The estrogen pathway as a modulator of response to immunotherapy

Abstract

Lung cancer is the leading cause of cancer deaths worldwide, with a 5-year survival rate of about 18%. Thus, there is a great need for novel therapeutic approaches to treat non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) have improved outcomes for a subset of patients, especially those with high programmed death-ligand 1 expression and/or high tumor mutational burden, but have failed in the majority of patients. Increasing evidence suggests that the estrogen signaling pathway may be a therapeutic target in metastatic NSCLC and that the estrogen pathway may play a role in sex-based responses to ICIs. This report will review the epidemiologic, preclinical and clinical data on the estrogen pathway in NSCLC, its implications in sex-based responses to ICIs and the potential use of antiestrogen therapy in combination with ICIs.

Keywords::

• antiestrogen therapy
• checkpoint inhibitors
• estrogen pathway
• non-small-cell lung cancer
• sex differences
• tumor microenvironment

Author contributions

MA Velez prepared the manuscript, table and figure. LP Stabile assisted with manuscript preparation, provided essential input on content and organization, and edited the manuscript. TF Burns provided vital information and reviewed and edited the manuscript.

Acknowledgments

The authors acknowledge support from The Breath of Hope Lung Foundation to TF Burns and LP Stabile.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.