Therapeutic Associations Comprising Anti-PD-1/PD-L1 in Breast Cancer: Clinical Challenges and Perspectives

Simple Summary Breast cancer remains the leading cause of death in women. Despite improved treatment in recent years, new therapeutic options are still needed for some types of breast cancer. In view of the poor response of breast cancer to immunotherapy, it is important to develop therapeutic combinations in order to sensitize breast tumors to anti-PD-(L)1 immunotherapy. This review presents the different combinations developed in pre-clinical and clinical studies according to the immune characterization of breast cancers. Despite a few cases of long-responder patients, immunotherapy with anti-PD-(L)1 has so far proved rather disappointing in monotherapy in metastatic breast cancer, prompting the use of synergistic therapeutic combinations incorporating immunotherapy by immune-checkpoint inhibitors. In addition, a better understanding of both the mechanisms of sensitivity and resistance to immunotherapy, as well as the immunological effects of the usual treatments for breast cancer, make it possible to rationally consider this type of therapeutic combination. For several years, certain treatments, commonly used to treat patients with breast cancer, have shown that in addition to their direct cytotoxic effects, they may have an impact on the tumor immune microenvironment, by increasing the antigenicity and/or immunogenicity of a "cold" tumor, targeting the immunosuppressive microenvironment or counteracting the immune-exclusion profile. This review focuses on preclinical immunologic synergic mechanisms of various standard therapeutic approaches with anti-PD-(L)1, and discusses the potential clinical use of anti-PD-1/L1 combinations in metastatic or early breast cancer.