Arima Jun, Chida Kohei, Wu Rongrong, Taniguchi Kohei, McKenery Amber, Morreale Brian G, Monell Andrea M, Abrams Scott I, Ebos John M L, Hakamada Kenichi, Ishikawa Takashi, Hagihara Seita, Kimura Kosei, Iwamoto Mitsuhiko, Lee Sang-Woong, Takabe Kazuaki
Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
Department of General and Gastroenterological Surgery, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, Japan.
Ann Surg Oncol. 2025 Sep 16. doi: 10.1245/s10434-025-18260-2.
Immune checkpoint inhibitors (ICIs) can improve the pathological complete response (pCR) rate in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC), particularly in patients with low estrogen receptor alpha (ERα) expression. This would imply that ERα expression could be a predictive biomarker for ICI response. In clinical trials, centralized immunohistochemistry (IHC) minimizes variability, but routine clinical practice faces challenges from staining artifacts and interpretation variability. Transcriptomic analyses offer a standardized, quantitative alternative. Based on this, we investigated ESR1, the gene encoding ERα, as a predictive biomarker for ICI response.
We analyzed bulk and single-cell RNA sequencing (RNAseq) BC cohorts. Patients were stratified by ESR1 expression.
In the ER+/HER2- subtype, high ESR1 expression was associated with significantly less tumor-infiltrating lymphocytes. High ESR1 expression was also associated with lower levels of key immune populations such as CD8 T cells, CD4 T effector memory T cells, type 1 macrophages, B cells, and dendritic cells, suggesting a less inflamed tumor microenvironment (TME). High ESR1 also correlated with decreased cytolytic activity and lower pCR rates after neoadjuvant chemoimmunotherapy. Single-cell RNAseq further revealed an inverse correlation between ESR1 expression and ICI response across cancer epithelial, normal epithelial, endothelial, and myeloid cells. Additionally, the predictive performance of ESR1 surpassed PDL1 in ER+ BC.
High ESR1 expression was associated with an immunosuppressive TME in ER+/HER2- BC and is a more robust predictive biomarker for ICI response in this BC subtype.
免疫检查点抑制剂（ICI）可提高雌激素受体阳性（ER+）/人表皮生长因子受体2阴性（HER2-）乳腺癌（BC）的病理完全缓解（pCR）率，尤其是在雌激素受体α（ERα）低表达的患者中。这意味着ERα表达可能是ICI反应的预测生物标志物。在临床试验中，集中式免疫组织化学（IHC）可将变异性降至最低，但常规临床实践面临染色伪像和解读变异性的挑战。转录组分析提供了一种标准化的定量替代方法。基于此，我们研究了编码ERα的基因ESR1作为ICI反应的预测生物标志物。
我们分析了批量和单细胞RNA测序（RNAseq）的BC队列。患者按ESR1表达进行分层。
在ER+/HER2-亚型中，ESR1高表达与肿瘤浸润淋巴细胞显著减少相关。ESR1高表达还与关键免疫细胞群水平较低有关，如CD8 T细胞、CD4 T效应记忆T细胞、1型巨噬细胞、B细胞和树突状细胞，提示肿瘤微环境（TME）炎症较轻。ESR1高表达还与新辅助化疗免疫治疗后的细胞溶解活性降低和pCR率降低相关。单细胞RNAseq进一步揭示了ESR1表达与癌症上皮细胞、正常上皮细胞、内皮细胞和髓样细胞的ICI反应呈负相关。此外，ESR1在ER+ BC中的预测性能超过了PDL1。
ESR1高表达与ER+/HER2- BC中的免疫抑制性TME相关，是该BC亚型中ICI反应更强有力的预测生物标志物。
