HER2阳性早期乳腺癌（EBC）患者新辅助治疗期间残留病灶（RD）生物学及基因表达变化的预后价值

Prognostic value of residual disease (RD) biology and gene expression changes during the neoadjuvant treatment in patients with HER2-positive early breast cancer (EBC).

作者信息

Fernandez-Martinez A, Tanioka M, Ahn S G, Zagami P, Pascual T, Rediti M, Tang G, Hoadley K A, Venet D, Rashid N U, Spears P A, Di Cosimo S, de Azambuja E, Choudhury A, Rastogi P, Islam M N, Cortes J, Llombart-Cussac A, Swain S M, Sotiriou C, Prat A, Perou C M, Carey L A

机构信息

Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, USA; Department of Genetics, University of North Carolina, Chapel Hill, USA.

Okayama University, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Medical AI Project, Okayama, Japan.

出版信息

Ann Oncol. 2025 Apr;36(4):403-413. doi: 10.1016/j.annonc.2024.12.010. Epub 2024 Dec 18.

DOI:10.1016/j.annonc.2024.12.010

PMID:39706338

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11949722/

Abstract

BACKGROUND

In human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), we investigated tumor and immune changes during neoadjuvant treatment and their impact on residual disease (RD) biology and prognostic implications across four neoadjuvant studies of trastuzumab with or without lapatinib, and with or without chemotherapy: CALGB 40601, PAMELA, NeoALTTO, and NSABP B-41.

PATIENTS AND METHODS

We compared tumor and immune gene expression changes during neoadjuvant treatment and their association with event-free survival (EFS) by uni- and multivariable Cox regression models in different cohorts and timepoints: 452 RD samples at baseline including 169 with a paired RD, and biomarker changes during neoadjuvant therapy, evaluating model performance via the c-index.

RESULTS

Analysis of 169 paired tumor samples revealed a shift in intrinsic subtype proportions from HER2-enriched at baseline (50.3%) to normal-like (49.1%) followed by luminal A (18.9%) in RD. This luminal phenotypic change was supported by decreased correlation to the HER2-enriched centroid, ERBB2, and HER2 amplicon genes and increased correlation to the luminal A centroid (Wilcoxon test P < 0.001). Additionally, RD showed relative immune activation marked by significant increases in B-cell, CD8 T-cell, and natural killer cell signatures (Wilcoxon test P < 0.05). In multivariable Cox models, intrinsic subtypes at baseline provided more prognostic information, while immune gene expression signatures provided more prognostic information in RD. Notably, the best multivariable EFS model (c-index = 0.77) integrated the immunoglobulin G signature from RD samples (adjusted hazard ratio 0.45, 95% confidence interval 0.30-0.67, adjusted P = 0.002).

CONCLUSIONS

In patients with HER2-positive EBC and RD, tumor biomarkers provide more prognostic information at baseline. In contrast, immune biomarkers perform better for EFS prognosis in RD.

摘要

背景

在人表皮生长因子受体2（HER2）阳性早期乳腺癌（EBC）中，我们在四项曲妥珠单抗联合或不联合拉帕替尼、联合或不联合化疗的新辅助治疗研究（CALGB 40601、PAMELA、NeoALTTO和NSABP B-41）中，研究了新辅助治疗期间肿瘤和免疫变化及其对残留疾病（RD）生物学的影响和预后意义。

患者和方法

我们通过单变量和多变量Cox回归模型，比较了不同队列和时间点新辅助治疗期间肿瘤和免疫基因表达变化及其与无事件生存期（EFS）的关联：基线时452份RD样本，包括169份配对的RD样本，以及新辅助治疗期间的生物标志物变化，通过c指数评估模型性能。

结果

对169对肿瘤样本的分析显示，内在亚型比例从基线时HER2富集型（50.3%）转变为正常样型（49.1%），随后RD中为管腔A型（18.9%）。这种管腔表型变化得到了与HER2富集型质心、ERBB2和HER2扩增子基因相关性降低以及与管腔A型质心相关性增加的支持（Wilcoxon检验P<0.001）。此外，RD显示出相对免疫激活现象，其特征为B细胞、CD8 T细胞和自然杀伤细胞特征显著增加（Wilcoxon检验P<0.05）。在多变量Cox模型中，基线时的内在亚型提供了更多的预后信息，而免疫基因表达特征在RD中提供了更多的预后信息。值得注意的是，最佳的多变量EFS模型（c指数=0.77）整合了RD样本中的免疫球蛋白G特征（调整后风险比0.45，95%置信区间0.30-0.67，调整后P=0.002）。