# Prevalence and Outcomes of HER2-Low Versus HER2-0 Status in Patients with Metastatic Breast Cancer

## TL;DR

HER2-low breast cancer is common in metastatic cases and is linked to better survival than HER2-0, with changes in HER2 status between primary and metastatic tumors showing the need for reassessment.

## Contribution

This study provides real-world evidence on the prevalence and outcomes of HER2-low metastatic breast cancer and highlights the importance of reassessing HER2 status due to tumor heterogeneity.

## Key findings

- HER2-low disease was common in both de novo and recurrent metastatic breast cancer.
- HER2-low status was associated with longer overall survival compared to HER2-0 disease.
- HER2 status often changed between primary tumors and metastatic sites, especially in recurrent disease.

## Abstract

Breast cancers with low levels of HER2 expression (HER2-low) represent a large proportion of tumors traditionally classified as HER2-negative and have recently become clinically relevant with the availability of effective HER2-targeted antibody–drug conjugates. In this large, real-world cohort of patients with metastatic breast cancer, we found that HER2-low disease was common in both de novo and recurrent metastatic settings and was associated with longer overall survival compared with HER2-0 disease. We also observed frequent changes in HER2 status between primary tumors and metastatic sites, particularly in recurrent disease, highlighting tumor heterogeneity and the dynamic nature of HER2 expression over time. These findings support routine reassessment of HER2 status in metastatic breast cancer prior to changing therapy when feasible and underscore the need for more accurate and reproducible methods to measure low levels of HER2 expression.

Background: HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 antibody–drug conjugate trastuzumab deruxtecan over standard chemotherapy in patients with metastatic breast cancer (MBC) defined as HER2-low. More recently, the DESTINY-Breast06 trial confirmed this benefit in hormone receptor-positive and HER2-ultralow (less than 1+, but with ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining) cases, prompting re-evaluation of HER2 diagnostic thresholds and treatment strategies. Methods: Eligible patients were women with HER2-low or HER2-0 MBC evaluated at MD Anderson between January 2006 and January 2019. HER2-low was defined as either (1) IHC 1+ or (2) IHC 2+ and negative on fluorescence in situ hybridization. Multivariate logistic regression was used to evaluate distinct clinicopathologic features of patients with HER2-low status. Overall survival (OS) was estimated by the Kaplan–Meier method. Multivariate Cox proportional hazards regression was applied to assess the effects of covariates of interest on OS across different HER2 groups. Results: We included 3834 women: 2637 (69%) with recurrent and 1197 (31%) with de novo MBC; HER2-low disease was present in 1575 (60%) and 712 (59%), respectively. In de novo cases, higher nuclear grade was associated with HER2-low status (grade 2 vs. 1, OR = 2.02, p = 0.007; grade 3 vs. 1, OR = 1.87, p = 0.015), while recurrent cases were associated with ER-positivity (OR = 1.96, p < 0.001) and prior adjuvant radiotherapy (OR = 0.79, p = 0.007). Median OS was 3.2 years (95% CI 3.0–3.5). In de novo disease, Black race (HR = 1.48), metaplastic (HR = 3.15) or other non-ductal/lobular histologies (HR = 2.36), and grade 3 (HR = 1.67) predicted worse OS, whereas Hispanic ethnicity (HR = 0.74) and Other races (HR = 0.57), higher ER (HR = 0.48–0.41) and PR (HR = 0.72–0.53), and HER2-low status (HR = 0.77) conferred improved outcomes. In recurrent disease, Black race predicted worse OS (HR = 1.21, 95% CI 1.05–1.39), while Other race (HR = 0.78, 95% CI 0.62–0.97), higher ER (HR = 0.69–0.44) and PR (HR = 0.73–0.73), and HER2-low (HR = 0.89) were protective. HER2 discordance between primary and metastatic sites occurred in 38.8% of recurrent and 13.1% of de novo cases. Conclusions: HER2-low status was significantly associated with longer OS compared to HER2-0 status in both recurrent and de novo MBC cases. These real-world data help establish the prevalence of HER2-low status and its distinct outcomes. The discrepancy in HER2-low status between the primary tumor and metastatic sites highlights the potential for changes in HER2 expression over time, exploring the interaction between HER2-low breast cancer and the tumor microenvironment and emphasizing the importance of monitoring and reassessing HER2 status at various stages to guide treatment decisions effectively and the need for more quantitative and reproducible HER assays.