The definition of HR+ breast cancer continues to evolve, with a growing recognition of biologic heterogeneity within this subtype. Emerging insights into HER2-low expression and TROP2 targeting are expanding treatment options, particularly with ADCs. Advances in quantitative biomarker assessment may further refine patient selection and optimize therapeutic sequencing.

ER was the very first biomarker in breast cancer, but its definition has continued to evolve over time. Historically, HR+ status was determined by ligand-binding assays and, later, by immunohistochemistry. From there, guidelines in 2010 established the cutoff. It used to be that any hint of immunohistochemistry positivity was defined as HR+, but now we have 2 categories: low ER+ (1%-10%) and strongly ER+ (>10%). We use the term HR+ (vs ER+) since approximately 99% of HR+ cases are also ER+, and, while cases that are less than 10% ER+ are still considered low HR+, they often behave more like triple-negative breast cancer (TNBC).

This evolving classification has important implications for treatment. In the past, patients with HR+ metastatic breast cancer (MBC) would all get endocrine therapy combined with CDK4/6 inhibitors. These patients were originally considered to have HR+/HER2- disease (ie, absence of HER2 overexpression or ERBB2 amplification), but we now know that these are different categories of disease (ie, HER2-null vs HER2-low) that require different management. Someone with true HR+/HER2- disease is not a candidate for traditional HER2-targeted therapy; these patients will get either immunotherapy or an ADC for other non-HER2 targets.

Interestingly, work from our laboratory showed that approximately 50% of patients with metastatic TNBC and up to 75% of patients with HR+/HER2- MBC actually have some HER2 expression. As a field, we need better methods for determining HER2 status. Traditional assays all look at HER2 gene amplification or massive overexpression, but this does not mean that there is not any HER2 present. In fact, many patients without gene amplification still express a fair amount of HER2, and these individuals tend to benefit from trastuzumab deruxtecan (T-DXd) and potentially other HER2-targeted ADCs. It is also important to note that the emergence of HER2-low and HER2-ultralow disease has shifted HER2 from a binary biomarker to a therapeutic spectrum, underscoring the need for repeat biomarker testing over time and across metastatic sites. Indeed, patients with HER2-low or HER2-ultralow MBC in the clinical trials DESTINY-Breast04 and DESTINY-Breast06 experienced meaningful benefit from T-DXd.

Presently, the therapies that are US Food and Drug Administration (FDA) approved for HR+ MBC are the ADCs sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd). Both SG and Dato-DXd are TROP2-targeting ADCs, and they work by similar mechanisms. Time will tell which one is more effective. TROP2 is an interesting target; it is highly expressed on breast cancer cells, so there is typically a lot of target present. However, at least one study showed that patients with metastatic TNBC with high/medium TROP2 expression did better on SG compared with the standard of care. Despite this correlation, neither SG nor Dato-DXd require a companion diagnostic test.

Beyond treatment decisions, I think that another challenge is determining which drug to give first, and this is a difficult question to address given the lack of head-to-head trials. To overcome this, we need to look toward other biomarkers. Currently, there are not many that can help in making treatment decisions, but I think that this is where we are headed in the future. I also think that testing for HER2 and TROP2 will become standard, which will allow clinicians to provide patients with the most appropriate therapy for the biology of their tumor based on which target is expressed at a greater level.