Carlino Francesca, Diana Anna, Piccolo Antonio, Ventriglia Anna, Bruno Vincenzo, De Santo Irene, Letizia Ortensio, De Vita Ferdinando, Daniele Bruno, Ciardiello Fortunato, Orditura Michele
Department of Precision Medicine, Division of Medical Oncology, University of Campania Luigi Vanvitelli, 80131 Naples, Italy.
Medical Oncology Unit, Ospedale Ave Gratia Plena, San Felice a Cancello, 81027 Caserta, Italy.
Cancers (Basel). 2022 Apr 23;14(9):2102. doi: 10.3390/cancers14092102.
Triple-negative breast cancer (TNBC) has been considered for many years an orphan disease in terms of therapeutic options, with conventional chemotherapy (CT) still representing the mainstay of treatment in the majority of patients. Although breast cancer (BC) has been historically considered a "cold tumor", exciting progress in the genomic field leading to the characterization of the molecular portrait and the immune profile of TNBC has opened the door to novel therapeutic strategies, including Immune Checkpoint Inhibitors (ICIs), Poly ADP-Ribose Polymerase (PARP) inhibitors and Antibody Drug Conjugates (ADCs). In particular, compared to standard CT, the immune-based approach has been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in metastatic PD-L1-positive TNBC and the pathological complete response rate in the early setting, regardless of PD-L1 expression. To date, PD-L1 has been widely used as a predictor of the response to ICIs; however, many patients do not benefit from the addition of immunotherapy. Therefore, PD-L1 is not a reliable predictive biomarker of the response, and its accuracy remains controversial due to the lack of a consensus about the assay, the antibody, and the scoring system to adopt, as well as the spatial and temporal heterogeneity of the PD-L1 status. In the precision medicine era, there is an urgent need to identify more sensitive biomarkers in the BC immune oncology field other than just PD-L1 expression. Through the characterization of the tumor microenvironment (TME), the analysis of peripheral blood and the evaluation of immune gene signatures, novel potential biomarkers have been explored, such as the Tumor Mutational Burden (TMB), Microsatellite Instability/Mismatch Repair Deficiency (MSI/dMMR) status, genomic and epigenomic alterations and tumor-infiltrating lymphocytes (TILs). This review aims to summarize the recent knowledge on BC immunograms and on the biomarkers proposed to support ICI-based therapy in TNBC, as well as to provide an overview of the potential strategies to enhance the immune response in order to overcome the mechanisms of resistance.
多年来，三阴性乳腺癌（TNBC）在治疗选择方面一直被视为一种罕见病，传统化疗（CT）仍是大多数患者的主要治疗方法。尽管乳腺癌（BC）在历史上一直被认为是一种“冷肿瘤”，但基因组领域令人兴奋的进展，使得TNBC的分子图谱和免疫图谱得以表征，这为包括免疫检查点抑制剂（ICIs）、聚ADP-核糖聚合酶（PARP）抑制剂和抗体药物偶联物（ADCs）在内的新型治疗策略打开了大门。特别是，与标准CT相比，基于免疫的方法已被证明可改善转移性PD-L1阳性TNBC的无进展生存期（PFS）和总生存期（OS），以及早期阶段的病理完全缓解率，无论PD-L1表达如何。迄今为止，PD-L1已被广泛用作ICI反应的预测指标；然而，许多患者并未从免疫治疗的添加中获益。因此，PD-L1不是反应的可靠预测生物标志物，由于在检测方法、抗体、评分系统的采用以及PD-L1状态的空间和时间异质性方面缺乏共识，其准确性仍存在争议。在精准医学时代，迫切需要在BC免疫肿瘤学领域识别除PD-L1表达之外更敏感的生物标志物。通过对肿瘤微环境（TME）的表征、外周血分析和免疫基因特征评估，人们探索了新的潜在生物标志物，如肿瘤突变负荷（TMB）、微卫星不稳定性/错配修复缺陷（MSI/dMMR）状态、基因组和表观基因组改变以及肿瘤浸润淋巴细胞（TILs）。本综述旨在总结关于BC免疫图谱以及为支持TNBC中基于ICI的治疗而提出的生物标志物的最新知识，并概述增强免疫反应以克服耐药机制的潜在策略。
