Serrano García Lucía, Jávega Beatriz, Llombart Cussac Antonio, Gión María, Pérez-García José Manuel, Cortés Javier, Fernández-Murga María Leonor
Medical Oncology Department, Hospital Arnau de Vilanova, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO), Valencia, Spain.
Grupo Oncología Traslacional, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-Centro de Estudios Universitarios (CEU), Alfara del Patriarca, Spain.
Front Immunol. 2024 Dec 13;15:1513421. doi: 10.3389/fimmu.2024.1513421. eCollection 2024.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of progesterone and estrogen receptors and low (or absent) HER2 expression. TNBC accounts for 15-20% of all breast cancers. It is associated with younger age, a higher mutational burden, and an increased risk of recurrence and mortality. Standard treatment for TNBC primarily relies on cytotoxic agents, such as taxanes, anthracyclines, and platinum compounds for both early and advanced stages of the disease. Several targeted therapies, including bevacizumab and sunitinib, have failed to demonstrate significant clinical benefit in TNBC. The emergence of immune checkpoint inhibitors (ICI) has revolutionized cancer treatment. By stimulating the immune system, ICIs induce a durable anti-tumor response across various solid tumors. TNBC is a particularly promising target for treatment with ICIs due to the higher levels of tumor-infiltrating lymphocytes (TIL), increased PD-L1 expression, and higher mutational burden, which generates tumor-specific neoantigens that activate immune cells. ICIs administered as monotherapy in advanced TNBC yields only a modest response; however, response rates significantly improve when ICIs are combined with cytotoxic agents, particularly in tumors expressing PD-L1. Pembrolizumab is approved for use in both early and advanced TNBC in combination with standard chemotherapy. However, more research is needed to identify more potent biomarkers, and to better elucidate the synergism of ICIs with other targeted agents. In this review, we explore the challenges of immunotherapy in TNBC, examining the mechanisms of tumor progression mediated by immune cells within the tumor microenvironment, and the signaling pathways involved in both primary and acquired resistance. Finally, we provide a comprehensive overview of ongoing clinical trials underway to investigate novel immune-targeted therapies for TNBC.
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，其特征是缺乏孕激素和雌激素受体，且HER2表达低（或无）。TNBC占所有乳腺癌的15%-20%。它与较年轻的年龄、更高的突变负荷以及复发和死亡风险增加相关。TNBC的标准治疗主要依赖细胞毒性药物，如紫杉烷类、蒽环类和铂类化合物，用于疾病的早期和晚期。包括贝伐单抗和舒尼替尼在内的几种靶向治疗在TNBC中未能显示出显著的临床益处。免疫检查点抑制剂（ICI）的出现彻底改变了癌症治疗。通过刺激免疫系统，ICI在各种实体瘤中诱导持久的抗肿瘤反应。由于肿瘤浸润淋巴细胞（TIL）水平较高、PD-L1表达增加以及突变负荷较高，TNBC是ICI治疗特别有前景的靶点，较高的突变负荷会产生激活免疫细胞的肿瘤特异性新抗原。ICI单药用于晚期TNBC时仅产生适度反应；然而，当ICI与细胞毒性药物联合使用时，反应率显著提高，尤其是在表达PD-L1的肿瘤中。帕博利珠单抗被批准与标准化疗联合用于早期和晚期TNBC。然而，需要更多研究来确定更有效的生物标志物，并更好地阐明ICI与其他靶向药物的协同作用。在本综述中，我们探讨了TNBC免疫治疗的挑战，研究肿瘤微环境中免疫细胞介导的肿瘤进展机制以及原发性和获得性耐药所涉及的信号通路。最后，我们全面概述了正在进行的临床试验，这些试验旨在研究TNBC的新型免疫靶向治疗。
