Pathologic response rates in HER2-low versus HER2-zero early breast cancer patients receiving neoadjuvant therapy: a systematic review and meta-analysis
Francisco Cézar Aquino de Moraes, Camila Maria Barreto Ribeiro, Felipe Dircêu Dantas Leite Pessôa, Juliana Ramos Chaves, Ana Paula Borges de Souza, Diego Di Felipe Ávila Alcântara, Margareth Maria Braun Guimarães Imbiriba, Maria Cristina Figueroa Magalhães, Rommel Mário Rodríguez Burbano
Abstract
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 I2 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; I2 = 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; I2 = 12%) and 0.75 (95% CI 0.70–0.81; p < 0.000001; I2 = 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.