Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 310 Zhang et al. (2021) revealed the critical roles of different immune cells in TNBC treatment response. The presence of CXCL13+ T cells, B cells, and pro-inflammatory macrophages was closely associated with tumor sensitivity to immunotherapy. Combination therapies can significantly reshape the tumor immune microenvironment, with anti-PD-L1 combined with chemotherapy demonstrating stronger immune activation effects (Figure 2). 4 Clinical Efficacy of ICIs in TNBC 4.1 Overview of key ICIs studied in TNBC Anti-PD-1/PD-L1 inhibitors, such as pembrolizumab and atezolizumab, have been extensively studied in the context of triple-negative breast cancer (TNBC). Pembrolizumab, a PD-1 inhibitor, has shown promise in various clinical trials, particularly when combined with chemotherapy (Uhlik et al., 2020; Garrido-Castro et al., 2021; Kyte et al., 2023). Atezolizumab, a PD-L1 inhibitor, has also demonstrated efficacy, especially in PD-L1-positive TNBC patients (Schmid et al., 2019; Ali et al., 2020; Kyte et al., 2023). Anti-CTLA-4 inhibitors, such as ipilimumab, have been explored in combination with other ICIs and therapies. Dual blockade with anti-PD-1 and anti-CTLA-4 has shown enhanced activity in other malignancies and is being investigated in TNBC (Page et al., 2019; Li et al., 2023). 4.2 Key clinical trials and their findings The IMpassion130 trial was a landmark study that evaluated the efficacy of atezolizumab in combination with nab-paclitaxel in patients with metastatic TNBC. The trial demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS) in patients with PD-L1-positive tumors (Schmid et al., 2019; Kyte et al., 2023). Specifically, the addition of atezolizumab to chemotherapy resulted in a median PFS of 7.2 months compared to 5.5 months with chemotherapy alone (Kyte et al., 2023). The Keynote-355 trial assessed the efficacy of pembrolizumab combined with chemotherapy in patients with advanced TNBC. The trial showed that pembrolizumab significantly improved PFS compared to chemotherapy alone, particularly in patients with PD-L1-positive tumors. The median PFS was 9.7 months for the pembrolizumab plus chemotherapy group versus 5.6 months for the chemotherapy-alone group (Ali et al., 2020). 4.3 Subgroup efficacy analysis Both the IMpassion130 and Keynote-355 trials highlighted the importance of PD-L1 status in predicting response to ICIs. In the IMpassion130 trial, the benefit of atezolizumab was primarily observed in PD-L1-positive patients, with a significant improvement in both PFS and OS (Schmid et al., 2019; Kyte et al., 2023). Similarly, the Keynote-355 trial demonstrated that pembrolizumab was more effective in PD-L1-positive tumors, underscoring the role of PD-L1 as a predictive biomarker (Ali et al., 2020). Emerging evidence suggests that tumor mutational burden (TMB) and other biomarkers may also influence the efficacy of ICIs in TNBC. High TMB has been associated with better responses to ICIs, as it may increase neoantigen load and enhance immune recognition. Additionally, the presence of tumor-infiltrating lymphocytes (TILs) and specific immune gene signatures have been correlated with improved outcomes in patients receiving ICIs (Tomioka et al.., 2017; Gao et al., 2020). 5 Application of Combination Therapies with ICIs in TNBC 5.1 Chemotherapy and ICIs The combination of immune checkpoint inhibitors (ICIs) with chemotherapy has shown promising results in the treatment of triple-negative breast cancer (TNBC). The IMpassion130 trial demonstrated that the combination of atezolizumab, an anti-PD-L1 antibody, with nab-paclitaxel significantly improved progression-free survival (PFS) in patients with metastatic TNBC compared to chemotherapy alone (Cyprian et al., 2019; Mittendorf et al., 2020). This combination has been particularly effective in patients with PD-L1-positive tumors, showing a clinically meaningful overall survival benefit. Additionally, a meta-analysis of 41 cohorts involving 6558 TNBC patients found that ICIs combined with chemotherapy improved pathologic complete response rates and event-free survival in early-stage TNBC, as well as PFS in metastatic TNBC (Wu et al., 2020).
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