Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 312 5.4 Ongoing clinical trials exploring combination therapies Several ongoing clinical trials are investigating various combination therapies involving ICIs in TNBC. For instance, the IMpassion031 trial is evaluating the combination of atezolizumab with nab-paclitaxel and anthracycline-based chemotherapy in early-stage TNBC, with preliminary results showing improved pathological complete response rates (Mittendorf et al., 2020). Another trial is exploring the combination of ipatasertib, a PI3K/AKT pathway inhibitor, with atezolizumab and taxane chemotherapy, showing promising anti-tumor activity in metastatic TNBC (Schmid et al., 2021). These trials aim to identify the most effective combination strategies to enhance the efficacy of ICIs in TNBC. 6 Challenges in the Application of ICIs in TNBC 6.1 Immune-related adverse events (irAEs) and their management The incidence and severity of immune-related adverse events (irAEs) in TNBC patients treated with immune checkpoint inhibitors (ICIs) are significant concerns. Studies have shown that combining ICIs with chemotherapy increases the occurrence of irAEs compared to chemotherapy alone. For instance, a pooled analysis of 41 cohorts involving 6558 TNBC patients revealed that ICIs plus chemotherapy led to a higher incidence of serious adverse events (AEs) (Wu et al., 2022). Additionally, real-world data indicate that while ICIs are effective in advanced TNBC, they are associated with tolerable but notable adverse effects, including endocrine disorders and skin reactions (Zhao et al., 2023). The early onset of irAEs has been correlated with improved survival outcomes, suggesting that these events might serve as predictive markers for treatment efficacy (Das and Johnson, 2019; Morehouse et al., 2019). 6.2 Limitations of biomarkers The heterogeneity of PD-L1 expression and the lack of reliable predictive markers pose significant challenges in the application of ICIs in TNBC. PD-L1 expression varies widely among patients, and its role as a predictive biomarker is not fully reliable. For example, the IMpassion130 trial highlighted that while PD-L1 positivity is a criterion for treatment with atezolizumab, the variability in expression levels complicates patient selection (Cyprian et al., 2019). Furthermore, the search for other biomarkers, such as tumor mutational burden and microsatellite instability, has not yet yielded consistent results, making it difficult to predict which patients will benefit most from ICIs (Das and Johnson, 2019). 6.3 Resistance mechanisms Understanding the mechanisms of primary and acquired resistance to ICIs is crucial for improving their efficacy in TNBC. Primary resistance can be attributed to the inherently low immunogenicity of breast cancers, which limits the effectiveness of immune checkpoint blockade (Yuan et al., 2018). Acquired resistance, on the other hand, involves complex interactions between tumor cells and the immune system, including the upregulation of alternative immune checkpoints and changes in the tumor microenvironment (Farshbafnadi et al., 2021). Ongoing research aims to elucidate these mechanisms to develop strategies that can overcome resistance and enhance the therapeutic benefits of ICIs. 6.4 Economic and accessibility challenges The high cost of ICIs presents a significant barrier to their widespread use, particularly in resource-limited settings. The economic burden of these therapies is substantial, and their accessibility is often limited to patients in high-income countries. This disparity underscores the need for cost-effective strategies and policies to make ICIs more accessible to a broader patient population (Singh et al., 2021). Additionally, the development of companion diagnostics, such as the Ventana diagnostic antibody SP142 for selecting TNBC patients for atezolizumab treatment, adds to the overall cost, further complicating accessibility (Cyprian et al., 2019). 7 Future Directions 7.1 Development of next-generation ICIs The exploration of novel targets beyond PD-1/PD-L1 and CTLA-4 is crucial for advancing the efficacy of immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC). Emerging targets such as T-cell inducible co-stimulator (ICOS), CD40, CD47, V-domain Ig suppressor of T-cell activation (VISTA),
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