Vol. 8, Issue 3, Part A (2025)

Background: Breast cancer is a biologically diverse disease and recent advancements further highlight the significance of the level of HER2 expression for determining prognosis and therapy. While HER2-positive tumors respond significantly to targeted anti-HER2 therapy, the novel emerging subgroup of HER2-low breast cancer, defined by immunohistochemistry expression 1+ or 2+ with negative for gene amplification on in-situ hybridization has shown good results following the treatment by antibody-drug conjugates (ADCs) like trastuzumab deruxtecan. However, there remains limited comparative data on HER2-low versus HER2-zero breast cancers.
Objective: To compare the clinicopathological features and disease-free survival outcomes between HER2-low and HER2-zero breast cancer patients and to assess their prognostic differences, especially in relation to hormone receptor (HR) status.
Methods: A retrospective, single-center study was done at Kailash Cancer Hospital and Research Centre, Gujarat, involving 783 HER2-negative breast cancer patients who were subjected to surgical and systemic interventions between January 2016 and December 2023. This cohort was further subdivided into tumors with low HER2 expression (N=329) and tumors with absent/ zero HER2 expression (N=454) groups analyzed over IHC and ISH results. Clinicopathological data, treatment details and disease-free survival outcomes were interpretated using chi-square tests, Kaplan-Meier survival curves, and Cox proportional hazards regression models.
Results: In this study, HER2-low tumors were found to be frequently positive for hormone receptor expression (ER &/ PR) (81.76% in HER2 low and 67.62% in HER2 zero, p<0.0001), they were more frequently associated with lymphovascular invasion (72.34% in HER2 low and 59.25% in HER2 zero, P=0.0001), nodal involvement (67.47% in HER2 low and 56.60% in HER2 zero, P=0.002) and presented at advanced stage (44.07% in HER2 low and 34.8% in HER2 zero, P=0.008. Other factors including age, tumor size or histological grade did not reveal any significant differences amongst the two groups. Among the patients with hormone receptor negative breast cancers, those with low HER2 expression revealed a worse disease-free survival (P=0.007) when followed up to a median follow-up period of 51 months. However, disease free survival was not significantly different in overall cohort or those with HR-positive subgroup. On performing multivariate analysis, HER2-low status, HR-negativity, and LVI were identified as independent predictors of worse DFS.
Conclusion: Breast cancers with low HER2 expression in hormone receptor negative cases show a trend towards poorer prognosis compared to HER2-zero tumors. These findings further emphasizes that HER2 low tumors are heterogenous and there is a need for refined classification, standardized HER2 testing, and prospective validation in larger, multicenter studies to improve patient stratification and treatment planning.