the effectiveness of the drug is assumed relevant since it will help to select patients who may receive the most benefit from certain therapy regimens.

Objective: identification of immunological predictors of the therapeutic effectiveness of eribulin in patients with locally advanced or metastatic triple-negative breast cancer.

Materials and methods. The study included 20 patients with locally advanced and metastatic triple negative breast cancer. 50 % had a short-term response (progression-free survival <3 months) to eribulin therapy, and 50 % had a long-term response (progression-free survival >6 months). Seven-color immunofluorescence was used to determine the subpopulation composition of tumor-infiltrating lymphocytes and their PD1 expression. Image acquisition and analysis were performed using the Vectra® 3.0 system and InForm® software (Akoya Biosciences, USA).

Results. It has been shown that the ratio of the number of PD1-negative to PD1-positive CD20+ B-lymphocytes less than 5.5 associated with the long-term effectiveness of eribulin in patients with locally advanced or metastatic triple negative breast cancer.

Conclusion. The results showed that the ratio of the number of PD1-negative to PD1-positive CD20+ B-lymphocytes can be considered as a possible marker to predict the effectiveness of eribulin in patients with breast cancer.

1. Kuznetsov G., Towle M.J., Cheng H. et al. Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389. Cancer Res 2004;64(16):5760–6.

2. Jordan M.A., Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer 2004;4(4):253–65.

3. Hüsemann L.C., Reese A., Radine C. et al. The microtubule targeting agents eribulin and paclitaxel activate similar signaling pathways and induce cell death predominantly in a caspase-independent manner. Cell Cycle 2020;19(4):464–78. DOI: 10.1080/15384101.2020.1716144.

4. Yoshida T., Ozawa Y., Kimura T. et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) states. J Br J Cancer 2014;110(6):1497–505.

5. Funahashi Y., Okamoto K., Adachi Y. et al. Eribulin mesylate reduces tumor microenvironment abnormality by vascular remodeling in preclinical human breast cancer models. Cancer Sci 2014;105(10):1334–42. DOI: 10.1111/cas.12488.

6. Kashiwagi S., Asano Y., Goto W. et al. Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One 2017;12(2):e0170634. DOI: 10.1371/journal.pone.0170634.

7. Goto W., Kashiwagi S., Asano Y. et al. Eribulin promotes antitumor immune responses in patients with locally advanced or metastatic breast cancer. Anticancer Res 2018;38(5):2929–38.

8. Dieci M.V., Radosevic-Robin N., Fineberg S. et al. International ImmunoOncology Biomarker Working Group on Breast Cancer. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: A report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol 2018;52(Pt 2):16–25. DOI: 10.1016/j.semcancer.2017.10.003.

9. Gao G., Wang Z., Qu X., Zhang Z. Prognostic value of tumor-infiltrating lymphocytes in patients with triple-negative breast cancer: a systematic review and meta-analysis. BMC Cancer 2020;20(1):179. DOI: 10.1186/s12885-020-6668-z.

10. Brockhoff G., Seitz S., Weber F. et al. The presence of PD-1 positive tumor infiltrating lymphocytes in triple negative breast cancers is associated with a favorable outcome of disease. Oncotarget 2017;9(5):6201–12. DOI: 10.18632/oncotarget.23717.