Immunotherapy for Metastatic Triple Negative Breast Cancer: Current Paradigm and Future Approaches

In approximately 15-20% of the patients diagnosed with breast cancer, it comprises the triple negative (TN) subtype, which until recently lacked targets for specific treatments and is known for its aggressive clinical behavior in patients with metastatic disease. TNBC is considered the most immunogenic breast cancer subtype due to higher levels of tumor infiltrating lymphocytes (TILs), tumor mutational burden and PD-L1 expression, providing a rationale for immunotherapy. The addition of pembrolizumab to chemotherapy as first-line treatment resulted in significantly improved PFS and OS for PD-L1 positive mTNBC, leading to FDA approval. However, response rate of ICB in unselected patients is low. Ongoing (pre)clinical trials aim to further optimize ICB efficacy and widen its application beyond PD-L1 positive breast tumors. Novel immunomodulatory approaches to induce a more inflamed tumor microenvironment include dual checkpoint blockade, bispecific antibodies, immunocytokines, adoptive cell therapies, oncolytic viruses, and cancer vaccines. Preclinical data for these novel strategies seems promising, but solid clinical data to further support its application for mTNBC is awaited. Biomarkers capturing the degree of immunogenicity such as but not limited to TILs, CD8 T cell levels, and IFNg signatures could support deciding which therapeutic strategy is most appropriate for which patient. Given 1) the accumulating therapy options for patients with metastatic disease and 2) the heterogeneity of mTNBC from inflamed to immune-desert tumors, the challenge is to work towards immunomodulatory strategies for specific subgroups of patients with TNBC to enable personalized (immuno)therapy for patients with metastatic disease.