Cancer Genetics and Epigenetics 2024, Vol.12 http://medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved.
Cancer Genetics and Epigenetics 2024, Vol.12 http://medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. MedSci Publisher is an international Open Access publisher specializing in cancer genetics, cancer epigenetics, clinical pharmacology, cancer biology at the publishing platform that is operated by Sophia Publishing Group (SPG), founded in British Columbia of Canada. Publisher MedSci Publisher Editedby Editorial Team of Cancer Genetics and Epigenetics Email: edit@cge.medscipublisher.com Website: http://medscipublisher.com/index.php/cge Address: 11388 Stevenston Hwy, PO Box 96016, Richmond, V7A 5J5, British Columbia Canada Cancer Genetics and Epigenetics (ISSN 2369-2995) is an open access, peer reviewed journal published online by MedSci Publisher. The journal is aimed to publish all works in the areas that with quality and originality, with a scope that spans the areas of cancer genetics and cancer epigenetics. It is archived in LAC (Library and Archives Canada) and deposited in CrossRef. The journal has been indexed by ProQuest as well, expected to be indexed by PubMed and other datebases in near future. All the articles published in Cancer Genetics and Epigenetics are Open Access, and are distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MedSci Publisher uses CrossCheck service to identify academic plagiarism through the world’s leading plagiarism prevention tool, iParadigms, and to protect the original authors’ copyrights.
Cancer Genetics and Epigenetics (online), 2024, Vol. 12, No. 6 ISSN 2369-2995 http://medscipublisher.com/index.php/cge © 2024 MedSci Publisher, registered at the publishing platform that is operated by Sophia Publishing Group, founded in British Columbia of Canada. All Rights Reserved. Latest Content Efficacy of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer: Current Status and Future Directions Qiyan Lou, Xiaoying Xu Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 6, 306-316 Genetic Mutation Profiles of Colorectal Cancer and Their Prospects in Diagnosis Zeyi Zhang, Haodong Wu, Huimin Sun, Yue Zhao Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 6, 317-328 Epigenetic Regulation Mechanisms of Non-coding RNAs in Ovarian Cancer Shanshan Li, Mingzi Huang, Chunyan Ji Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 6, 329-345 Exploring Molecular Mechanisms of DNA Methylation in Liver Cancer Liting Wang Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 6, 346-357 Regulatory Roles of lncRNAs and miRNAs in Colon Cancer Progression Jie Lian, Junhao Xu, Nanlin Huang, Haibo Lu Cancer Genetics and Epigenetics, 2024, Vol. 12, No. 6, 358-367
Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 306 Review Article Open Access Efficacy of Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer: Current Status and Future Directions Qiyan Lou, Xiaoying Xu Biotechnology Research Center, Cuixi Academy of Biotechnology, Zhuji, 311800, Zhejiang, China Corresponding author: xiaoying.xu@cuixi.org Cancer Genetics and Epigenetics, 2024, Vol.12, No.6 doi: 10.5376/cge.2024.12.0029 Received: 08 Sep., 2024 Accepted: 14 Oct., 2024 Published: 09 Nov., 2024 Copyright © 2024 Lou and Xu, This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Lou Q.Y., and Xu X.Y., 2024, Efficacy of immune checkpoint inhibitors in triple-negative breast cancer: current status and future directions, Cancer Genetics and Epigenetics, 12(6): 306-316 (doi: 10.5376/cge.2024.12.0029) Abstract Immune checkpoint inhibitors (ICIs), as a novel immunotherapy, restore anti-tumor immune responses by blocking immune suppressive pathways, demonstrating potential in treating triple-negative breast cancer (TNBC). This review systematically evaluates the clinical applications of ICIs in TNBC, including efficacy, biological basis, and associated challenges, while exploring combination therapy strategies and the predictive value of biomarkers. It also proposes future research directions. ICIs provide a groundbreaking therapeutic option for TNBC patients, significantly improving survival in some cases. Trials such as IMpassion130 and Keynote-355 have shown that PD-L1-positive TNBC patients respond well to ICIs combined with chemotherapy, though outcomes remain limited by patient heterogeneity and the accuracy of biomarkers. Additionally, combination strategies involving ICIs with chemotherapy, targeted therapies (e.g., PARP inhibitors, VEGF inhibitors), and radiotherapy exhibit synergistic effects, markedly enhancing efficacy. However, challenges such as heterogeneous efficacy, limitations of biomarker prediction, and issues of economic accessibility need to be addressed. This review provides a theoretical basis for optimizing ICI combination therapies and developing personalized immunotherapy. Future efforts should focus on biomarker development and multidisciplinary collaboration to improve global access and treatment outcomes for TNBC patients. Keywords Triple-negative breast cancer (TNBC); immune checkpoint inhibitors (ICIs); combination therapy; biomarkers; immune-related adverse events (irAEs) 1 Introduction Triple-negative breast cancer (TNBC) is recognized as the most aggressive subtype of breast cancer, characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expressions (Farshbafnadi et al., 2021; Singh et al., 2021). This subtype is notorious for its high recurrence rates, rapid progression, and poor prognosis compared to other breast cancer types (Tomioka et al., 2017; Zhao et al., 2023). The lack of specific molecular targets has historically limited the treatment options for TNBC, making it a challenging disease to manage (Blackley and Loi, 2019; Farshbafnadi et al., 2021). Conventional therapies for TNBC, primarily involving chemotherapy, have shown limited efficacy and are often associated with significant adverse effects (Farshbafnadi et al., 2021; Singh et al., 2021). Despite initial responses, many patients experience relapse and metastasis, leading to poor long-term outcomes (Varma et al., 2022; Zhao et al., 2023). The absence of hormone receptors and HER2 expression precludes the use of targeted therapies that are effective in other breast cancer subtypes, further complicating treatment strategies (Blackley and Loi, 2019; Farshbafnadi et al., 2021). Consequently, there is a critical need for novel therapeutic approaches that can improve survival and quality of life for TNBC patients (Singh et al., 2021; Uchimiak et al., 2022). Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic approach for TNBC, leveraging the body's immune system to target and destroy cancer cells (Farshbafnadi et al., 2021; Singh et al., 2021). ICIs, such as pembrolizumab and atezolizumab, have shown potential in improving outcomes for TNBC patients by blocking inhibitory pathways that prevent immune cells from attacking tumors (Cyprian et al., 2019; Uchimiak et al., 2022). Clinical trials have demonstrated that ICIs, particularly when combined with chemotherapy, can enhance pathologic complete response rates and progression-free survival in both early-stage and metastatic TNBC
Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 307 (Cyprian et al., 2019; Varma et al., 2022; Wu et al., 2022). However, the efficacy of ICIs varies among patients, and their use is often accompanied by immune-related adverse events, necessitating further research to optimize their application (Semba et al., 2020; Wu et al., 2022; Zhao et al., 2023). This review will comprehensively summarize the current status, efficacy, limitations, and future directions of immune checkpoint inhibitors (ICIs) in the treatment of triple-negative breast cancer (TNBC). By analyzing the latest clinical evidence and exploring the potential mechanisms of ICIs, this review highlights the potential of these therapies to improve TNBC management and identifies research areas needed to further enhance their effectiveness and safety. 2 Biological Basis of ICIs in TNBC 2.1 Tumor immunogenicity in TNBC Triple-negative breast cancer (TNBC) is characterized by a high mutational burden, which leads to the generation of numerous neoantigens. These neoantigens can be recognized by the immune system, making TNBC more immunogenic compared to other breast cancer subtypes (Thomas et al., 2021; Yi et al., 2021). The presence of these neoantigens is crucial for the effectiveness of immune checkpoint inhibitors (ICIs), as they provide targets for the immune system to attack the cancer cells (Farshbafnadi et al., 2021). The tumor microenvironment (TME) of TNBC is highly immunosuppressive, which poses a significant challenge for effective immune responses. TNBC tumors often exhibit high levels of tumor-infiltrating lymphocytes (TILs), including both cytotoxic T cells and regulatory T cells (Tregs) (Semba et al., 2022; Zhao et al., 2023). The presence of TILs is associated with better responses to ICIs, as these immune cells can be reactivated to attack the tumor. However, the TME also contains myeloid-derived suppressor cells (MDSCs) and other immunosuppressive factors that inhibit anti-tumor immunity (Semba et al., 2022). 2.2 Immune evasion mechanisms in TNBC TNBC employs several mechanisms to evade immune detection and destruction. One of the primary strategies is the upregulation of immune checkpoint molecules such as PD-L1, which binds to PD-1 on T cells and inhibits their activity (Singh et al., 2021). Additionally, TNBC tumors can secrete immunosuppressive cytokines and chemokines, such as CCL2, which attract Tregs and MDSCs to the TME, further dampening the immune response (Semba et al., 2022). These mechanisms collectively create an environment that is hostile to immune cell activity, allowing the tumor to grow and metastasize. 2.3 Role of immune checkpoint molecules (PD-1, PD-L1, CTLA-4) in TNBC progression Immune checkpoint molecules play a critical role in the progression of TNBC by inhibiting the activity of cytotoxic T cells. PD-1 and its ligand PD-L1 are the most studied checkpoint molecules in TNBC. The interaction between PD-1 on T cells and PD-L1 on tumor cells leads to the suppression of T cell activity, allowing the tumor to evade immune surveillance (Cyprian et al., 2019; Farshbafnadi et al., 2021). PD1/PDL1 antibodies have demonstrated significant efficacy across various solid tumors. However, their effectiveness varies depending on the tumor microenvironment and PDL1 expression levels in patients. CTLA4 blockade provides a complementary effect by modulating the initial activation of T cells, CTLA-4 is another checkpoint molecule that inhibits T cell activation by competing with CD28 for binding to B7 molecules on antigen-presenting cells (Figure 1) (Yi et al., 2021). The expression of these molecules in TNBC is associated with poor prognosis and resistance to conventional therapies. 2.4 Scientific rationale for the use of ICIs in TNBC The use of ICIs in TNBC is based on the premise that blocking these checkpoint molecules can restore the activity of cytotoxic T cells and enhance anti-tumor immunity. Clinical trials have shown that ICIs, particularly when combined with chemotherapy, can improve progression-free survival and overall response rates in both early-stage and metastatic TNBC (Simmons et al., 2020; Wu et al., 2022). The combination of ICIs with chemotherapy is thought to be particularly effective because chemotherapy can increase the release of tumor antigens and enhance the immunogenicity of the tumor, making it more susceptible to immune attack (Varma et al., 2022; Zhao et aL.,
Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 308 2023). The promising results from these trials provide a strong rationale for the continued investigation and use of ICIs in the treatment of TNBC. Figure 1 Schematic diagram of immune checkpoint blockade (Adopted from Yi et al., 2021) Image caption: MHC generally presents antigen on the surface of cancer cells for recognition by CD8+ T cells via their TCR. CTLA4, as a negative regulator, is homologous to the T cell co-stimulatory protein CD28, both of which bind to CD80 and CD86 on the surface of cancer cell but with different affinity. Overall, CTLA4 has a much higher affinity than CD28 to CD80/CD86. PD1 is expressed on T lymphocyte surface. The binding of PD1 on the T cell with PDL1 functions to suppress signals downstream of TCR activation, leading to apoptosis of the CTL. Antibodies (anti-CTLA4, anti-PD1, anti-PDL1) inhibit these checkpoint targeting proteins to restore the activity of T cells and kill cancer cells. MHC, major histocompatibility complex; TCR, T cell receptor; Ag, antigen (Adopted from Yi et al., 2021) 3 Predictive Markers for ICI Efficacy in TNBC 3.1 PD-L1 expression levels PD-L1 expression has emerged as a critical predictor of the efficacy of immune checkpoint inhibitors (ICIs) in triple-negative breast cancer (TNBC). Studies have shown that high PD-L1 expression is associated with better clinical outcomes, including improved objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in patients treated with ICIs (Qi et al., 2022; Khan et al., 2023). For instance, a meta-analysis demonstrated that PD-L1 positive TNBC patients had significantly better OS and PFS when treated with ICIs compared to PD-L1 negative patients (Qi et al., 2022). However, the predictive value of PD-L1 expression is not without limitations. Negative results from recent phase III trials, such as IMPassion131 and IMPassion132, have raised questions about the consistency of PD-L1 as a biomarker. Additionally, the variability in PD-L1 testing methods and cut-off values for positivity further complicates its utility as a universal predictive marker (Khan et al., 2023). 3.2 Tumor mutational burden (TMB) Tumor mutational burden (TMB) is another potential biomarker for predicting the efficacy of immunotherapy in TNBC. High TMB is generally associated with increased neoantigen load, which can enhance the immune system's ability to recognize and attack tumor cells. Studies have shown that high TMB correlates with better responses to ICIs in TNBC (Karn et al., 2020; Karn et al., 2022). For example, in the GeparNuevo study, high TMB was associated with increased pathological complete response (pCR) rates in patients receiving neoadjuvant chemo-ICB2. Interestingly, some data suggest that even TNBC patients with low TMB may benefit from ICI therapy, indicating that TMB alone may not be sufficient to predict response and should be considered alongside other biomarkers (Karn et al., 2022). 3.3 Other potential biomarkers Microsatellite instability (MSI) is a condition of genetic hypermutability that results from impaired DNA mismatch repair. While MSI is a well-established biomarker in other cancers, its role in TNBC is less clear.
Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 309 Limited studies suggest that MSI-high tumors may respond well to ICIs, but more research is needed to validate these findings in TNBC (Karn et al., 2020). The presence of tumor-infiltrating lymphocytes (TILs) has been shown to be a strong prognostic factor in TNBC. High levels of TILs are associated with better responses to ICIs and improved survival outcomes (Tomioka et al., 2017; Stanowska et al., 2022). For instance, patients with high TILs and high PD-L1 expression have shown significantly better disease-free survival (DFS) and overall survival (OS) compared to those with low TILs (Tomioka et al., 2017). TILs are currently being investigated as a potential biomarker to guide ICI therapy in TNBC (Blackley and Loi, 2019). 3.4 Integrated analysis of multiple biomarkers Given the limitations of individual biomarkers, integrated analysis of multiple biomarkers is being explored to enhance predictive accuracy. Combining TMB with immune gene expression profiles (GEP) or TILs has shown promise in predicting responses to ICIs more accurately than any single biomarker alone. For example, a study found that patients with both high TMB and high GEP had significantly higher pCR rates compared to those with low levels of both markers (Karn et al., 2020). Multifactorial models that incorporate PD-L1 expression, TMB, TILs, and other immune-related factors are likely to provide a more comprehensive assessment of ICI efficacy in TNBC (Zhang et al., 2021). Figure 2 Summary of immune cell features and dynamics in TNBC tumors (Adopted from Zhang et al., 2021) Image caption: (A) Characteristics and dynamics of key immune cell subsets following different treatments. Red (or green) arrows represent higher baseline levels predicting favorable (or unfavorable) responses, or the increase (or decrease) of immune cell subsets in responsive patients following treatment; (B) Immune features in responsive and nonresponsive tumors and their dynamics following different treatment regimens. TNBC tumors with substantial baseline CXCL13 T cells, B cells, and proinflammatory macrophages would show sensitivity, in contrast to resistance of TNBC tumors with substantial immunosuppressive macrophages, to the combination therapy. Paclitaxel regimen decreased while atezolizumab increased key antitumor immune cells in responsive tumors.+; (C) Potential crosstalk between CXCL13 T cells and their correlated immune cells inferred based on treatment-induced temporal dynamics. Expa, expansion; Migr, migration; Recr, recruitment (Adopted from Zhang et al., 2021)
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).
Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 311 5.2 ICIs and targeted therapies The combination of ICIs with PARP inhibitors has shown potential in BRCA-mutated TNBC. PARP inhibitors exploit the DNA repair deficiencies in BRCA-mutated cells, and when combined with ICIs, they may enhance the anti-tumor immune response by increasing tumor mutational burden and neoantigen load, thereby making the tumor more recognizable to the immune system (Farshbafnadi et al., 2021). VEGF inhibitors can modulate the tumor microenvironment by normalizing tumor vasculature, reducing hypoxia, and enhancing immune cell infiltration. This creates a more favorable environment for ICIs to exert their effects. Combining VEGF inhibitors with ICIs has shown promise in preclinical models and early-phase clinical trials, suggesting that this strategy could improve outcomes in TNBC (Farshbafnadi et al., 2021; Thomas et al., 2021). 5.3 Integration of ICIs with radiotherapy and other treatment modalities Radiotherapy can induce immunogenic cell death and enhance the presentation of tumor antigens, potentially synergizing with ICIs to boost anti-tumor immunity. The combination of radiotherapy with ICIs is being explored in clinical trials, with early results indicating that this approach may improve response rates and survival outcomes in TNBC (Adams et al., 2016; Thomas et al., 2021). Thomas et al. (2021) found that TNBC has limited treatment options due to the absence of traditional targets for therapy. Immune checkpoint inhibitors (ICIs) show potential in cancer immunotherapy by restoring T cell activity. However, their efficacy is constrained by the complexity of the tumor microenvironment and immune evasion mechanisms. Studies indicate that combining ICIs with chemotherapy, PARP inhibitors, or immunotherapies such as cancer vaccines and NK cell therapy can significantly enhance therapeutic efficacy and provide more durable anti-tumor responses (Figure 3).Additionally, combining ICIs with other treatment modalities such as CDK4/6 inhibitors has shown synergistic effects in preclinical models, suggesting that multi-modal approaches could be beneficial (Teo et al., 2017). Figure 1 Current Approaches for PD-1 and PD-L1 immune checkpoint inhibition in TNBC (Adopted from Thomas et al., 2021) Image Caption: The efficacy of PD-1 and PD-L1 therapy may be hampered due to cancer cell-intrinsic interactions and/or microenvironmental factors along with the expression of immune checkpoint molecules such as PD-L1 that define a potent and durable anti-tumor immune response. Immune checkpoint blockade could be used as monotherapy or in combination with different therapeutic approaches, including chemotherapy, PARP inhibitors with or without VEGFR/CDK/MEK inhibitors, cancer vaccines, and NK cell therapy (Adopted from Thomas et al., 2021)
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),
Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 306-316 http://medscipublisher.com/index.php/cge 313 cyclin-dependent kinase (CDK)12, enhancer of Zeste homolog 2 (EZH2), toll-like receptors (TLRs), and OX-40 (CD134) have shown potential in overcoming resistance mechanisms and enhancing anti-tumor immune responses (Omar and Tolba, 2019). These novel targets could provide additional pathways to modulate the immune system and improve patient outcomes. 7.2 Personalized immunotherapy The integration of multi-omics data, including genomics, transcriptomics, proteomics, and metabolomics, is essential for tailoring individualized treatment regimens (Chen, 2024). By analyzing the tumor mutational burden, immune cell infiltration, and specific biomarkers, personalized immunotherapy can be developed to enhance the efficacy of ICIs in TNBC (Thomas et al., 2021). This approach aims to identify patient-specific factors that predict response to ICIs, thereby optimizing treatment strategies and improving clinical outcomes. 7.3 Innovation in combination therapy strategies Investigating novel combination approaches involving ICIs and other modalities is a promising strategy to enhance therapeutic efficacy. Combining ICIs with chemotherapy, targeted therapies, cancer vaccines, and other immune modulatory drugs such as PARP inhibitors, MEK inhibitors, and TGF-β inhibitors has shown potential in preclinical and clinical studies (Liu et al., 2018; Cyprian et al., 2019; Majidpoor and Mortezaee, 2021; Patience et al., 2021; Guo et al., 2024). For instance, the combination of an mRNA vaccine encoding tumor antigen MUC1 with anti-CTLA-4 monoclonal antibody significantly enhanced anti-tumor immune responses in TNBC models (Liu et al., 2018). These innovative combination therapies aim to create a more favorable immune environment and potentiate the anti-tumor effects of ICIs. 7.4 Addressing equity issues Enhancing global accessibility of ICIs and conducting trials in diverse populations is critical to ensure equitable healthcare outcomes. The current landscape of clinical trials often lacks representation from diverse ethnic and socioeconomic groups, which can lead to disparities in treatment efficacy and accessibility (Thomas et al., 2021). Efforts should be made to conduct inclusive clinical trials and develop strategies to make ICIs more affordable and accessible worldwide. This includes addressing logistical, financial, and educational barriers that hinder the widespread adoption of ICIs in underrepresented populations. Acknowledgments We sincerely thank the anonymous peer reviewers for their valuable comments and constructive suggestions. Conflict of Interest Disclosure The authors affirm that this research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest. References Adams S., Diamond J., Hamilton E., Pohlmann P., Tolaney S., Molinero L., Zou W., Liu B., Waterkamp D., Funke R., and Powderly J., 2016, Abstract p2-11-06: safety and clinical activity of atezolizumab (Anti-Pdl1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer, Cancer Research, 76(4_Supplement): P2-11-06. https://doi.org/10.1158/1538-7445.sabcs15-p2-11-06 PMID: 33568344 Ali M.A., Aiman W., Shah S.S., Hussain M., Kashyap R., 2020, Efficacy and safety of pembrolizumab based therapies in triple-negative breast cancer: a systematic review of clinical trials, Critical Reviews in Oncology/Hematology, 157: 103197. https://doi.org/10.1016/j.critrevonc.2020.103197 Blackley E., and Loi S., 2019, Targeting immune pathways in breast cancer: review of the prognostic utility of tils in early stage triple negative breast cancer (Tnbc), Breast, 48(Suppl 1): s44-s48. https://doi.org/10.1016/s0960-9776(19)31122-1 Chen S.Y., 2024, Optimizing drug therapy using genomic information: a pathway to personalized medicine, International Journal of Molecular Medical Science, 14(1): 61-68. https://doi.org/10.5376/ijmms.2024.14.0009 Cyprian F.S., Akhtar S., Gatalica Z., and Vranić S., 2019, Targeted immunotherapy with a checkpoint inhibitor in combination with chemotherapy: a new clinical paradigm in the treatment of triple-negative breast cancer, Bosnian Journal of Basic Medical Sciences, 19(3): 227-233. https://doi.org/10.17305/bjbms.2019.4204
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Cancer Genetics and Epigenetics 2024, Vol.12, No.6, 317-328 http://medscipublisher.com/index.php/cge 317 Review Article Open Access Genetic Mutation Profiles of Colorectal Cancer and Their Prospects in Diagnosis Zeyi Zhang, Haodong Wu, Huimin Sun , Yue Zhao Department of Urology, Xiang’an Hospital of Xiamen University, Xiamen University, Xiamen, 361000, Fujian, China Corresponding author: hlg9999@xmu.edu.cn; hmsun@xah.xmu.edu.cn Cancer Genetics and Epigenetics, 2024, Vol.12, No.6 doi: 10.5376/cge.2024.12.0030 Received: 23 Sep., 2024 Accepted: 30 Oct., 2024 Published: 26 Nov., 2024 Copyright © 2024 Zhang et al., This is an open access article published under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Preferred citation for this article: Zhao Z.Y., Wu H.D., Sun H.M., and Zhao Y., 2024, Genetic mutation profiles of colorectal cancer and their prospects in diagnosis, Cancer Genetics and Epigenetics, 12(6): 317-328 (doi: 10.5376/cge.2024.12.0030) Abstract Colorectal cancer (CRC) is a complex and highly heterogeneous disease driven by various genetic mutations that play critical roles in tumor initiation, progression, and treatment resistance. This study provides a comprehensive overview of the genetic mutation landscape in CRC, with a focus on key mutations in genes such as APC, KRAS, TP53, and BRAF, which serve as core biomarkers for diagnosis, prognosis, and the development of personalized treatment strategies. The study also discusses advanced methods for detecting genetic mutations, including next-generation sequencing (NGS) and liquid biopsy techniques, and explores the clinical relevance of these mutations in CRC management. Looking ahead, this research examines the future prospects of genetic mutation profile analysis, emphasizing the potential of novel diagnostic markers, the integration of genetic data with other diagnostic tools, and the ongoing development of personalized medicine in CRC management. The study concludes with recommendations for clinical practice and future research, highlighting the importance of adopting personalized treatment strategies and further investigating mechanisms of resistance to improve patient outcomes. Keywords Colorectal cancer (CRC); Genetic mutations; Next-generation sequencing (NGS); Liquid biopsy techniques; Personalized medicine 1 Introduction Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies worldwide, representing a significant public health challenge. It originates in the colon or rectum and is often detected at an advanced stage, contributing to its high mortality rate. Despite advancements in treatment modalities, including surgery, chemotherapy, and radiotherapy, the prognosis for CRC patients remains closely tied to early detection and the molecular characterization of the disease. Understanding the genetic underpinnings of CRC is crucial for improving diagnostic accuracy, predicting disease progression, and tailoring personalized treatment strategies (Santos et al., 2021; Abdullah et al., 2022; Rhead et al., 2023). Genetic mutation profiling has emerged as a pivotal tool in the management of colorectal cancer. Mutations in key genes such as APC, KRAS, TP53, and BRAF play critical roles in the initiation and progression of CRC. These genetic alterations not only drive tumorigenesis but also influence the response to therapy, making them essential biomarkers for diagnosis, prognosis, and therapeutic targeting. Advances in genomic technologies have enabled the comprehensive analysis of these mutations, offering new insights into the molecular landscape of CRC and opening avenues for the development of more effective, individualized treatment regimens (Santos et al., 2019; Wang et al., 2019; Heide et al., 2021). This study provides a comprehensive analysis of the genetic mutation profiles associated with colorectal cancer (CRC) and their impact on clinical practice. The research will explore the most common genetic alterations in CRC, their roles in tumor biology, and their potential applications in diagnosis and treatment. Additionally, it will discuss the latest advancements in genomic analysis technologies and their prospects for enhancing the accuracy of CRC diagnosis. This study highlights the importance of understanding genetic mutation profiles in advancing the diagnosis and management of colorectal cancer, ultimately improving patient outcomes.
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