Di Grazia Giuseppe, Dri Arianna, Grieco Angela, Martinelli Claudia, Palleschi Michela, Martorana Federica, Barchiesi Giacomo, Arpino Grazia, De Angelis Carmine, De Laurentiis Michelino, Del Mastro Lucia, Puglisi Fabio, Vigneri Paolo, Giuliano Mario
School of Specialization in Medical Oncology, Department of Human Pathology "G. Barresi", Azienda Ospedaliera Universitaria Policlinico "G. Martino", University of Messina, Via Consolare Valeria N. 1, Gazzi, 98125 Messina, Italy.
Department of Medicine (DMED), University of Udine, 33100 Udine, Italy.
Cancers (Basel). 2025 Sep 8;17(17):2940. doi: 10.3390/cancers17172940.
Hormone-receptor-positive (HR+)/HER2-negative (HER2-) breast cancer (BC) is characterized by low immunogenicity and an immunosuppressive microenvironment. These features likely contribute to the inconsistent clinical activity of immune checkpoint inhibitors (ICIs) in this BC subtype. We conducted a systematic review of clinical trials evaluating ICIs in HR+/HER2- BC patients, focusing on potential biomarkers of response and resistance to these drugs. We systematically searched in Medline via PubMed, EMBASE, and CENTRAL for phase II/III clinical trials published between 2013 and 2023, testing ICIs alone or in combination with other agents in HR+/HER2- BC patients at any stage. All the searches were performed up to 27 January 2024. Data on study characteristics, clinical outcomes, and biomarker profiles were extracted, and due to study heterogeneity, a narrative synthesis was performed, without risk-of-bias assessment or meta-analysis. Twenty-five studies were included, with 3298 patients enrolled overall. Eighteen of these trials enrolled patients with advanced disease. All trials investigated ICI combination regimens, more frequently with chemotherapy, CDK4/6 inhibitors, or other immunotherapeutic agents. Most of the studies enrolling patients with advanced disease failed to show a significant clinical activity of ICIs. In the early setting, neoadjuvant chemo-immunotherapy with nivolumab or pembrolizumab increased the rate of complete responses compared to chemotherapy alone. Moreover, high programmed death-ligand 1 (PD-L1) expression, low ER (estrogen receptor), and high tumor-infiltrating lymphocyte (TIL) levels correlated with improved outcomes. Consistently, markers indicating enhanced immune activation, such as the MammaPrint High 2 (MP2) genomic signature, were associated with increased ICI sensitivity. Despite the limited overall efficacy, ICIs may represent a viable therapeutic option for a selected subset of HR+/HER2- BC patients. However, this systematic review is limited by study heterogeneity and the inclusion of ongoing or immature trials, which prevents quantitative analysis and may affect future conclusions on ICIs in HR+/HER2- breast cancer. Finally, optimized combination strategies could enhance tumor immunogenicity, while predictive biomarkers such as PD-L1, TILs, or specific genomic signatures could identify responsive patients.
激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2-）乳腺癌（BC）的特点是免疫原性低和免疫抑制微环境。这些特征可能导致免疫检查点抑制剂（ICI）在这种BC亚型中的临床活性不一致。我们对评估ICI在HR+/HER2-BC患者中的临床试验进行了系统评价，重点关注对这些药物反应和耐药的潜在生物标志物。我们通过PubMed、EMBASE和CENTRAL在Medline中系统检索2013年至2023年发表的II/III期临床试验，这些试验在任何阶段单独测试ICI或与其他药物联合用于HR+/HER2-BC患者。所有检索截至2024年1月27日。提取了关于研究特征、临床结果和生物标志物谱的数据，由于研究的异质性，进行了叙述性综合分析，未进行偏倚风险评估或荟萃分析。纳入了25项研究，共纳入3298例患者。其中18项试验纳入了晚期疾病患者。所有试验均研究了ICI联合方案，更常见的是与化疗、CDK4/6抑制剂或其他免疫治疗药物联合。大多数纳入晚期疾病患者的研究未能显示ICI有显著的临床活性。在早期阶段，与单纯化疗相比，使用纳武单抗或帕博利珠单抗的新辅助化疗免疫疗法提高了完全缓解率。此外，高程序性死亡配体1（PD-L1）表达、低雌激素受体（ER）和高肿瘤浸润淋巴细胞（TIL）水平与更好的结果相关。一致地，表明免疫激活增强的标志物，如MammaPrint High 2（MP2）基因组特征，与ICI敏感性增加相关。尽管总体疗效有限，但ICI可能是一部分选定的HR+/HER2-BC患者的可行治疗选择。然而，本系统评价受到研究异质性以及纳入正在进行或不成熟试验的限制，这妨碍了定量分析，并可能影响未来关于ICI在HR+/HER2-乳腺癌中的结论。最后，优化的联合策略可以增强肿瘤免疫原性，而诸如PD-L1、TIL或特定基因组特征等预测性生物标志物可以识别有反应的患者。
