Targeted Treatment for High-Risk Early-Stage Triple-Negative Breast Cancer: Spotlight on Pembrolizumab

Triple-negative breast cancer (TNBC) is a biologically aggressive yet heterogeneous disease that disproportionately affects younger women and women of color compared to other breast cancer subtypes. The paucity of effective targeted therapies and the prevalence of chemotherapeutic resistance in high-risk, early-stage TNBC pose significant clinical challenges. Deeper insights into the genomic and immune landscape have revealed key features of TNBC, including intrinsic genomic instability, DNA repair deficiency, and potentially an immunogenic tumor microenvironment. These advances led to landmark trials with immune checkpoint inhibitors in the advanced-stage setting, which subsequently translated into immunotherapy-based clinical trials in the early-stage setting and recent promising results. Pembrolizumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was investigated in combination with platinum-, taxane- and anthracycline-based neoadjuvant chemotherapy followed by adjuvant pembrolizumab monotherapy for patients with high-risk, early-stage TNBC in the randomized, double-blind, placebo-controlled phase 3 KEYNOTE-522 trial. In July 2021, the US Food and Drug Administration (FDA) granted approval for pembrolizumab based on marked improvement in pathologic complete response rate and 3-year event-free survival compared to neoadjuvant chemotherapy alone. This advance immediately altered the longstanding treatment paradigm. Here, we review the impact of pembrolizumab plus chemotherapy for the treatment of patients with high-risk, early-stage TNBC, and discuss immunotherapy-related toxicity considerations, key immunomodulatory biomarkers under active investigation, and remaining clinical questions for future research directions.