de Moraes Francisco Cezar Aquino, de Castro Ribeiro Caio Henrique Duarte, Pessôa Felipe Dircêu Dantas Leite, Chaves Juliana Ramos, de Souza Ana Paula Borges, Di Felipe Ávila Alcantara Diego, Imbiriba Margareth Maria Braun Guimarães, Magalhães Maria Cristina Figueroa, Burbano Rommel Mario Rodríguez
Federal University of Pará, R. Augusto Corrêa, Guamá, nº01, Belem, PA, 66075-110, Brazil.
University of São Paulo - USP, São Paulo, 01246-903, Brazil.
Breast Cancer Res. 2025 Mar 15;27(1):39. doi: 10.1186/s13058-025-01989-9.
Currently, the primary methods for detecting HER2 expression levels are immunohistochemistry (IHC) and in situ hybridization (ISH), with the traditional standard being a HER2-positive score of 3 + accompanied by ERBB2 gene amplification detected through ISH. However, a new entity has recently emerged: HER2-low, defined as HER2 IHC 1 + or 2 + with negative ISH. HER2-low breast cancer, representing 45-60% of all HER2-negative tumors, has distinct biological characteristics and uncertain responses to conventional HER2-targeted therapies. Recent studies suggest varied clinical outcomes, highlighting the need for further investigation into the impact of HER2-low status on treatment efficacy and prognosis.
This meta-analysis evaluates the difference in complete pathological response (pCR), disease-free survival (DFS), and overall survival (OS) between HER2-low and HER2-zero phenotypes.
We systematically searched the main databases PubMed, Scopus, and Web of Science for articles evaluating women in neoadjuvant therapy expressing HER2-low and HER2-zero. We computed odds ratios (ORs) or hazard ratios (HRs) using DerSimonian and Laird random-effect models for all endpoints, with 95% confidence intervals (CIs). We assessed the heterogeneity using I statistics. R, version 4.2.3, was used for statistical analyses.
38 studies totaling 70,104 patients were included. The HER2-low group accounted for 61.3% of patients while HR + status represented 52.4% in the whole research. In 67,839 women, the pCR was analyzed, which in the overall cohort analysis favored the HER2-zero group (OR 0.84; 95% CI 0.78-0.90; p = 0.000005; I = 15%). Subgroup analyses for triple-negative breast cancer (TNBC) and HR + patients also favored HER2-zero expression, with an OR of 0.91 (95% CI 0.83-1.0; p < 0.041; I = 12%) and 0.75 (95% CI 0.70-0.81; p < 0.000001; I = 0%), respectively. In the multivariate analysis across all patients, both DFS and OS outcomes were significantly favorable for the HER2-low expression group, with HR 0.8317 (95% CI 0.7036-0.9832; p = 0.031) for DFS and HR 0.806 (95% CI 0.663-0.979; p = 0.03) for OS.
Based on our findings, HER2-zero status is associated with a significantly higher pathological complete response (pCR) rate compared to HER2-low in early-stage breast cancer, and other survival outcomes. These results suggest that HER2-zero should be considered a prognostic factor in early-stage breast cancer and taken into account in neoadjuvant treatment planning and future clinical research.
目前，检测HER2表达水平的主要方法是免疫组织化学（IHC）和原位杂交（ISH），传统标准是HER2阳性评分为3+，并伴有通过ISH检测到的ERBB2基因扩增。然而，最近出现了一种新情况：HER2低表达，定义为HER2 IHC 1+或2+且ISH阴性。HER2低表达乳腺癌占所有HER2阴性肿瘤的45%-60%，具有独特的生物学特征，对传统HER2靶向治疗的反应尚不确定。最近的研究表明临床结果各异，这凸显了进一步研究HER2低表达状态对治疗疗效和预后影响的必要性。
本荟萃分析评估HER2低表达和HER2零表达表型之间在完全病理缓解（pCR）、无病生存期（DFS）和总生存期（OS）方面的差异。
我们系统检索了主要数据库PubMed、Scopus和Web of Science，以查找评估接受新辅助治疗的HER2低表达和HER2零表达女性的文章。对于所有终点，我们使用DerSimonian和Laird随机效应模型计算优势比（OR）或风险比（HR），并给出95%置信区间（CI）。我们使用I统计量评估异质性。使用R 4.2.3版本进行统计分析。
纳入了38项研究，共70104例患者。HER2低表达组占患者的61.3%，而HR+状态在整个研究中占52.4%。对67839名女性的pCR进行了分析，在总体队列分析中，HER2零表达组更具优势（OR 0.84；95%CI 0.78-0.90；p = 0.000005；I = 15%）。三阴性乳腺癌（TNBC）和HR+患者的亚组分析也支持HER2零表达，OR分别为0.91（95%CI 0.83-1.0；p < 0.041；I = 12%）和0.
