Dr Werutsky on Assessing the Prognostic Value of HER2-Low in Early Breast Cancer

“HER2-low is a new entity or subtype of breast cancer that has had a lot of development in the [past few] years, particularly with the development of ADCs that target HER2. New information in the metastatic setting [has led to] approvals for this indication. In the MINDACT exploratory analysis, [we tried to understand whether] HER2-low [status] has prognostic significance in early breast cancer and [to identify] the intrinsic characteristics of these tumors.”

Gustavo Werutsky, MD, PhD, medical oncologist, Breast Cancer Program, Hospital Moinhos de Vento; investigator, Oncology Research Centre, Hospital São Lucas PUCRS University, discusses the rationale behind an exploratory analysis of the phase 3 EORTC10041/BIG 03-04 MINDACT trial (NCT00433589) that examined the molecular characteristics of HER2-low early breast cancer and its association with clinical outcomes following chemotherapy and endocrine therapy.

Werutsky notes that this analysis evaluated HER2-low tumors, defined as those that are HER2 1+ or 2+ nonamplified by immunohistochemistry, within the MINDACT trial population. HER2 expression was assessed using the HercepTest, and molecular subtyping was conducted via the BluePrint classification system, categorizing tumors into luminal A, luminal B, HER2-enriched, and basal subtypes. Genomic risk stratification was determined using the MammaPrint 70-gene signature.

The study assessed the prognostic implications of HER2-low disease in early-stage breast cancer, given the increasing relevance of HER2 in the metastatic setting with the advent of HER2-targeted therapies. Historically, retrospective analyses have indicated that HER2-low status is not an independent prognostic factor in early breast cancer, Werutsky says. However, the intrinsic molecular characteristics of these tumors and their potential effect on treatment outcomes remain poorly understood, he explains.

In this analysis, investigators examined the relationship between HER2-low subtypes and distant metastasis-free survival, adjusting for chemotherapy and endocrine therapy administration. Werutsky highlights that although HER2-low has emerged as a distinct entity in metastatic breast cancer, its clinical relevance in early-stage disease requires further investigation and that understanding the molecular landscape of HER2-low tumors is critical for optimizing treatment strategies and identifying patients who may benefit from targeted therapies. Findings from the MINDACT exploratory analysis provide insight into the heterogeneity of HER2-low early breast cancer, demonstrating that molecular subtype and genomic risk influence clinical outcomes, Werutsky concludes.