Novel combinatorial strategies for boosting the efficacy of immune checkpoint inhibitors in advanced breast cancers.

The year 2019 witnessed the first approval of an immune checkpoint inhibitor (ICI) for the management of triple negative breast cancers (TNBC) that are metastatic and programmed death ligand (PD)-L1 positive. Extensive research has focused on testing ICI-based combinatorial strategies, with the ultimate goal of enhancing the response of breast tumors to immunotherapy to increase the number of breast cancer patients benefiting from this transformative treatment. The promising investigational strategies included immunotherapy combinations with monoclonal antibodies (mAbs) against human epidermal growth factor receptor (HER)-2 for the HER2 + tumors versus cyclin-dependent kinase (CDK)4/6 inhibitors in the estrogen receptor (ER) + disease. Multiple approaches are showing signals of success in advanced TNBC include employing Poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, MEK inhibitors, phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling inhibitors or inhibitors of adenosine receptor, in combination with the classical PD-1/PD-L1 immune checkpoint inhibitors. Co-treatment with chemotherapy, high intensity focused ultrasound (HIFU) or interleukin-2-βɣ agonist have also produced promising outcomes. This review highlights the latest combinatorial strategies under development for overcoming cancer immune evasion and enhancing the percentage of immunotherapy responders in the different subsets of advanced breast cancers.