Massa Davide, Vernieri Claudio, Nicolè Lorenzo, Criscitiello Carmen, Boissière-Michot Florence, Guiu Séverine, Bobrie Angélique, Griguolo Gaia, Miglietta Federica, Vingiani Andrea, Lobefaro Riccardo, Taurelli Salimbeni Beatrice, Pinato Claudia, Schiavi Francesca, Brich Silvia, Pescia Carlo, Fusco Nicola, Pruneri Giancarlo, Fassan Matteo, Curigliano Giuseppe, Guarneri Valentina, Jacot William, Dieci Maria Vittoria
Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy.
Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy.
J Natl Cancer Inst. 2024 Dec 1;116(12):1914-1927. doi: 10.1093/jnci/djae178.
The cutoff of <1% positive cells to define estrogen receptor (ER) negativity by immunohistochemistry (IHC) in breast cancer (BC) is debated. We explored the tumor immune microenvironment and gene-expression profile of patients with early-stage HER2-negative ER-low (ER 1%-9%) BC, comparing them to ER-negative (ER <1%) and ER-intermediate (ER 10%-50%) tumors.
Among 921 patients with early-stage I-III, ER ≤50%, HER2-negative BCs, tumors were classified as ER-negative (n = 712), ER-low (n = 128), or ER-intermediate (n = 81). Tumor-infiltrating lymphocytes (TILs) were evaluated. CD8+, FOXP3+ cells, and PD-L1 status were assessed by IHC and quantified by digital pathology. We analyzed 776 BC-related genes in 116 samples. All tests were 2-sided at a <.05 significance level.
ER-low and ER-negative tumors exhibited similar median TILs, statistically significantly higher than ER-intermediate tumors. CD8/FOXP3 ratio and PD-L1 positivity rates were comparable between ER-low and ER-negative groups. These groups showed similar enrichment in basal-like intrinsic subtypes and comparable expression of immune-related genes. ER-low and ER-intermediate tumors showed significant transcriptomic differences. High TILs (≥30%) were associated with improved relapse-free survival (RFS) in ER-low (5-year RFS 78.6% vs 66.2%, log-rank P = .033, hazard ratio [HR] 0.37 [95% CI = 0.15 to 0.96]) and ER-negative patients (5-year RFS 85.2% vs 69.8%, log-rank P < .001, HR 0.41 [95% CI = 0.27 to 0.60]).
ER-low and ER-negative tumors are similar biological and molecular entities, supporting their comparable clinical outcomes and treatment responses, including to immunotherapy. Our findings contribute to the growing evidence calling for a reevaluation of ER-positive BC classification and management, aligning ER-low and ER-negative tumors more closely.
通过免疫组织化学（IHC）将乳腺癌（BC）中雌激素受体（ER）阴性定义为阳性细胞<1%的临界值存在争议。我们探讨了早期HER2阴性ER低表达（ER 1%-9%）BC患者的肿瘤免疫微环境和基因表达谱，并将其与ER阴性（ER<1%）和ER中等表达（ER 10%-50%）的肿瘤进行比较。
在921例I-III期、ER≤50%、HER2阴性的早期BC患者中，肿瘤被分为ER阴性（n = 712）、ER低表达（n = 128）或ER中等表达（n = 81）。评估肿瘤浸润淋巴细胞（TILs）。通过IHC评估CD8+、FOXP3+细胞和PD-L1状态，并通过数字病理学进行定量。我们在116个样本中分析了776个BC相关基因。所有检验均为双侧检验，显著性水平<0.05。
ER低表达和ER阴性肿瘤的TILs中位数相似，在统计学上显著高于ER中等表达肿瘤。ER低表达组和ER阴性组的CD8/FOXP3比值和PD-L1阳性率相当。这些组在基底样固有亚型中显示出相似的富集情况，并且免疫相关基因的表达相当。ER低表达和ER中等表达肿瘤表现出显著的转录组差异。高TILs（≥30%）与ER低表达（5年无复发生存率[RFS] 78.6%对66.2%，对数秩P = 0.033，风险比[HR] 0.37 [95%置信区间 = 0.15至0.96]）和ER阴性患者（5年RFS 85.2%对69.8%，对数秩P<0.001，HR 0.41 [95%置信区间 = 0.27至0.60]）的无复发生存改善相关。
ER低表达和ER阴性肿瘤是相似的生物学和分子实体，支持它们具有可比的临床结局和治疗反应，包括对免疫治疗的反应。我们的研究结果为越来越多呼吁重新评估ER阳性BC分类和管理的证据做出了贡献，使ER低表达和ER阴性肿瘤的分类更加紧密。
