Immune system and angiogenesis-related potential surrogate biomarkers of response to everolimus-based treatment in hormone receptor-positive breast cancer: an exploratory study

Breast Cancer Res Treat. 2020 Nov;184(2):421-431. doi: 10.1007/s10549-020-05856-3. Epub 2020 Aug 7.


Purpose: mTOR inhibitor everolimus is used for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC). No reliable predictive biomarker of response is available. Following evidences from other solid tumors, we aimed to assess the association between treatment-associated immune system features and everolimus activity.

Methods: We retrospectively explored a correlation with the therapeutic activity of everolimus and tumor-associated immune pathways with ingenuity pathway analysis (IPA), neutrophil-to-lymphocyte ratio (NLR), circulating lymphocytes, and endothelial cells (CECs) in 3 different HR+ mBC studies, including the BALLET phase IIIb study.

Results: The circulating levels of CD3+/CD8+, CD3+/CD4+, and overall T lymphocytes were higher in responders versus non-responders at baseline (p = 0.017, p < 0.001, p = 0.034) and after treatment (p = 0.01, p = 0.003, p = 0.023). Reduced CECs, a tumor neoangiogenesis marker, were observed in responders after treatment (p < 0.001). Patients with low NLR (≤ 4.4) showed a better progression-free survival compared to patients with high NLR (> 4.4) (p = 0.01). IPA showed that the majority of immunity-related genes were found upregulated in responders compared to non-responders before treatment, but not after.

Conclusions: Lymphocytes subpopulations, CECs and NLR could be interesting biomarkers predictive of response to everolimus-based regimens, potentially useful in daily clinical practice to select/monitor everolimus-based treatment in mBC. Further studies to confirm such hypotheses are warranted.

Keywords: Biomarker; Breast cancer; Everolimus; Hormone receptors; Immunomodulation; mTOR.

Publication types

  • Clinical Trial, Phase III

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols
  • Biomarkers, Tumor
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Endothelial Cells
  • Everolimus / therapeutic use
  • Female
  • Hormones / therapeutic use
  • Humans
  • Immune System
  • Receptor, ErbB-2
  • Retrospective Studies


  • Biomarkers, Tumor
  • Hormones
  • Everolimus
  • Receptor, ErbB-2