Immunotherapy in rare histologies of breast cancer: challenges, opportunities, and future perspectives

Immunotherapy has transformed the management of several malignancies, yet its role in rare breast cancer histologies remains poorly defined due to limited research and few dedicated clinical trials. This review critically assesses current knowledge and emerging opportunities for immunotherapy in these uncommon breast cancer subtypes.

Rare breast cancer histologies exhibit heterogeneous immunogenicity, including variable expression of programmed death-ligand 1 (PD-L1), differing levels of tumor-infiltrating lymphocytes (TILs), and distinct mutational burdens. Recent studies highlight potential immunotherapy responsiveness in metaplastic, invasive lobular, apocrine, and other rare breast cancer types, though predictive biomarkers like PD-L1 and tumor mutational burden (TMB) alone appear insufficient. Currently, only two clinical trials specifically target rare breast cancer histologies, emphasizing significant knowledge gaps.

The effectiveness of immunotherapy in rare breast cancer histologies remains limited, likely due to inadequate patient selection using current biomarkers such as PD-L1 and TMB. Further research must focus on refining predictive biomarkers to better identify patients likely to from immunotherapy and enhance outcomes in these challenging clinical settings.