Unlocking the Potential of Immune Checkpoint Inhibitors in HR+/HER2− Breast Cancer: A Systematic Review

Background: Hormone-receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC) is characterized by low immunogenicity and an immunosuppressive microenvironment. These features likely contribute to the inconsistent clinical activity of immune checkpoint inhibitors (ICIs) in this BC subtype. We conducted a systematic review of clinical trials evaluating ICIs in HR+/HER2− BC patients, focusing on potential biomarkers of response and resistance to these drugs. Methods: We systematically searched in Medline via PubMed, EMBASE, and CENTRAL for phase II/III clinical trials published between 2013 and 2023, testing ICIs alone or in combination with other agents in HR+/HER2− BC patients at any stage. All the searches were performed up to 27 January 2024. Data on study characteristics, clinical outcomes, and biomarker profiles were extracted, and due to study heterogeneity, a narrative synthesis was performed, without risk-of-bias assessment or meta-analysis. Results: Twenty-five studies were included, with 3298 patients enrolled overall. Eighteen of these trials enrolled patients with advanced disease. All trials investigated ICI combination regimens, more frequently with chemotherapy, CDK4/6 inhibitors, or other immunotherapeutic agents. Most of the studies enrolling patients with advanced disease failed to show a significant clinical activity of ICIs. In the early setting, neoadjuvant chemo-immunotherapy with nivolumab or pembrolizumab increased the rate of complete responses compared to chemotherapy alone. Moreover, high programmed death-ligand 1 (PD-L1) expression, low ER (estrogen receptor), and high tumor-infiltrating lymphocyte (TIL) levels correlated with improved outcomes. Consistently, markers indicating enhanced immune activation, such as the MammaPrint High 2 (MP2) genomic signature, were associated with increased ICI sensitivity. Discussion: Despite the limited overall efficacy, ICIs may represent a viable therapeutic option for a selected subset of HR+/HER2− BC patients. However, this systematic review is limited by study heterogeneity and the inclusion of ongoing or immature trials, which prevents quantitative analysis and may affect future conclusions on ICIs in HR+/HER2− breast cancer. Finally, optimized combination strategies could enhance tumor immunogenicity, while predictive biomarkers such as PD-L1, TILs, or specific genomic signatures could identify responsive patients.