Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer

Simple Summary: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype accounting for approximately 10-20% of all cases. Due to a lack of actionable targets, chemotherapy has been for many decades the preferred, and often the only, available treatment option for this disease. There is now evidence, from several randomized controlled trials, that immune checkpoint inhibitors are effective as first-line treatment for advanced TNBC expressing PD-L1 and as neoadjuvant chemotherapy for high-risk early TNBC. Despite these encouraging results, there are still many open issues about the optimal use of immunotherapy in TNBC. This review summarizes the main results from clinical trials testing immunotherapy in TNBC and critically discusses some limitations of these study results. Finally, we present the challenges that need to be addressed soon in the evolving field of immune-oncology.Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials.